International Infection, Immunity and Inflammation ...cmdr.ubc.ca/bobh/wp-content/uploads/2019/05/14C-Program_Long-1.pdfInternational Infection, Immunity and Inflammation Conference

International Infection, Immunity and Inflammation Conference (I4C)

In celebration of Dr. Bob Hancock’s 70th Birthday and Research Career

May 14th & 15th 2019 Life Sciences Centre, University of British Columbia

Vancouver, BC Canada

International Infection, Immunity and Inflammation Conference (I4C) May 14-15, 2019, Vancouver BC, Canada

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Welcome ....................................................................................................................................... 3

The University of British Columbia ................................................................................................ 4

Program ........................................................................................................................................ 5

Day 1: Tuesday May 14th 2019 .................................................................................................. 5

Day 2: Wednesday May 15th 2019 ............................................................................................ 8

Abstracts ..................................................................................................................................... 10

Posters ........................................................................................................................................ 44

Scientific Organizers:

Dawn Bowdish, Bob Hancock, Evan Haney, Neeloffer Mookherjee, and Joerg Overhage,

Support: The organizing committee gratefully acknowledges the support of the following:

Follow the Hancock Lab on Twitter @thehancocklab

Twitter hashtag for the symposium: #i4cUBC


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Welcome Welcome from the organizing committee

It is with great honour and privilege to welcome you to the first annual International Infection, Immunity and Inflammation Conference (I4C) at the University of British Columbia in Vancouver, Canada. We are pleased to bring together a diverse group of researchers, academics, and industry leaders to share with you the latest in the fields of Pseudomonas, Systems Biology, Peptides, New Therapeutic Discoveries and Innate Immunity. We hope you will take this excellent opportunity to network, learn, and exchange ideas with colleagues in the field from all over the world. Organizing Committee, Dawn Bowdish, McMaster University Susan Farmer, University of British Columbia Bob Hancock, University of British Columbia Evan Haney, University of British Columbia Neeloffer Mookherjee, University of Manitoba Joerg Overhage, Carleton University Jillian Turner, University of British Columbia

Welcome from R.E.W. “Bob” Hancock

The I4C is being held to celebrate the 70th birthday and 40-year research career of Bob Hancock at UBC. During his time at UBC he has made numerous break-throughs in the field of cationic host defence (antimicrobial) peptides and finding alternate treatments to antibiotic resistance. Hancock is “considered a world leader in his field” and over his career he has published more than 720 papers and reviews, has 65 patents awarded, and is an ISI highly cited author in Microbiology with more than 72,000 citations and an h-index of 153. He has won several awards and is an Officer of the Order of Canada. He is a co-founder of Migenix, Inimex

Pharmaceuticals, ABT Innovations, Sepset Biotherapeutics, and the Centre for Drug Research and Development. Currently Hancock and his lab’s research interests include small cationic peptides as novel antimicrobials, broad-spectrum anti-biofilm agents, and modulators of innate immunity, the development of novel treatments for antibiotic resistant infections and inflammation, the systems biology of innate immunity, inflammatory diseases and Pseudomonas aeruginosa, and antibiotic uptake and resistance.


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The University of British Columbia

*Please note there is no food or drink in the lecture theatre.* Internet Access Wifi Wireless internet is available by connecting to the ubcvisitor network, for free light browsing, no login required. If you are from another education institution that uses eduroam you can also access that network at UBC.

• Select the "ubcvisitor" wireless network on your wireless device. • Open up a web browser, and you will be directed to the login page.

University of British Columbia (UBC) Located on the traditional unceded territory of the Musqueam people, UBC’s Vancouver campus is set at the edge of a peninsula overlooking the Strait of Georgia and the Salish Sea. The city of Vancouver is a short distance away and provides a sparkling backdrop for a university continually shaping its place as a world leader in research and teaching. From breathtaking ocean views to snow dusted mountaintops, world-renowned gardens and entertainment, the campus promises to welcome alumni and visitors at every step. We hope you left time in your travel schedule to explore UBC. Here are some interesting things to see on campus:

Museums and Galleries Beaty Biodiversity Museum www.beatymuseum.ubc.ca Irving K. Barber Learning Centre ikblc.ubc.ca Morris and Helen Belkin Art Gallery www.belkin.ubc.ca Museum of Anthropology www.moa.ubc.ca Pacific Museum of the Earth pme.ubc.ca Gardens Nitobe Memorial Garden www.botanicalgarden.ubc.ca/nitobe UBC Botanical Garden www.botanicalgarden.ubc.ca UBC Welcome Centre The UBC Welcome Centre is located in the Robert H. Lee Alumni Centre and is the perfect place to start your journey on the Vancouver campus. Their knowledgeable staff can answer your questions, provide maps and directions and let you know what events are happening during your visit. Located at 6163 University Blvd, or call: 604-822-3313

8:00 a.m. – 6:00 p.m. Monday to Friday 8:00 a.m. – 4:00 p.m. Saturday 10:00 a.m. – 4:00 p.m. Sunday


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PROGRAM Day 1: Tuesday May 14th 2019 Registration 08:00-08:30 Registration: Outside LSC 1

Symposium Opening 08:30-08:40 Welcome, introduction and general information

Dawn Bowdish and Jillian Turner On behalf of the organizing committee

08:40-08:55 Symposium Introduction Bob Hancock Professor, University of British Columbia

Session One: Pseudomonas Chair: Joerg Overhage

08:55-09:15 Structure and function of lipase LipA from Pseudomonas aeruginosa. Karl-Erich Jaeger University of Düsseldorf and Forschungszentrum Jülich

09:15-09:30 Let’s stick together – adaptation of P. aeruginosa to reactive chlorine stress Joerg Overhage Carleton University

09:30-09:45 A multi-host approach to identifying the origin of host association in Pseudomonas Cara Haney, University of British Columbia

09:45-10:05 Recent insights from Pseudomonas aeruginosa genome analysis and implications for infectious disease control Fiona Brinkman Simon Fraser University

10:05-10:25 Aminoglycoside-promoted changes to lipopolysaccharide in Pseudomonas aeruginosa: involvement of the MexXY multidrug efflux system Keith Poole Queen’s University


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10:25-10:45 Conversion of the pyrophosphate-specific OprO- into phosphate- specific OprP- porin of Pseudomonas aeruginosa by exchanging key amino acids at the channel constrictions Roland Benz Jacobs University Bremen

10:45-11:00 Discovery and Development of New Mechanism Novel Antimicrobials Enabled by the Discuva Platform Elena Breidenstein Summit Therapeutics

11:00-11:10 Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections Richard Siehnel University of Washington

11:10-11:30 Coffee Break

Session Two: Peptides Chair: Evan Haney

11:30-11:55 Regulating Host Defence Against Infection: the Cathelicidin Fire Alarm Donald J Davidson University of Edinburgh

11:55-12:10 Exploring the Chemical Space of Multifaceted Host Defence Peptides Evan Haney University of British Columbia

12:10-12:30 Peptoids as mimics of antimicrobial host defence peptides. Havard Jenssen Roskilde University

12:30-13:45 Lunch 13:45-14:05 Strategies to mitigate antimicrobial peptide toxicity

Suzana K Straus University of British Columbia


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14:05-14:25 Structure-function-guided exploration of an antimicrobial peptide identifies activity determinants and generates synthetic therapeutic candidates. Cesar de La Fuente-Nunez Massachusetts Institute of Technology

14:25-14:35 The activity of an innate defence regulator peptide is selectively altered by disrupting a central hydrophobic tryptophan Hadeesha Piaydasa University of Manitoba

14:35-15:15 Coffee Break

Session Three: Innate Immunity Chair: Dawn Bowdish

15:15-15:50 Twenty years of AREST-ING cystic fibrosis. Stephen Stick Telethon Kids Centre for Respiratory Research

15:50-16:10 Age-associated inflammation, macrophage function and longevity. Dawn Bowdish McMaster University

16:10-16:30 New strategies for prevention and treatment of Pseudomonas aeruginosa infections Bernd H. A. Rehm Griffith University

16:30-16:50 Utilising differentiated wild type and knockout human stem cells to investigate mechanisms of innate immunity in macrophages Christine Hale Wellcome Sanger Institute

16:50-17:10 Transgenerational immune protection in the pacific oyster Crassostrea gigas Celine Cosseau Host Pathogen Environment interaction Laboratory

17:10-17:30 Childhood vasculitis syndromes microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) have different etiologies as indicated by integrating blood transcriptomic and clinical metadata Kelly Brown University of British Columbia


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Day 2: Wednesday May 15th 2019 Session Four: Systems Biology Chair: Amy Lee

09:00-09:25 Studying emerging diseases through genomics and stem cells; Antibiotic resistant typhoid as an exemplar Gordon Dougan University of Cambridge and Wellcome Sanger Institute

09:25-09:45 Transcriptional Profiling of Stem Cell-Derived Macrophages Provide Functional Insights to Genome-wide Association Studies Amy Lee University of British Columbia

09:45-10:05 Innate defence regulator (IDR) peptide in airway inflammation Neeloffer Mookherjee University of Manitoba

10:05-10:25 The influence of microbiota in early-life on optimal vaccine responses David Lynn South Australian Health & Medical Research Institute

10:25-10:45 Towards Immersive Network-based Visual Analytics for Systems Biology Jeff Xia McGill University

10:45-11:05 Characterizing the molecular determinants underlying severe Ebola virus disease and post-recovery persistence: science under negative pressure Jason Kindrachuk University of Manitoba

11:05-11:15 Bridging Basic Scientists, Clinicians and Patient’s Voices Worldwide to Improve Sepsis Diagnosis and Treatment Olga Pena University of British Columbia

11:15-12:15 Lunch


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Session Five: New Therapeutic Discoveries Chair: Neeloffer Mookherjee

12:15-12:40 Oral Blis- Streptococcus salivarius probiotics to promote a healthy oral microbiota John Hale Blis Technologies

12:40-13:00 The taming of the phage: turning bacterial viruses into antibiofilm agents. Lucia Fernandez Llamas Instituto de Productos Lácteos de Asturias (IPLA-CSIC)

13:00-13:20 Small molecules that repress exopolysaccharide expression have antibiofilm and antivirulence activities against Pseudomonas aeruginosa. Shawn Lewenza Athabasca University

13:20-13:40 The plasticity of bacterial multidrug transporters Melissa Brown Flinders University

13:40-14:00 Bacterial chemotaxis and changing paradigms. Victoria Korolik Griffith University

14:00-14:20 Signaling heterogeneity in the conserved PhoPQ-PmrD-PmrAB regulatory cascade governing host-defence peptide resistance in Escherichia coli Joe McPhee Ryerson University

14:20-14:30 Synthetic peptides to combat acute and chronic Pseudomonas aeruginosa skin infections Daniel Pletzer University of British Columbia

14:30-15:00 Survivors of Bob group photo Location to be announced at end of session

14:30-17:00 Poster Session


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Abstracts Day 1 Session one Pseudomonas

Karl-Erich Jaeger University of Düsseldorf Jülich, Germany

Structure and function of lipase LipA from Pseudomonas aeruginosa Karl-Erich Jaeger1,2, Filip Kovacic1, Peter Dollinger1, Florian Bleffert1, Renu Batra-Safferling3, Joachim Granzin3, Jakub Kubiak4, Claus A.M. Seidel4, Aldino Viegas5, Manuel Etzkorn5, Neha Verma6, Holger Gohlke6 1. Institute of Molecular Enzyme Technology, Heinrich Heine University Düsseldorf, Jülich, Germany 2. Institute of Bio- and Geosciences IBG-1: Biotechnology, Forschungszentrum Jülich GmbH, Jülich, Germany 3. Institute of Complex Systems, ICS-6: Structural Biochemistry, Forschungszentrum Jülich GmbH, D-52425 Jülich,Germany 4. Institute for Molecular Physical Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany 5. Institute of Physical Biology, Heinrich Heine University Düsseldorf,, Düsseldorf, Germany 6. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Pseudomonas aeruginosa produces many virulence factors, among them lipases and phospholipases which can mediate infections through damage of host cell components. The extracellular lipase LipA needs a specific chaperone named lipase-specific foldase (Lif) which mediates activation of lipase during secretion through the cytoplasmic membrane. Lif consists of five-domains, including a mini domain MD1 essential for LipA folding. We have studied the conformational dynamics of Lif by high-precision FRET and molecular dynamics simulations revealing reversible collapses and extensions on the microsecond to sub-microsecond timescale. To further study the mechanism of LipA activation, we have solved the NMR solution structure of P. aeruginosa Lif MD1. We also show that in unbound conformation Lif loses its secondary and tertiary structure which increases the flexibility of the molecule. Our findings provide important details about the putative mechanism for LipA activation and might point to a general mechanism of protein folding by multidomain steric chaperones.


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Day 1 Session one Pseudomonas

Joerg Overhage Carleton University Ottawa, Canada

Let’s stick together – adaptation of P. aeruginosa to reactive chlorine stress

Bacteria are able to survive under a variety of often harmful environmental conditions such as heat or cold, nutrient limitation or antimicrobial treatment due to a multitude of adaptation processes and stress responses. One important adaptation and survival strategy exhibited by a wide range of bacteria is the formation of biofilms. Biofilms are communities of microorganisms attached to a surface and embedded in a self-produced, polymeric matrix. Biofilm bacteria have been shown to possess unique characteristics including increased stress resistance and higher antimicrobial tolerance leading to failures in bacterial eradication in many technical and clinical settings including drinking water industries and hospitals.

Here, we investigated the adaptation of P. aeruginosa to reactive chlorine species including hypochlorite (HClO), a phagocyte-derived host defense compound and frequently used disinfectant (household bleach). We identified that reactive chlorine species strongly stimulated P. aeruginosa stress responses and increased biofilm formation at sublethal concentrations. This enhanced formation of biofilms was very specific to reactive chlorine species such as hypochlorite and chloramine, but did not occur in response to other tested oxidants likes hydrogen peroxide [H2O2] or the herbicide paraquat. Subsequent gene expression profiling, LC-MS analyses and mutant studies revealed a key role of the intracellular second messenger cyclic-di-GMP in HClO-induced biofilm development.


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Cara Haney Michael Smith Laboratories University of British Columbia Vancouver, Canada

A multi-host approach to identifying the origin of host association in Pseudomonas Members of the genus Pseudomonas are commensals and pathogens across diverse hosts including plants and animals. Plant and animal innate immune systems show functional conservation at a molecular level, and there are common virulence factors required for Pseudomonas to infect diverse hosts. Using comparative genomics and forward genetics, we identified genes involved in LPS modification and polyamine metabolism that predict host association and are required to evade plant and animal immunity. By using an accessible and high-throughput model of the plant root (“rhizosphere”) microbiome coupled with validation in an opportunistic infection (mouse abscess) model, our goal is to identify conserved mechanisms by which commensals and pathogens can persist in association with a host.


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Fiona Brinkman Simon Fraser University Burnaby, Canada

Recent insights from Pseudomonas aeruginosa genome analysis and implications for infectious disease control It has now been two decades since the Pseudomonas Community Annotation Project was initiated for the first Pseudomonas genome and now thousands of genomes have been sequenced with real-time genomic analysis of sets of isolates becoming possible. I will summarize our recent analysis tools developed, and insights gained regarding Pseudomonas aeruginosa (and Pseudomonas) evolution, antimicrobial resistance mobility, and therapeutic discovery. Collectively our results have broader implications for the design of a more interdisciplinary, multifactorial approach to infectious disease control.


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Keith Poole Queen’s University Kingston, Canada

Aminoglycoside-promoted changes to lipopolysaccharide in Pseudomonas aeruginosa: involvement of the MexXY multidrug efflux system Keith Poole1, Kevin Rome1, Courtney E. Chandler2, Christie Gilmour1 and Robert K. Ernst2 1Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada 2 Department of Microbial Pathogenesis, University of Maryland, Baltimore, MD, USA The Mg2+ antagonism of aminoglycoside activity in wild type (WT) Pseudomonas aeruginosa is dependent on the presence of the aminoglycoside (AG) resistance-promoting MexXY multidrug efflux system (Antimicrob Agents Chemother 45:2001), and MexXY expression has been linked to changes in lipopolysaccharide (LPS) and susceptibility to the LPS-targetting polymyxin antimicrobials (Antimicrob Agents Chemother 59:7276), indications that this efflux system has functional links to LPS. In agreement with this, treatment of P. aeruginosa with the mexXY-inducing AG, paromomycin (PAR), and the related antimicrobial, spectinomycin (SPC), yielded an increase in lipid A fatty acylation and increased hydroxylation of the fatty acids, and this was absent or markedly reduced in a MexXY- mutant strain. These results were consistent with an AG-promoted, MexXY-dependent decrease in activity of the PagL lipid A deacylase and increase in one or both of the LpxO1/LpxO2 lipid A hydroxylases. In support of this, PAR and SPC promoted a decrease in expression of the pagL gene and an increase in expression of the lpxO1 gene in WT P. aeruginosa that was largely lost in the MexXY- mutant. These AG-promoted changes in gene expression were independent of the PhoPQ two-component system (TCS) that is known to regulate pagL expression in P. aeruginosa. The AG-promoted increase in lpxO1 expression was, however, lost in a pmrA mutant, an indication that the PmrAB TCS mediated this effect. Given the importance of LPS for AG binding and entry into P. aeruginosa cells, MexXY-driven changes to this macromolecule may contribute to AG resistance, and the reduced AG accumulation typically associated with MexXY operation may, thus, reflect reduced binding and uptake vs. efflux-mediated exclusion.


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Roland Benz Jacobs University Bremen, Germany

Conversion of the pyrophosphate-specific OprO- into phosphate-specific OprP- porin of Pseudomonas aeruginosa by exchanging key amino acids at the channel constrictions Roland Benz, Sonalli Ganguly, Anusha Kesireddy, Ulrich Kleinekathöfer Pseudomonas aeruginosa is a major opportunistic pathogen that represents a considerable cause of nosocomial infections in humans. Its outer membrane has very low permeability for antibiotics caused by the presence of many specific porins. Among them are OprP and OprO that represent phosphate specific channels expressed in P. aeruginosa under phosphate starvation conditions. The crystal structures of both outer membrane channels show trimeric arrangements, where each monomer consists of 16 antiparallel β-strands connected by long extracellular loops and short periplasmic turns. Phosphate specific OprP and pyrophosphate specific OprO, show despite large homology, structural differences in their binding sites situated in the pore constriction region. Previously, it was shown that the mutation of amino acids in Y62F and Y114D of OprP, led to an exchange in substrate specificity similar to OprO. In order to support the role of these key amino acids in the substrate sorting of these specific channels, we created the reverse mutants for OprO (F62Y, D114Y and F62Y/D114Y) in this study. We studied the phosphate and diphosphate binding of the mutated channels in planar lipid bilayers. The experimental findings together with molecular dynamics simulations support the view that just a few strategically positioned amino acids are mainly responsible for the substrate specificity of OprP and OprO. The mutation of these amino acids in the channels allows interchanging their properties.


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Elena Breidenstein Summit Therapeutics Cambridge, United Kingdom

Discovery and Development of New Mechanism Novel Antimicrobials Enabled by the Discuva Platform

INTRODUCTION:

Increasing antimicrobial resistance among Gram-negative bacteria combined with the current antibiotic innovation gap highlights the need for novel antimicrobial agents. We have developed a tightly integrated set of proprietary technologies which, following phenotypic screening, reveal the molecular targets and resistance liabilities associated with antimicrobial compounds.

APPROACH AND RESULTS:

High density (typically every 7-15 bp) transposon mutant libraries are generated in key pathogenic bacterial strains. The engineered transposons can influence gene regulation across the entire genome (upregulation, disruption and down regulation) depending on the context of the insertion site. Next Generation Sequencing processing and analysis of surviving transposon mutants following exposure to antimicrobial compounds reveals the range of molecular mechanisms that the target pathogen can utilize to survive in the presence of the compound: key target signals and resistance drivers included. The Discuva Platform has been validated with established, marketed and clinical phase antibiotics. To exemplify the depth of the Discuva Platform, we present data generated on known antibiotics (such as fosfomycin) against Pseudomonas aeruginosa and Escherichia. coli. The analysis clearly reveals engagement with murA (cell wall synthesis target of fosfomycin) and a number of additional potential drivers of resistance including ptsI, cyaA, uhpT/A/C, phnG-P for E. coli and glpT, glpR and hypothetical protein with phosphohydrolase function for P. aeruginosa. More importantly we are using the Discuva Platform in our internal novel antibiotic research and development activities including in our programs targeting Neisseria gonorrhoeae and ESKAPE pathogens.

CONCLUSIONS:

The Discuva Platform provides high quality data on the mode of action and resistance liabilities of antimicrobial compounds and also allows the accurate triaging from hit selection, through chemical optimization, and best clinical candidate nomination. The rapid cycle time of the process permits integration into medicinal chemistry design and SAR rationalization. We believe our Discuva Platform opens up the pool of available antibiotic starting points, increasing the chance of generating new mechanism novel antibiotic drugs.


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Richard Siehnel University of Washington

Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections

Targeting bacterial nutritional and metabolic vulnerabilities is currently an unconventional antibacterial strategy. Bacterial iron metabolism can be disrupted by the metal gallium because it substitutes for iron when taken up by bacteria and, under physiological conditions, does not undergo the redox cycling necessary for iron's biological functions. Here we investigated the antibiotic activity of gallium in several ways: in sputum samples from patients with cystic fibrosis (CF), ex vivo against key iron-dependent bacterial enzymes, in a mouse model of airway infection, and in a phase 1 clinical trial in individuals with CF and chronic Pseudomonas aeruginosa airway infections. Since gallium is already FDA approved for use in humans to treat malignant hypercalcemia, our findings raise the possibility that human infections could also be treated with gallium by targeting iron metabolism or, more broadly, by other strategies targeting nutritional vulnerabilities of bacterial pathogens.

This poster is based on: Goss et al., Sci. Transl. Med. 10 (460), eaat7520 (2018) 26 September 2018, -which contains the complete list of authors.


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Day 1 Session two Peptides

Donald J. Davidson University of Edinburgh Centre for Inflammation Research Edinburgh, United Kingdom

Regulating Host Defence Against Infection: the Cathelicidin Fire Alarm The threat of antibiotic-resistant pathogens has been declared a global emergency, requiring the urgent development of novel approaches for the treatment of infectious diseases. Strategies aimed at augmenting effective host defence, by harnessing critical components of innate immunity, have the potential to bypass common resistance mechanisms.

Antimicrobial Host Defence Peptides (HDP) are key, evolutionarily conserved components of the innate immune system. Mammalian HDP are widely expressed throughout the body, with key, non-redundant roles in protection against infectious threats. In addition to direct microbicidal potential, HDP have pleiotropic modulatory properties that impact upon the inflammatory response, adaptive immunity, and repair. However, the relative importance of these properties to host defence against infection in vivo, remains to be determined.

HDP of the cathelicidin family are highly expressed in neutrophil granules and are inducible in other immune effector cells. Regulation of human cathelicidin (hCAP-18/LL-37) has been implicated in a range of disease processes, while mice deficient in cathelicidin have increased susceptibility to infections in the lung, skin, gastrointestinal tract, urinary tract and eye. Cathelicidin has been shown to modify the balance of inflammatory processes; both dampening potentially harmful pro-inflammatory cytokine responses and inducing protective cellular inflammatory responses.

We demonstrate in vivo that i) exogenously-applied cathelicidin promotes pulmonary clearance of the multi-drug resistant pathogen Pseudomonas aeruginosa primarily by inflammomodulation, and that ii) induction of endogenous cathelicidin in the lung is essential for an effective host response, via promotion of protective pulmonary neutrophil responses. We also present a novel intracellular, NLRP3-dependent mechanism for cathelicidin-mediated promotion of protective airway epithelial cell responses to P. aeruginosa infection, resulting in altruistic cell death and enhanced neutrophil recruitment.

These modulatory properties of HDP have the potential to inform new alternative and/or complementary interventions for the treatment of antibiotic-resistant infections.


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Day 1 Session two Peptides Evan Haney Center for Microbial Diseases and Immunity Research, University of British Columbia Vancouver, Canada

Exploring the Chemical Space of Multifaceted Host Defence Peptides Host defence peptides (HDPs) are short polypeptide sequences found ubiquitously in nature that have garnered significant attention as alternatives to antibiotics. Originally appreciated for their direct antibacterial effect, HDPs are now known to exhibit a wide range of biological activities including antibiofilm and immunomodulatory functions. Curiously, HDPs with potent activity in one arena may possess weak activity in other areas suggesting that the various activities of HDPs exist on independent but overlapping activity landscapes. In principle, synthetic peptides could be optimized for specific biological purposes provided sufficient sequence information were available to predict the activity of novel peptides. Unfortunately, beyond the generic properties of HDPs (eg. positive charge and amphipathicity), our current understanding of the chemical space occupied by active HDPs is limited. Using various peptide screening and activity-guided design strategies, we have begun to explore the various activity landscapes of synthetic HDPs in an effort to understand the peptide sequence requirements that govern these diverse biological functions. Ultimately, an improved understanding of the chemical space and activity landscapes of HDPs will be necessary to fully realize their therapeutic potential.


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Havard Jenssen Roskilde University Roskilde, Denmark

Peptoids as mimics of antimicrobial host defence peptides.

Within the last couple of decades, antimicrobial peptides have proven a potential to become the next treatment for multi-drug resistant bacteria. However, their therapeutic potential is limited as they possess a number of disadvantages like susceptibility to proteolytic degradation and reduced activity in the presence of salt and serum. By contrast, peptoids (oligomers of N-substituted glycines) demonstrate higher proteolytic stability and bioavailability than the corresponding peptides, however if the altered backbone conformation affects antimicrobial activity has been debated. Similarly, recent studies have demonstrated that incorporation of fluorine atoms into peptidomimetics, leads to increased antimicrobial activity while leaving the haemolytic activity unaffected; however the effect of other halogens has been poorly explored.

In the present study we will investigate similarities in peptide and peptoid antimicrobial mode of action, through a comparative study of homologues sequences. The results demonstrates expected similarities but does also indicate interesting mechanistic differences. In the second part of the study, we have designed and synthesized a library of peptoids containing fluorine, chlorine, bromine, and iodine atoms, which vary by length and the level of halogen substitution. All compounds were tested against both Gram-positive and Gram-negative bacteria. We could clearly see that introduction of a halogen atom at a single position of the phenyl ring was sufficient to increase antimicrobial activity towards S. aureus and S. epidermidis, while there was mainly little to no effect on E. coli and P. aeruginosa.

The biological effect of the halogens seems to be highly linked to the hydrophobicity and self-assembly of the compounds. By small angle x-ray scattering (SAXS) we have studied how the self-assembled structures are dependent on the size of the halogen used, degree of halogen substitution and length of the peptoid, and linked these features to their effect on Gram-positive bacteria.

In conclusion, peptoids serves as an attractive template for future development of antimicrobial compounds, and design strategies can likely capitalize on previous investments in antimicrobial peptide development and design.


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Suzana K. Straus University of British Columbia Vancouver, British Columbia, Canada

Strategies to mitigate antimicrobial peptide toxicity Antibiotic resistance is projected as one of the greatest threats to human health in the future and hence there is a great need to find alternatives. Antimicrobial peptides (AMPs) have shown great promise, because bacteria develop no or low resistance to AMPs. However, only few antimicrobial peptides are used as therapeutics, due to problems such as toxicity, short circulation half-life, and rapid kidney clearance. This contribution describes a number of strategies to circumvent such challenges by: 1) formulating AMPs with pegylated phospholipid micelles; and 2) conjugating the peptides to polymers to alter residence time and biodistribution in the body, without significant loss in activity. In the first instance, results will demonstrate how pegylated micelle formulated peptides have potential as therapeutic agents for treating high-density infections in a murine cutaneous abscess model. For the second strategy, results of conjugation to the natural aurein 2.2 and more active derivatives to hyperbranched polyglycerol (HPG) will be presented. Hyperbranched polyglycerol (HPG) has gained attention due to its excellent biocompatibility, multifunctionality and plasma half-life, which can be tuned by changing its molecular weight. HPGs have been used as scaffolds for the development of long circulating drug conjugates, anticoagulant neutralizing agents, for cell surface modification, as an osmotic agent in peritoneal dialysis and organ preservation, making them an excellent candidate to conjugate AMPs. Finally, release strategies from HPG will also be discussed.


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Cesar de la Fuente-Nunez Massachusetts Institute of Technology Cambridge, United States

Structure-function-guided exploration of an antimicrobial peptide identifies activity determinants and generates synthetic therapeutic candidates. Antimicrobial peptides (AMPs) constitute promising alternatives to classical antibiotics for the treatment of drug-resistant infections, which are a rapidly emerging global health challenge. However, our understanding of the structure-function relationships of AMPs is limited, and we are just beginning to rationally engineer peptides in order to develop them as therapeutics. Here, we leverage a physicochemical-guided peptide design strategy to identify specific functional hotspots in the wasp-derived AMP polybia-CP and turn this toxic peptide into a viable antimicrobial. Helical fraction, hydrophobicity, and hydrophobic moment are identified as key structural and physicochemical determinants of antimicrobial activity, utilized in combination with rational engineering to generate synthetic AMPs with therapeutic activity in a mouse model. We demonstrate that, by tuning these physicochemical parameters, it is possible to design nontoxic synthetic peptides with enhanced sub-micromolar antimicrobial potency in vitro and anti-infective activity in vivo. We present a physicochemical-guided rational design strategy to generate peptide antibiotics.


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Hadeesha Piaydasa

University of Manitoba

The activity of an innate defence regulator peptide is selectively altered by disrupting a central hydrophobic tryptophan Hadeesha Piyadasa1,2, Mahadevappa Hemshekhar2, Natasha Osawa2, Dylan Lloyd1, Anthony Altieri1,2, Sujata Basu3,4, Oleg Krokhin2, Andrew J. Halayko3,4 and Neeloffer Mookherjee1,2,4. 1Department of Immunology, 2Manitoba Center for Proteomics and Systems Biology, Department of Internal Medicine, 3Department of Physiology, University of Manitoba. 4Children’s Hospital Research Institute of Manitoba, Winnipeg, MB, Canada. Innate defence regulator (IDR) peptides are synthetic immunomodulatory peptides. We have previously shown that an IDR peptide, IDR-1002, controls airway inflammation and improves airway hyper-responsiveness (AHR) in a murine model of allergic asthma. As disrupting a single amino acid tryptophan (W) within the hydrophobic region of IDR-1002 mitigates its antimicrobial functions, we examined the effects of IDR-1002 and its W-substituted analog, IDR-1002(W/R), in an allergen house dust mite (HDM)-challenged murine model and in human bronchial epithelial cells (HBEC). IDR peptides (6 mg/kg) were administered (subcutaneous; X3/week) in HDM-challenged BALB/c mice. Assessment of AHR using flexiVent™ small animal ventilator showed that similar to IDR-1002, IDR-1002(W/R) maintained the capacity to improve AHR in HDM-challenged mice. However, cell differentials and cytokine analyses demonstrated that in contrast to IDR-1002, IDR-1002(W/R) did not suppress either leukocyte accumulation or the production of IL-33 in lungs of HDM-challenged mice. In-vitro studies with HBEC demonstrated that IDR-1002 enhanced the production of anti-inflammatory mediators such as IL-1RA and stanniocalcin-1, and suppressed IFNγ-induced IL-33, whereas IDR-1002(W/R) did not. These results suggest that the ability of the peptide IDR-1002 to alleviate airway inflammation is mitigated by disrupting its central hydrophobic region, without abrogating its capacity to reduce AHR. Further, these two peptides can be used as probes to delineate disparate mechanisms associated inflammation and AHR in the airways.


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Day 1 Session Three Innate Immunity

Stephen Stick Telethon Kids Centre for Respiratory Research Nedlands, Australia

Twenty years of AREST-ING cystic fibrosis.

The Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program commenced in 1998 and focusses on understanding the pathobiology of early CF lung disease. The biobank, data and image archives are the largest repositories of globally accessible materials being used to develop disease biomarkers and outcome measures. AREST CF has adopted a comprehensive multimodal approach to studying early CF lung disease from diagnosis, that has included sampling of the lower airways and structure function measurements (imaging and infant/preschool lung physiology). The AREST CF initiative has allowed the development of an international network of collaborators focussed on early lung disease. These partnerships provide extensive access to our unique data, biobanks and image archives and skills transfers between collaborating centres. Our initial cross-sectional data have been bolstered by longitudinal observations that are providing important insights regarding early disease pathobiology, biomarkers of disease severity and predictors of long-term outcomes. Of approximately 150 studies of children with CF < 5 years in the past 10 years, AREST CF has contributed > 35%, a body of work recognised internationally as paradigm shifting (Editorial NEJM 2013). Worldwide, fifty per cent of patients with CF die before the age of 40 years and the rate of lung function decline has stayed the same for successive adult cohorts. The knowledge from the AREST CF initiative has significantly contributed to a change in emphasis by clinicians, researchers and industry from amelioration of established disease to prevention of lung damage. AREST CF data have informed international care guidelines and provided the scientific rationale for 2 important international, multicentre studies of early interventions to prevent lung disease,(COMBAT CF NCT01270074:SHIP-CT NCT02950883). Our quantitative CT assessment tool has been implemented as a 1° endpoint in at least 5 industry/investigator initiated clinical trials in children < 6yrs. This comprehensive approach has provided unique insight into the development of the early airway microbiome, pathogen prevalence and relative pathogen pathogenicity. These data will inform strategies to prevent lung disease in the very young with CF.


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Dawn Bowdish McMaster University Hamilton, Canada

Age-associated inflammation, macrophage function and longevity.

As we age levels of cytokines in the circulation and tissue increase. Individuals with higher than average levels of ‘age-associated inflammation’ are more likely to develop chronic conditions, to become frail and die prematurely. In contrast, those with lower than age-average levels are more likely to lead active, independent and healthy lives. Even though age-associated inflammation is a predictor of poor health and premature mortality, it is not clear what causes it. Using aged (2 yr) conventional and germ-free mice, we have demonstrated that age-associated inflammation does not occur in the absence of a microbiome. Furthermore, age-related changes in the composition of the gut microbiota also contribute to age-associated inflammation as transferring the microbiome from old mice leads to higher levels of intestinal permeability and systemic inflammation than that of young mice. This systemic inflammation, and specifically increasing levels of tumour necrosis factor alpha (TNF) result alter myeloid cell development and ultimately monocyte and macrophage function, which contributes to the development of age-related conditions (e.g. frailty, sarcopenia, chronic conditions) and impairs host defence against infection. These mechanistic observations are consistent with the epidemiological data on longevity, which show that a ‘microbiome-friendly’ diet high in fibre and exercise (which is an effective way of reducing systemic inflammation), are the most effective strategies for living a long and healthy life.


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Bernd H.A. Rehm Griffith University Brisbane, Australia

New strategies for prevention and treatment of Pseudomonas aeruginosa infections Pseudomonas aeruginosa is one of the leading causes of nosocomial infections and causes serious life-threatening infections due to intrinsic and acquired antibiotic resistances 1. Immuno-compromised individuals are most at risk, such as those with severe burns and wounds, infected by human immunodeficiency virus (HIV) as well as CF patients. The formation of characteristic biofilms coincide with antibiotic resistance and persistent infections ie successful evasion of the immune system. There is an unmet demand for vaccines to prevent infections and for anti-bacterial compounds for the treatment of acute and chronic P. aeruginosa infections. Vaccines provide a strategy for prevention of the disease caused by P. aeruginosa 2-3. We have developed a new strategy to design and produce multivalent particulate vaccines for induction of protective immunity. Antigens (epitopes/domains of outer membrane proteins such e.g. OprF, OprI, OprL and AlgE) were engineered to constitute chimeric proteins which include a functional polyester synthase to synthesize and assemble antigen-coated biopolyester inclusions in recombinant E. coli and/or P. aeruginosa. Such biopolyester beads (200-500 nm) coated with antigens of interest were previously shown to induce protective immunity against a range of bacterial pathogens and HCV 4. The knockout of competing polymer biosynthesis pathway in P. aeruginosa enhanced carbon flux toward production of the desired polyester inclusions. The immunological properties of antigen (protein and carbohydrate) coated biopolyester beads were investigated in vivo up to challenge studies assessing protective immunity in an acute pneumonia model. Small molecule drugs derived from large libraries (Compounds Australia, NatureBank Australia) were screened against P. aeruginosa biofilms grown in microtiter plates by using high content imaging combined with live/dead and biofilm matrix staining. The persistent in vivo biofilm were mimicked by using strains engineered to produce biofilms reflecting various adaptations. Hits have been subjected to omics analyses in order to identify new targets. Phenotypic characterisation (biofilm formation, EPS production etc) of cells exposed to sub-lethal concentrations of drug candidates provided insight into the mechanism of action. Overall, I will present and discuss our recent advances in vaccine development and anti-bacterial drug discovery.

1. Moradali, M. F.; Ghods, S.; Rehm, B. H., Pseudomonas aeruginosa Lifestyle: A Paradigm for Adaptation, Survival, and Persistence. Front Cell Infect Microbiol 2017, 7, 39.

2. Finco, O.; Rappuoli, R., Designing vaccines for the twenty-first century society. Frontiers in immunology 2014, 5. 3. Priebe, G. P.; Goldberg, J. B., Vaccines for Pseudomonas aeruginosa: a long and winding road. Expert review of vaccines

2014, 13 (4), 507-519. 4. Rehm, B. H., Bioengineering towards self-assembly of particulate vaccines. Curr Opin Biotechnol 2017, 48, 42-53. 5. Lee, J. W.; Parlane, N. A.; Wedlock, D. N.; Rehm, B. H., Bioengineering a bacterial pathogen to assemble its own particulate

vaccine capable of inducing cellular immunity. Sci Rep 2017, 7, 41607.


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Day 1 Session Three Innate Immunity Christine Hale Wellcome Sanger Institute Hinxton, United Kingdom

Utilising differentiated wild type and knockout human stem cells to investigate mechanisms of innate immunity in macrophages

Human induced pluripotent stem cells engineered via Cas9/CRISPR technology to bear a 49 base pair (bp) missense mutation in exon 5 of the SLC11A1 gene were differentiated to the macrophage lineage and compared phenotypically to their parental line, A1ATD-1. Differential expression data from RNAseq pathway analysis indicated that, as expected, genes involved with iron metabolism were statistically different between the parent and KO lines but also highlighted differences in key immune and phagosomal/lysosomal pathways. Subsequent in vitro experimentation revealed alterations in the resulting knockout macrophages in terms of numbers isolated, the process of differentiation, immune surface markers, phagocytic ability, metabolic state as well as increased susceptibility to Salmonella Typhimurium infection. We would suggest that the SLC11A1 mutated macrophages derived through the in vitro differentiation process are activated and/or polarised to a different lineage from the parental line and thus explain the altered phenotypic characteristics described within.


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Day 1 Session Three Innate Immunity Celine Cosseau Host Pathogen Environment interaction Laboratory France

Transgenerational immune protection in the pacific oyster Crassostrea gigas Manon Falleta, Bruno Pettonb, Julien de Lorgerilc, Cristian Chaparroa, Eve Toulzaa, jean-Michel Escoubasc, Guillaume Mittaa, Christoph Grunaua, Caroline Montagnanic, and Céline Cosseau a

a) Univ. Perpignan Via Domitia, IHPE UMR 5244, CNRS, IFREMER, Univ. Montpellier, F-66860 Perpignan, France b) Ifremer, Laboratoire des Sciences de l'Environnement Marin, UMR 6539 LEMAR (UBO/CNRS/IRD/Ifremer), Centre de

Bretagne, CS 10070, 29280 Plouzané, France c) Ifremer, IHPE UMR 5244, Univ. Perpignan Via Domitia, CNRS, Univ. Montpellier, F-34095 Montpellier, France

More and more studies show how the environmental parameters during the early stages of development of living organisms may lead to significant positive or negative carryover effects on their subsequent life stages and also on their offspring. In this sense, parental experience with parasites and pathogens can lead to increased offspring resistance to infection, through a process known as transgenerational immune priming (TGIP). In this study, we investigated if we can educate the innate immune system to induce enhanced survival capacities through immune shaping in the Pacific oyster Crassostrea gigas. This species is currently confronted of massive recurring mortalities, called the Pacific oyster mortality syndrome (POMS) without existing therapeutic treatment. This syndrome, of complex etiology, involves different types of pathogen including bacteria and a virus, the herpesvirus OsHV-1 μVar. An exposure to a microbiota-rich (non-infectious) water during larval development was compared to filtered and UV-treated water control. The exposure was applied on two full-sib families from 2 hours to 10 days post-fertilization, which is an important developmental window (e.g. immune system ontogenesis) during which epigenetic information might be integrated from the environment. This microbial exposure successfully led to increased survival capacities during oyster juvenile stages in response to the POMS disease, in laboratory conditions and in the field for the exposed generation as well as the subsequent one. This result clearly suggests transgenerational immune priming (TGIP), where parents enhance offspring immune defense based on their own immunological experience. Transcriptomic analysis further shows that TGIP elevates baseline expression of immune effectors in offspring and shapes offspring to induce immune-related genes more rapidly when faced to the disease. Microbiota influences as well as epigenetic determinants orchestrating these phenomena are currently being investigated to bring insight on the oyster capacities to build an innate immune memory.


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Kelly Brown University of British Columbia Vancouver, Canada

Childhood vasculitis syndromes microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) have different etiologies as indicated by integrating blood transcriptomic and clinical metadata Gill EE1, Smith ML1, Gibson KM2,3, Morishita K4,5, Graham J6, Foell D7, Benseler S8, Luqmani R9, Ross C10, Cabral DA2,3, Hancock REW1,11 and Brown KL3,4 on behalf of the PedVas study group

1Department of Microbiology and Immunology, 2Department of Medical Genetics, 4Department of Pediatrics, 6Department of Microbiology and Immunology, and 10Faculty of Pharmaceutical Sciences, University of British Columbia, 3BC Children’s Hospital Research Institute and 5Division of Rheumatology, BC Children’s Hospital, Vancouver, BC, Canada, 6Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada, 7Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Muenster, Germany, 8Department of Pediatrics, Alberta Children’s Hospital, Calgary, AB, Canada, 9Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom, 11Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC, Canada

Introduction Primary vasculitis encompasses several life threatening diseases with differing phenotypic clinical manifestations that are classified in part by the size of the predominantly inflamed blood vessels. Small vessel, anti- neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) subtypes Microscopic Polyangiitis (MPA) and Granulomatosis with Polyangiitis (GPA) may benefit from different treatments. Yet overlapping clinical features in the absence of a mutually exclusive classification criteria make these subtypes of AAV difficult to differentiate.

Objective The purpose of this study is to determine if blood transcriptomic data from children with MPA and GPA can aid classification and provide insight into disease etiology.

Methods RNA sequencing (Illumina HiSeq 2500) was performed on whole blood from 30 pediatric patients at the time of initial diagnosis of GPA or MPA. Sequence data (fastq reads) were mapped to the human genome (STAR software) and differential expression (DESeq2) and pathway overrepresentation analysis (InnateDB and Reactome pathway annotation system) performed.

Results Hierarchical clustering based on Euclidean distances between samples placed patients in two main groups each consisting primarily of patients with an initial classification of either GPA or MPA. More than 3,000 genes were differentially expressed between the groups with MPA patients showing enrichment for T cell receptor signaling pathways, cell adhesion molecules and cytokine-cytokine receptor interactions, and GPA patients enriched, among others, for Toll-like, NOD-like, and B cell receptor signaling pathways and neutrophil activation suggestive of a bacterial stimulus.

Conclusion Differentiating signatures and preliminary etiologies for GPA and MPA support different treatment paradigms for their management and is a step towards improved molecular diagnostics for classification of vasculitidies and other diseases with overlapping clinical phenotypes.


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Day 2 Session four Systems Biology

Gordon Dougan

University of Cambridge Wellcome Sanger Institute United Kingdom

Studying emerging diseases through genomics and stem cells; Antibiotic resistant typhoid as an exemplar

Infectious diseases remain a serious threat in the modern world with the emergence of new pathogens that can evade current therapeutic approaches. Antibiotic resistant bacteria are exemplars of such threats. An explosion in new technologies, such as genome sequencing (host and pathogen) and stem cell biology, are providing blueprints for the design of systems both for tracking disease and for exploring new interventions. Further, we are now understanding how even relatively avirulent microbes can influence health and disease in the shape of the microbiota.

Using Salmonella as an example I will describe how genomics can be used to monitor the evolution and spread of diseases, such as typhoid, that are still extremely common in resource poor settings and in travellers to such regions. Now forms of antibiotic resistant typhoid have spread globally and are still acquiring resistance even to the newest antibiotics. Salmonella Typhi, the cause of typhoid, normally only infects humans and cannot be studied effectively in animals. I will describe how controlled human challenge and stem cell biology are providing new opportunities to study this pathogen in ‘in vitro’ systems such as Induced Pluripotent Human Stem Cell-derived macrophages and organoids.


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Amy Lee University of British Columbia Vancouver, Canada

Transcriptional Profiling of Stem Cell-Derived Macrophages Provide Functional Insights to Genome-wide Association Studies Lee AH*, Montandon R*, Acton E, Muraro D, Gill EE, Schwach F, Yeung AT, Hale C, Pance A, Goffin E, Letchford L, Harper S, Alderton A, Skarnes WC, Dougan G, Billker O and Hancock REW

Genome-wide association studies have uncovered numerous genetic variants with potential impacts on complex human diseases such as autoimmune diseases. However, functional studies aimed at untangling the role of genetic variations and environment cues underlying these human diseases have lagged. To help decipher this puzzle, we developed a mouse embryonic stem cell-derived macrophage model and created 26 immune gene knock-outs to characterize their transcriptomic responses to two live pathogens (Salmonella typhimurium and influenza A) and four pathogen-associated molecular patterns (CpG oligodeoxynucleotides, lipopolysaccharide, peptidoglycan and polyinosinic-polycytidylic acid).

We used the weighted correlation network analysis (WGCNA) and the grade of membership (GoM) model to define biologically functional modules from >800 RNA-Seq samples. In WGCNA, modules are defined as groups of genes with similar expression, whereas GoM partitions each sample into biologically-distinct modules by allowing partial membership of each sample. Pathway over-representation analysis of both WGCNA and GoM modules confirmed biologically-meaningful functional enrichment. To identify human diseases associated with any particular module, we performed disease ontology semantic and enrichment analysis and identified mutants that impact the expression of those modules with human disease associations. We hypothesize that a mutation that impacts the gene expression profile of a particular module will provide a mechanistic underpinning for the associated diseases enriched within this module. Using this approach, we have identified that the dysregulation in VEGF ligand-receptor interactions and stimulator of IFN gene (STING)-mediated induction of host immune responses pathways provide a potential functional link between Ncf1 mutation and lupus.


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Neeloffer Mookherjee Manitoba Centre for Proteomics and Systems Biology University of Manitoba Winnipeg, Canada

Innate defence regulator (IDR) peptide in airway inflammation Innate Defence Regulator (IDR) peptides, synthetic derivatives of cationic host defence peptides, can resolve both infections and regulate inflammation. Exogenous administration of IDR peptides can confer protection and control inflammation in a variety of infection models. We examined the effects of IDR peptides in a house dust mite-challenged murine model of airway inflammation, which is routinely used as a preclinical model for asthma. We showed that our lead IDR peptide significantly improves airway hyper-responsiveness (breathing capacity) and suppresses infiltration of inflammatory cells, in particular eosinophils and neutrophils, in the lungs. System-level analyses revealed that the peptide suppresses the expression of several molecular candidates within the inflammatory network activated in the lungs. Our studies demonstrate that an immunomodulatory IDR peptide controls the pathophysiology related to airway inflammation in a murine model of allergic asthma. Further interrogation of underlying mechanisms demonstrated that IDR peptides regulate airway inflammation by targeting the chronic inflammatory cytokine IL-33 in bronchial epithelial cells (in murine lung tissue and in human primary bronchial epithelial cells). As IL-33 is implicated in steroid-refractory severe asthma, our findings suggest that IDR peptides exhibit the potential to control steroid-refractory severe asthma. These studies provide the foundation for the development of IDR peptides as immunomodulatory therapy for chronic inflammatory respiratory diseases. The advantage of IDR peptide-based therapy is the ability to control inflammation without compromising resolution of infections.


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David Lynn

South Australian Health and Medical Research Institute Adelaide, Australia

The influence of microbiota in early-life on optimal vaccine responses Lynn MA1†, Tumes DJ1†, Clarke M2, Choo JM1,3, Ryan F1, Mobegi F1, Sribnaia A1, Blake SB1, Leong LEX1,3, Walker MS2, Lee S2, Riley KE2, Heath C2, Goodchild L2, Young GP4, Wesselingh SL1,3, Rogers GB1,3, Marshall HS1,2,5, Lynn DJ1,3*

1. Infection & Immunity Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia.

2. Vaccinology and Immunology Research Trials Unit, Women's and Children's Health Network, 72 King William Rd, North Adelaide, SA 5006, Australia.

3. School of Medicine, College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia. 4. Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, SA 5042, Australia. 5. Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia.

†These authors contributed equally

Antibody-mediated responses play a critical role in vaccine-mediated immunity. However, for reasons that are poorly understood, these responses are highly variable between individuals. We have recently found that antibiotic-driven intestinal dysbiosis, specifically in early-life, leads to significantly impaired antibody responses to five different adjuvanted and live vaccines. Restoration of the commensal microbiota following antibiotic exposure rescues these impaired responses. In contrast, antibiotic-treated adult mice do not exhibit impaired antibody responses to vaccination. Interestingly, in contrast to impaired antibody responses, immunized mice exposed to early-life antibiotics display significantly enhanced T cell cytokine recall responses upon ex vivo restimulation with the vaccine antigen. Our results demonstrate that, in mice, antibiotic-driven dysregulation of the gut microbiota in early-life can modulate immune responses to vaccines that are routinely administered to infants worldwide. While animal models are informative, we now require a better understanding of the relationships between the microbiota and vaccine responses in human infants. To do this, we have initiated a clinical study (the AIR study) of human infants who have either been exposed, or are unexposed, to antibiotics in the neonatal period. More than 100 infants have already been recruited. In this presentation, I will summarise our preclinical work to date and will present an overview of the AIR clinical study and the innovative systems vaccinology approach we are using to identify and validate the key microbial and host pathways through which the gut microbiota modulates immune responses to all routine infant immunisations.


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Jianguo (Jeff) Xia McGill University Montreal, Canada

Towards Immersive Network-based Visual Analytics for Systems Biology

Network analysis is a powerful approach in systems biology. Networks capture known relationships among different entities (molecules, diseases, etc.) of interest. Multiple algorithms can be applied to reveal important connections and “hot spots”. Researchers can then visually explore these relationships to gain insight or develop new hypothesis. The process is appealing, as networks intuitively engage and empower users to make more informed decision based on systems-level considerations.

The wide applications of different omics technologies necessitate generation and visualization of increasingly large networks. This once enjoyable experience in network analysis has now become a big challenge. In this talk, I will discuss our recent efforts in leveraging cloud technology, machine learning and virtual reality (VR) to develop a new-generation platform for network-based visual analytics directly accessible from web browsers. If conditions permit, audiences will have the opportunity to experience “immersive” network visualization by the end of my talk.


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Jason Kindrachuck Laboratory of Emerging and Re-emerging Viruses, University of Manitoba Winnipeg, Canada

Characterizing the molecular determinants underlying severe Ebola virus disease and post-recovery persistence: science under negative pressure

Emerging and re-emerging viruses pose a significant threat to global public health. Outbreaks attributable to these pathogens, including ebolaviruses and influenza viruses, continue to increase in frequency as a result of changing socio-economic, environmental, and ecological factors. Many of these viruses result in severe illness and complex pathogenesis during the course of infection; however, the molecular processes underlying clinical illness are often poorly understood. To this end, an integration of basic research and clinical data can accelerate translational research for emerging and re-emerging viruses. Detailed molecular investigations of the severe clinical and pathologic manifestations associated with these viruses provides important insight into disease pathogenesis and may advance therapeutic discovery. Characterization of the global activation state of host cell kinases (the kinome) provides direct insight into cellular responses at the level of complex cell signaling networks and individual kinases. Further, kinome analysis may also guide patient management strategies and facilitate therapeutic discovery. The utility of kinome analysis and systems biology approaches for investigating emerging and re-emerging viral diseases will be discussed with a focus on Ebola virus pathogenesis throughout the course of nonfatal human clinical disease and convalescence. In particular, I will highlight: i) the relation of viral-mediated cell response dysregulation with clinical disease progression; and ii) the molecular mechanisms underlying asymptomatic Ebola virus testicular persistence and sexual transmission during convalescence.


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Olga Pena University of British Columbia Vancouver, Canada

Bridging Basic Scientists, Clinicians and Patient’s Voices Worldwide to Improve Sepsis Diagnosis and Treatment

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is a significant cause of morbidity and mortality in Canada and across the world. Currently, microbiology diagnoses take at least 30 hours and clinicians are forced to treat empirically with antibiotics while waiting for results. In patients who survive the first 48 hours, the next phase of illness is profound immune suppression. In this phase, deadly secondary infections become a driver of mortality rates but clinicians have had no means of identifying this immune dysregulation. This data support the strong need for a diagnostic and prognostic tool for sepsis and one that recognizes such immune dysregulation.

Recently, we made a basic research breakthrough discovery with enormous clinical implications. The data informed by a meta-analysis and a clinical pilot study, indicated that a specific gene signature characteristic of immune-amnesia is observed in patients with Sepsis and associated with worse outcomes. Currently, we are developing one of the largest international observational clinical Omic studies ever made to validate this gene signature. Bridging basic scientists, clinicians and listening to Sepsis survivors’ voices worldwide, we hope to develop a point of care system that will allow the rapid and efficient diagnosis of sepsis. This tool will also allow the monitoring of the immune-amnesia characteristic of sepsis, leading to more personalized treatments for sepsis patients and ideally better healthcare support after hospital discharge.

STEMCELL Technologies Inc. Sponsored Speaker


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Day 2 Session five New Therapeutic Discoveries

John Hale Blis Technologies Otgao, New Zealand

Oral Blis- Streptococcus salivarius probiotics to promote a healthy oral microbiota

Streptococcus salivarius is a commonly-occurring commensal bacterium found both exclusively and ubiquitously in the human oral cavity. The well-characterized S. salivarius strain K12 was originally selected for development as a probiotic on the basis of its particularly strong, megaplasmid-encoded inhibitory activity against the important disease- associated species Streptococcus pyogenes. As such, its initial application was to provide school-aged children with protection against streptococcal pharyngitis. Clinical trials have shown exciting results and have led to reduced absenteeism from school and work associate with simple probiotic application. Other work identified additional health benefits linked to the regular use of probiotic preparations of oral probiotics including the reduction of acute otitis media episodes in young children and decreased severity of symptoms in halitosis-affected adults. This talk will present the story behind the development of a probiotic bacterium for a new application including an insight to the science, development and challenges face as well as discussion about new opportunities and applications not previously anticipated at the time of original discovery.


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Lucia Fernandez Llamas Instituto de Productos Lácteos de Asturias (IPLA-CSIC) Villaviciosa, Spain

The taming of the phage: turning bacterial viruses into antibiofilm agents. Lucía Fernández*, Silvia González, Diana Gutiérrez, Pilar García, Ana Rodríguez

The human opportunistic pathogen Staphylococcus aureus forms biofilms on a wide range of biotic and abiotic surfaces, which protect the microbe from routine disinfection procedures and antibiotic treatment. This has become a serious problem in clinical settings as well as in the food industry. For this reason, it is necessary to develop novel strategies to prevent and eradicate staphylococcal biofilms from both inert surfaces and human tissues. One interesting option is the use of phages or their derived proteins as antibiofilm agents to complement other antimicrobials. However, before widespread implementation of this approach, it is necessary to carefully select the most suitable conditions for the application of these compounds. For instance, the virulent staphylophage vB_SauM_phiIPLA-RODI has potential as an antibiofilm agent. Indeed, previous studies have shown that this phage can successfully reduce the number of surface-adhered cells in single-species and mixed biofilms formed by multiple S. aureus strains as well as other staphylococci (Gutiérrez et al., 2015; González et al., 2017). Also, recent work has shown that it can successfully move across biofilms and propagate if a susceptible host is present (González et al., 2018). However, at subinhibitory doses, phage predation by phiIPLA-RODI promotes biofilm formation in several S. aureus strains due to accumulation of eDNA in the matrix (Fernández et al., 2017). This undesirable effect can be prevented by either including DNAse or by keeping pH ≥ 6 during phage treatment. Moreover, preventing development of the DNA-rich biofilms leads to increased killing of viable biofilm cells by the phage. These latest developments prove once again the importance of foreseeing, studying and avoiding possible negative side-effects derived from antimicrobial use. It is always better to be prepared.

References:

1. Fernández L, González S, Campelo AB, Martínez B, Rodríguez A, García P. Low-level predation by lytic phage phiIPLA-RODI promotes biofilm formation and triggers the stringent response in Staphylococcus aureus. Sci Rep. 2017 Jan 19;7:40965.

2. González S, Fernández L, Campelo AB, Gutiérrez D, Martínez B, Rodríguez A, García P. The behavior of Staphylococcus aureus dual-species biofilms treated with bacteriophage phiIPLA-RODI depends on the accompanying microorganism. Appl Environ Microbiol 2017 Jan 17;83(3). pii: e02821-16.

3. González S, Fernández L, Gutiérrez D, Campelo AB, Rodríguez A, García P. Analysis of different parameters affecting diffusion, propagation and survival of staphylophages in bacterial biofilms. Front Microbiol. 2018 Sep 28;9:2348.

4. Gutiérrez D, Vandenheuvel D, Martínez B, Rodríguez A, Lavigne R, García P. Two Phages, phiIPLA-RODI and phiIPLA-C1C, lyse mono- and dual-species staphylococcal biofilms. Appl Environ Microbiol. 2015 May 15;81(10):3336-48.


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Shawn Lewenza Athabasca University Alberta, Canada

Small molecules that repress exopolysaccharide expression have antibiofilm and antivirulence activities against Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an archetypal biofilm-forming organism that causes chronic lung infections in cystic fibrosis (CF) patients. Biofilm formation is a universal virulence strategy in which bacteria grow in dense microbial communities enmeshed within a polymeric extracellular matrix. Matrix-enclosed populations are protected from antibiotic exposure and the immune system. The main extracellular matrix polymers of P. aeruginosa are exopolysaccharides (EPS) and eDNA. Given the central importance of the EPS for biofilms, they are attractive targets for novel anti-infective compounds. We used a high-throughput gene expression screen to identify compounds that repress expression of the pel genes. The pel::lux repressors demonstrated antibiofilm activity against microplate and flow chamber biofilms formed by wild-type and hyperbiofilm-forming strains. To determine the potential role of EPS in virulence, pel/psl mutants were shown to have reduced virulence in feeding behavior and slow killing virulence assays in Caenorhabditis elegans. The antibiofilm molecules also reduced P. aeruginosa PAO1 virulence in the nematode slow killing model. Lastly, the combination of antibiotics and antibiofilm compounds increased killing of P. aeruginosa biofilms. These small molecules represent a novel anti-infective strategy for the possible treatment of chronic P. aeruginosa infections.


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Melissa H. Brown Flinders University S.A. Australia

The plasticity of bacterial multidrug transporters

Bacterial multidrug resistance poses an ever increasing threat to human health. Integral to this are multidrug resistance transporters, which are membrane proteins that have the ability to expel a broad spectrum of chemically dissimilar drugs out of the cell in an energy dependent manner. Structural information on these proteins is limited due to problems inherent to isolating and crystallising integral membrane proteins. Thus, we have combined bioinformatics, genetics, biophysical and biochemical tools to examine the multidrug resistance capacity of a number of proteins from different pathogens, namely Acinetobacter baumannii, Staphylococcus aureus and Neisseria gonorrhoeae, all bacteria that are increasingly difficult to treat due to their multiresistant characteristics. Our studies have focused on representative multidrug efflux proteins from different transport protein families to identify specific regions/residues of each protein that are important for the binding and expulsion of a range of antimicrobial compounds. These studies have highlighted the promiscuous nature of the binding pocket of multidrug binding proteins. This detailed knowledge is required to identify compounds that can potentially inhibit the action of these pumps or bypass them.


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Victoria Korolik Institute for Glycomics, Griffith University Brisbane, Australia

Bacterial chemotaxis and changing paradigms.

Bacteria have evolved to sense changes in their environment and move to change their position in order to avoid unfavourable conditions or manoeuvre towards new niches using chemotaxis signal transduction pathway. Bacterial chemosensors respond to external stimuli with unique precision and sensitivity - a key survival trait in search for nutrients and locating a target host cell, and as such, are considered to be critical for bacterial colonisation and pathogenicity The well-researched E. coli chemotaxis system pathway (receptor-CheA/CheW-CheY-flagella) has previously served as a reference for the characterisation of chemotaxis in other bacteria. In recent years, however, our knowledge of chemotaxis pathways has progressed from a simple E. coli paradigm to a much more complex scenarios in other bacteria where similar, but more complex pathways exist. Gastrointestinal pathogen Campylobacter jejuni encodes a single chemosensory pathway relaying signal through eleven sensory receptors, seven of which sense external ligands. We have now characterised six of the seven C. jejuni external sensors, including the aspartate chemosensory receptor CcaA and the multi-ligand receptor CcmL, capable of responding to 5 repellents and 5 attractants, CcrG which respond to galactose and now a new class of chemosensor, Tlp10.


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Joe McPhee Ryerson University Toronto, Canada

Signaling heterogeneity in the conserved PhoPQ-PmrD-PmrAB regulatory cascade governing host-defence peptide resistance in Escherichia coli Escherichia coli is a well-characterized model organism and also a significant cause of enteric and invasive infections in numerous populations. In order to successfully colonize the host and cause disease, E. coli must be able to respond to host signals and resist killing by effector molecules of the host innate or adaptive immune system. During inflammatory bowel disease, host-defense peptides are produced in a disease-specific manner, whereby patients with CD showed elevated levels of human beta-defensins while patients with Crohn's disease have elevated levels of LL-37. Here, we show that clinical isolates of E. coli vary greatly in their ability to resist molecules of the host immune system in a disease specific manner. We created transcriptional fusions to GFP to assess the level of PhoPQ or PmrAB signaling in a subset of these disease-associated strains. We observe large strain to strain variation in the ability of a particular strain to respond to a PhoPQ inducing signal and these difference are correlated with the ability of the strain in question to mount an appropriate response to those signals. We propose that regulatory heterogeneity in conserved signaling systems may be a critical feature of bacterial responses to a given host environment.


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Daniel Pletzer University of British Columbia Vancouver, Canada

Synthetic peptides to combat acute and chronic Pseudomonas aeruginosa skin infections 1Pletzer Daniel, 1Choi Ka-Yee Grace, 2Esposito Tullio V., 2Saatchi Kathy, 1Coleman Shannon, 1Wilkinson Lauren, 1Lee Amy, 2Hafeli Urs O., and 1Hancock Robert E. W. 1Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada 2Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada. There has been enormous publicity about the inexorable rise of antibiotic resistance and the lack of new therapies. However, less attention has been placed on adaptively multidrug-resistant high-density bacterial infections for which antibiotics are highly used but no effective therapies currently exist. Here we show how synthetic peptides can be used as an adjuvant therapy to target bacterial infections in a cutaneous mouse model of acute and chronic infection. In particular, the commonly used Pseudomonas aeruginosa PA14 strain was highly aggressive, responsible for rapid lethality of about 40% of mice over three days, when delivered in high-densities under the skin. We hypothesized that bacterial motility, a mechanism by which organisms move and colonize, was a key characteristic during acute infection. Previously, we identified that the anti-biofilm peptide 1018 suppressed P. aeruginosa swarming motility in vitro, and therefore we investigated the potential of the peptide to reduce motility in vivo. We found that peptide treatment reduced abscess formation and bacterial dissemination into various body organs. We adapted this model to enable chronic infection with P. aeruginosa strain LESB58 for three-weeks, by using hydroxyapatite, a natural mineral found in bones and teeth, as a growth surface within the host; this led to the formation of an internal abscess capsule. Using in vivo live imaging technology, the presence of neutrophils and metalloproteases were confirmed at the infection site. Treatment of the tissue lump with daily intra-abscess or intra-venous administration of the immunomodulatory peptide 1002 reduced the bacterial load and modulated the host immune system. Moreover, pharmacokinetics of peptide 1002 revealed that the peptide remained as within the host tissue for several hours to days depending on the route of administration. These peptides have therefore the potential to broaden our limited antibiotic arsenal for extremely difficult to treat infections caused by resistant pathogenic bacteria.


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Posters

# Title Presenter

1 Antimicrobial molecules in platelets fight the Mycibacterial infection. Flor de María Torres Juárez

2 Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections Christopher H. Goss, Yukihiro Kaneko, Lisa Khuu, Gail D. Anderson, Sumedha Ravishankar, Moira L. Aitken, Noah Lechtzin, Guolin Zhou, Daniel M. Czyz, Kathryn McLean, Oyebode Olakanmi, Howard A. Shuman, Mary Teresi, Ellen Wilhelm, Ellen Caldwell, Stephen J. Salipante, Douglas B. Hornick, Richard J. Siehnel, Lev Becker, Bradley E. Britigan and Pradeep K. Singh

Richard J. Siehnel

3 Surfing motility: A conserved yet diverse adaptive phenotype

Evelyn Sun, Amy T. Yeung, Siejie Liu, and Robert E.W. Hancock

Evelyn Sun

4 Twenty gene signature demarcates subtypes of pediatric small-to-

medium sized vessel vasculitis. Chen Y, Gill EE, Smith ML, Gibson KM, Lee AHY, Falsafi R, Cabral DA, Hancock REW, and Brown KL, on behalf of the Pediatric Vasculitis Initiative

Yuyan (Jenny) Chen

5 Multidrug adaptive resistance of Pseudomonas aeruginosa swarming

cells Shannon Coleman

6 Effect of treatment with metformin, insulin and glyburide on the

expression of antimicrobial peptides during infection with Mycobacterium tuberculosis in vitro models.

Adrian Rodriguez-Carlos

7 Synthetic peptides as adjuvant therapy for acute and chronic

Pseudomonas aeruginosa skin infections Pletzer Daniel, Choi Ka-Yee Grace, Esposito Tullio V., Saatchi Kathy, Coleman Shannon, Wilkinson Lauren, Lee Amy, Hafeli Urs O., and Hancock Robert E. W.

Daniel Pletzer

8 Mechanisms underlying Pseudomonas aeruginosa susceptibility to

antimicrobials in clinically relevant conditions Corrie Belanger

9 Machine Learning Approaches to predict ER patient progression to

sepsis. Arjun Baghela

10 Many Faces of Macrophages: Activation, Endotoxin Tolerance, and

Salmonella resistance. Kate Sedivy-Haley

11 Treating chronic rhinosinusitis by eradicating biofilms using

antimicrobial photodynamic therapy and recolonizing the sinus with a healthy microbiome by sinonasal microbiota transplants.

Michael J. Trimble

12 The development of peptidomimetics with immunomodulatory and

anti-biofilm activities. Hashem Etayash, Robert Hancock

Hashem Etayash


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13 Novel Biofilm-Specific Targets to Fight Adaptively Resistant Infections Dostert, Melanie, Belanger, Corrie R, Lee, Amy HY, Dhillon, Bhavjinder K, Falsafi, Reza and Hancock, Robert EW

Melanie Dostert

14 RNA-Seq reveals inflammatory mechanisms of pediatric vasculitis

before and after treatment. Maren Smith

15 Bioinformatic identification of Pseudomonas aeruginosa stringent

response regulon Travis Blimkie

16 Influence of nitrogen source and metabolism on virulence of

Pseudomonas aeruginosa Morgan Alford

17 Unraveling the Role of Monocytes/Macrophages during Endotoxin

Tolerance – a New Driver of Sepsis Beverlie Baquir

18 Investigating the host-bacterial interaction of Salmonella in

macrophages derived from a SLC11A1 (NRAMP1) knockout iPS cell line

Christine Hale

19 The taming of the phage: turning bacterial viruses into antibiofilm

agents. Lucía Fernández, Silvia González, Diana Gutiérrez, Pilar García, Ana Rodríguez

Lucia Fernandez Llamas

20 Identification and characterization of crocodylian beta-defensin

variants. Santana, FL, Haney, EF, Arenas, I., Hancock REW, Corzo, G

Felix L. Santana

21 Cdc42 Rho GTPase; the molecular switch regulating pro- and anti-

inflammatory functions of the human host defence peptide LL-37 Mahadevappa Hemshekhar, Ka-Yee Grace Choi and Neeloffer Mookherjee

Mahadevappa Hemshekhar

22 Interplay of LL-37 and IL-17: differential expression of proteins

associated with neutrophilic airway inflammation and remodeling Anthony Altieri, Hadeesha Piyadasa, Breann Recksiedler, Victor Spicer, Andrew J. Halayko, and Neeloffer Mookherjee.

Anthony Altieri

23 Disruption of the central hydrophobic region mitigates the anti-

inflammatory activity of an innate defence regulator (IDR) peptide, but not the ability to improve lung function. Hadeesha Piyadasa, Mahadevappa Hemshekhar, Natasha Osawa, Dylan Lloyd, Anthony Altieri, Sujata Basu, Oleg Krokhin, Andrew J. Halayko, and Neeloffer Mookherjee

Hadeesha Piyadasa

24 Antibiotics suppress intestinal antiviral responses in a Microbiota-

independent manner Andrew J. Sharon and Lisa C. Osborne

Andrew J. Sharon

25 The unusual convergence of steroid catabolic pathways in

Mycobacterium abscessus Jessica Chorolovski


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26 Elucidating novel regulators of EPEC virulence through transcriptomic analysis.

Zakhar Krekhno

27 The Small RNA, SrbA, is Important for Biofilms and Pathogenicity in

Pseudomonas aeruginosa Strain PA14 Patrick K. Taylor, Antonius T.M. Van Kessel, Antonio Colavita, Robert E.W. Hancock, and Thien-Fah Mah

Patrick K. Taylor

28 Cholesterol-mediated coenzyme-A depletion in Mycobacterium

tuberculosis catabolic mutants Kirstin L. Brown, Shipei Xing, Tao Huan, Lindsay D. Eltis

Kirstin L. Brown

29 Altered RNA turnover in Bordetella pertussis provides insight to

regulatory RNAs implicated in pathogenesis. Gyles Ifill Travis Blimkie., Amy Lee., Qing Chen., Scott Stibitz, Robert E. W. Hancock. and Rachel Fernandez

Gyles Ifill

30 Transcriptional regulation of type 2 innate lymphoid cells and

precursors by IL-7 receptor signalling Julia Lu, Abdalla Sheikh, Ninan Abraham

Julia Lu

31 The Pseudomonas sp. ColR/S two-component system regulates host

colonization Christina Wiesmann

32 Targeting bacterial shape to reduce Helicobacter and Campylobacter

Pathogenesis Anson C. K. Chan, Yanjie Liu, Kris Blair, Emilisa Frirdich, Jenny A. Taylor, Jenny Vermeulen, Reuben Ha, Erin C. Gaynor, Nina Salama, Martin Tanner and Michael E. P. Murphy

Anson C.K. Chan

33 The NTF2-like domain of Pgp2 is Required for the Helical Cell Shape

of Campylobacter jejuni Chang Sheng-Huei Lin, Anson C. K. Chan, Jenny Vermeulen, Jacob Brockerman, Arvind Soni, Erin C. Gaynor, Lawrence Mclntosh, Martin Tanner, Jean-Pierre Simorre, Michael E. P. Murphy

Chang Sheng-Huei (Angela) Lin

34 Structural and functional characterization of ArnD, an essential

enzyme in Burkholderia cenocepacia. Daniela Morales, Jason C. Grigg, Martin Tanner and Michael E.P. Murphy

Daniela Morales

35 Are eyes more than just windows to the soul? Exploring the link

between retinal pathology and Alzheimer's disease. Maria-Elizabeth Baeva

36 Functional characteristics of peripheral granulocytes in severe

congenital neutropenia 1. Martina Sundqvist, Qiao Liu, Wenyan Li, Lena Björkman, Claes Dahlgren, Xiaodong Zhao and Huamei Forsman

Martina Sundqvist

37 Comparison of PAXgene and Tempus whole blood RNA collection

and isolation systems for the quantification of type I interferon-stimulated gene expression Lamot L, Niemietz I, and Brown KL

Lovro Lamot


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38 Reference intervals of adenosine deaminase 2 activity in childhood for improved clinical utility Sarah M. Bowers, Kristen M. Gibson, David A. Cabral, and Kelly L. Brown

Sarah Bowers

39 Mixed phenotype in a case of an undefined autoinflammatory

syndrome. Iwona Niemietz, Lovro Lamot, Lori B Tucker, Brian K Chung, Gillian I Rice, David A Cabral, Stuart E Turvey, William T Gibson, Kelly L Brown

Iwona Niemietz

40 Characterizing CD44 on Increasingly Metastatic Melanoma Cells and

the Impact of Hyaluronan Binding on Cancer Metastasis Atif J., Arif A, Freeman S.A., Dean P., Gilmour M., Poon G., Dosanjh M., Dong Y., Gold M., McNagny K., Roskelley C.D., & Johnson P.

Jawairia Atif

41 Identification of novel Adenosine Deaminase 2 gene variants and

varied clinical phenotype in pediatric vasculitis. Gibson K.M., Morishita, K.A., Drögemöller, B., Han, X.,Graham, J., Hancock, R.E.W.,Ross, C.J., Cabral, D.A., and Brown, K.L, on behalf of the PedVas investigators network.

Kristen Gibson

42 Mass spectrometry-based multiplexing assays for direct detection and

absolute quantitation of pathogen-derived peptidyl biomarkers - The case of dengue virus infection. Steven J. McArthur, Leonard Foster, and François Jean

Steven McArthur

43 The MicroRNA-17~92 Cluster in CD8 T Cell Function and Response

to Lung Adenocarcinoma. Melese ES, Franks ES, Cederberg R, Seo JH, Lam WL, Bennewith KL2,3, Lockwood WW, Abraham N

Etienne S. Melese

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