Center for Immunity, Infection & Inflammation

Pediatrics & SSPPS

Focus 1: Bacterial Pathogenesis

Focus 2: Innate Immunity

Focus 3: Novel Infectious Disease Therapeutics & Vaccines

Basic & Translational Research on Commonand Serious Human Infectious Diseases

Research InterestsMolecular pathogenesis of commong invasive bacterial pathogens:

Virulence factor discovery, infectious disease modeling, understanding immune evasionGAS, GBS, MRSA, Pneumococcus, Anthrax, MDR Gram- Pathogens

Understanding basic functions of the innate immune system: Antimicrobial peptides, complement system, macrophage and neutrophil function,receptor signaling, transcriptional regulation, autophagy, cell death, chemotaxis

Glycobiology of the host-pathogen interface:Molecular mimicry by bacterial glycans (sialic acid, hyaluronic acid)Bacterial glycosidases in inflammatory activationHost glycan receptors (lectin) involved in pathogen recognition, immune regulationGlycoprotein remodeling in the immunopathogenesis of sepsis, coagulopathies

Genetics and mechanism of action of bacterial toxins:Strep and staph pore-forming toxins/hemolysins, immune-disrupting proteasesAnthrax toxins, cholera toxin, how they disrupt host barrier function

Novel approaches to treat multi-drug resistant bacterial infections:Virulence factor inhibitors (disarm rather than kill the pathogen)Drugs that boost the killing activity of phagocytic cells (neutrophils/macrophages)Studying how antibiotics synergize with the innate immune system

Passive and active vaccination strategies for challenging pathogens:Novel approach to safe and universal GAS vaccineDesigner antibodies and drugs for passive immunotherapy of drug-resistant pathogens.

Core Expertise

Bacterial molecular geneticsMutagenesis, cloning, virulence factor discovery, “Molecular Koch’s postulates”

Innate immune function analysisAntimicrobial peptides, complement system, macrophage and neutrophil function,receptor signaling, transcriptional regulation, autophagy, cell death, chemotaxisTissue culture, flow cytometry, cytokines, Westerns, immunofluorescence, apoptosis,neutrophils extracellular traps (NETs), signaling, transcriptional analyses.

Small animal models of bacterial infection:Past: Rats, rabbits, fishCurrent: Mice including multiple KO strains

Sepsis, pneumonia, meningitis, skin infection, wound infection, UTI, foreign bodyCollaborative: Fruit flies, Worms

Preclinical analysis of antibiotic activity:MIC/MBC testing (classical) and in the context of innate immune componentsHave hundreds of strains of all important contemporary MDR pathogens for testing.Spectrum and potency, post-antibiotic effect, risk of resistance, animal challenge for PK/PDTreatment in any of the animal models above

Collaborations with Biotechnology/Pharma Companies Ongoing in the Laboratory

Fit-for-function biotherapeutics (single and multidomain antibodies) that optimally interface with the biology of each target antigen (MDR bacteria), to focus immune activation and mediate enhanced signaling

Novel platform to recruit and activate neutrophils to the site of invasive fungal and bacterial pathogens.

Repositioning prolyl-hydroxlase inhibitor drugs used in anemia/vascular disease therapeutics to boost white blood cell killing of MDR bacteria.

New: high-throughput screening for compounds that sensitize MDR Gram-bacteria to clearance by the host innate immune system. (Liquid handlingsystem being delivered this month for 384/96 well plate screens)

Collaboration with Kary Mullis to redirect pre-existing antibodies we all possess to target MDR bacterial pathogens

Some of our collaborative research at scientific interfaces

Ethan Bier Bacterial Toxins

Richard GalloInnate Immunity

Ajit VarkiGlycobiolo

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Jack DixonPharmacolo

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Pieter DorresteinMicrobial Products

Chris Glass

Macrophages

Jeffrey EskoGlycobiology

Edmund Capparelli

PK/PD

Partho GhoshStructure/Function

Brad MooreMarine

Antibiotics

Emily TroemelBaxterial Toxins

Michael KarinCell

Signaling