Top 3 Basic Science Papers on Aspergillus fumigatus 2011 Top 3 Basic Science Papers. on Aspergillus

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  • 2 1. Top 3 Basic Science Papers

    on Aspergillus fumigatus 2011

    Nir Osherov, Tel-Aviv University, Israel

  • Let’s start with a quiz…

    2.

  • Q1: Which pathogenic fungus has the most scientific papers?

    Aspergillus Dermatophytes Candida

    Cryptococcus 46,468 32,101

    8,648 3,031

    3.

  • Q2: Is the number of Aspergillus papers increasing?

    0

    200

    400

    600

    800

    1000

    1200

    1400

    1600

    1800

    2000

    1980 1985 1990 1995 2000 2005 2010

    313

    1742

    McNeil MM et al CID 2001

    Aspergillosis

    400% increase!

    4.

  • Q3: Basic research or bedside? Who has more A. fumigatus papers?

    Bedside (Epidemiology, treatment, clinical resistance etc)

    Basic Research

    63% of papers 2011 37% of papers 2011

    5.

  • Q4: How many Aspergillus papers made it to Nature, Science or Cell?

    (last 20 years)

    2008

    2008

    1999

    2009

    2009

    2005

    2000

    1991

    1990

    9? 19? 29?

    6.

  • How did I select the three top papers?

    1. Pubmed: Aspergillus fumigatus and 2011

    2. Sort basic science papers into 4 categories

    Choose 3 papers

    7.

  • Each of the three papers I have chosen was built on the shoulders of many crucial others

    Therefore each paper will be represented as part of a larger story

    8.

  • Disclaimer of Opinion This lecture contains several possibly controversial opinions that you may find offensive. If you are offended by anything in this lecture, please leave a message and I will gladly elaborate. If you feel the need to trash this lecture, at least make it funny. Thank you! nosherov@post.tau.ac.il

    9.

    http://en.wikipedia.org/wiki/File:Information_icon.svg� http://en.wikipedia.org/wiki/Controversy� http://en.wikipedia.org/wiki/Opinion� http://en.wiktionary.org/wiki/offensive� http://en.wikipedia.org/w/index.php?title=User_talk:SwitChar/Opinion_disclaimer&action=edit&section=new� http://en.wikipedia.org/wiki/Wikipedia:BJAODN�

  • Story 1: What stresses does A. fumigatus encounter in the infected lung?

    Can we use this knowledge to improve treatment?

    10.

  • What conditions does A. fumigatus encounter during lung infection?

    I am hungry and unhappy in these lungs! I want to go back to live on dead leaves

    in the garden !!!

    McDonagh, Elaine Bignell. Plos Path. 4(9), Sept. 2008

    Iron uptake genes

    Proteases

    Toxin biosynthesis

    Alkaline response

    Nitrogen starvation

    11.

  • t During infection, A. fumigatus scavenges iron by secreting siderophores

    Low affinity uptake

    Reductive iron uptake

    FtrA

    Fe+3

    Transferrin-Fe

    Schrettl and Haas Curr. Op. Microbiol. 14:400 2011

    TAFC

    Sit1

    ΔSidA= no TAFC= avirulent

    12.

  • Can we use this knowledge to diagnose Aspergillosis?

    Paper #1

    13.

  • Fe 68Ga

    TAFC siderophore

    A. fumigatus

    The experiment and rationale:

    Sit1

    Petrik ey al. J. Nucl. Med. 51:639 2010

    14.

  • The results:

    Active 68 Ga-TAFC uptake into AF in vitro

    Lung

    Rapid uptake into AF infected lungs (PET)

    Signal correlates to severity of AF infection

    Infection: Severe Mild Negative

    Lung

    Conclusions: -Sensitive - Low non-specific binding -68Ga easily available -Short half life -68Ga in clinical use -Selective (?)

    Petrik ey al. J. Nucl. Med. 51:639 2010

    15.

  • Th1 response h

    IL2, 12, IFN-γ

    Story 2: What are the body’s main lines of defense against A. fumigatus?

    CMI

    Macrophage Neutrophil

    Fungus β-glucan Dectin 1 receptor

    Introducing:The NK cell, an added line of defence in IA

    16.

  • What are NK (natural killer) cells?

    Viruses Bacteria Parasites

    MO DC

    NK cell Lymphocyte lineage

    IL-12

    NK depletion leads to decreased IFN-γ and decreased survival of mice in IPA model

    Mehrad group: Morrison et al. J. Clin Invest. 112:1862 2003; Park et al. J. Imm. 182:4306 2009

    17.

  • Paper #2

    HKI, Jena, Germany

    18.

  • Hyphae

    Swollen conidia

    Dormant conidia IL-2 stimulated Human NK cells (No APCs!)

    Perforins

    Schmidt et al. J. Inf. Dis. 203:430 2010

    19.

  • Hyphae

    Swollen conidia

    Dormant conidia

    IFN-γ

    IL-2 stimulated Human NK cells (No APCs!)

    How does IFN-γ Kill AF?

    Conclusions: -NK cells kill growing AF - Important defence during infection -Possible NK immunotherapy?

    Bouzani et al J. Immunol. 187:1369 2011

    20.

  • Story 3: Are any completely new classes of antifungals being developed?

    21.

    •Antifungals: Growing needs, few choices

    •$5 billion/year world market • Amphotericin B, Azoles, Candins •Pharma research down •Basic Research up

  • Plasma membrane

    Cell Wall

    Glucan, chitin

    Cell wall proteins

    Goal: Inhibit CWP cross-linking to the cell wall

    Can we develop new classes of antifungals targeting the cell wall?

    22.

  • Plasma membrane

    ER

    Cell Wall

    Novel inhibitors that block incorporation of cell wall proteins into the fungal cell wall

    Kapei Tsukahara Mol Micro 48:1029 2003 Umemura JBC 278:23639 2003 Eisai Co. Japan

    BIQ MIC-3 μg/ml

    Inositol acylation (Gwp1)

    E1210 MIC-0.1 μg/ml

    23.

  • Paper #3 24.

  • E1210 summary

    Mode of action (candida)

    Inhibits inositol acylation by Gwt1p in vitro  Does not inhibit the human homolog Pig-W Gwt1p overexpression/mutation confers resistance  Reduces levels of Als1p a cell wall adhesin

    Reduces: Switch  Biofilm Adhesion

    Watanabe et al., AAC in press

    25.

  • E1210 summary

    In vitro

    MIC ~ 10 ng/ml Azole R Fungistatic Low toxicity (mammalian cells)

    Orally available Non toxic (10X/1 week) T1/2 = 2.2 h

    In vivo

    IPA

    mg/kg

    25

    10 4

    Hata et al., AAC 55:4543 2011

    26.

  • Conclusion: Panning for novel antifungals is now attainable at the RESEARCH Lab level

    Robot

    screen

    Gold is hard! Maybe I

    should try finding

    antifungals

    27.

  • Thank you for your attention!

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