VIRULENCE AS AN EMERGING PROPERTY. Arturo Casadevall Albert Einstein College of Medicine Bronx, NY

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1 VIRULENCE AS AN EMERGING PROPERTY Arturo Casadevall Albert Einstein College of Medicine Bronx, NY

2 THE PHYLOGENY OF SCIENCE SUPERSTITION PRE-HISTORY RELIGION BCE RELIGION PHILOSOPHY RENE DESCARTES NATURAL PHILOSOPHY 1800s SCIENCE EPISTEMOLOGY LOGIC ETHICS METAPHYSICS BETTER SCIENCE!!! HOW DO YOU KNOW WHAT YOU KNOW? VALID INFERENCES AND CORRECT REASONING RIGHT AND WRONG BEHAVIOR NATURE OF BEING AND THE WORLD

3 THE GERM THEORY OF DISEASE REVOLUTION 1670s Van Leeuwenhoek discovers microbes 1841 David Gruby shows a fungus causes favus 1840s Ignaz Semmelweiss puerperal fever reduced by hand washing 1850s John Snow Cholera epidemic London traced to well, not miasma 1870s Robert Koch proves B. anthracis causes anthrax BEFORE the Germ theory Miasma Contagion Public Lore Punishment ORIGIN OF VIRULENCE Microbes that cause disease are different than those that do not

4 Prevalence of disease THE 20 th -CENTURY PROBLEM IN MICROBIAL DISEASES: NON-PATHOGENS BECOME PATHOGENS Encapsulated microbes Organ transplants Chemotherapy Toxin diseases Viral diseases HIV pandemic Vector-borne diseases Sanitation Urbanization Toxoids Viral & Polysaccharide vaccines Candidiasis & other fungal diseases Serum therapy Drug resistant microbes Coagulase negative staphylococci Germ Theory Penicillin Global travel Intensive care units Intravenous catheters

5 DISEASE BY COMMENSALS GIVES RISE TO CONCEPTS OF MICROBIAL OPPORTUNISM MEDICAL PROGRESS ANTIBIOTICS CORTICOSTEROIDS ANTINEOPLASTIC THERAPY PLASTIC CATHETERS Candida albicans C. albicans BIOFILM

6 ARE PATHOGENIC MICROBES DIFFERENT? Ignaz Semmelweiss Louis Pasteur Joseph Lister GERM THEORY OF DISEASE LATE 1800s Robert Koch MAJOR PATHOGENIC MICROBES c1900 YES STREPTOCOCCUS PNEUMONIAE HEMOPHILUS Bail c1900 INFLUENZAE NEISSERIA MENINGITIS Rosenow Virulins Agressins CAPSULES TOXINS CAPSULES NO NO FUNDAMENTAL DIFFERENCE BETWEEN PATHOGENS AND NON-PATHOGENS TOXINS VIBRIO CHOLERA DIPHTHERIA CORYNEBACTERIUM CLOSTRIDIUM TETANI Bordet c Virulence not a stable trait 2. Immunization negates virulence

7 HOW DO YOU MAKE A MICROBE WITH PATHOGENIC POTENTIAL? MICROBE-CENTRIC VIEW (MICROBIOLOGISTS, GENETICISTS) MICROBE + SOMETHING = PATHOGEN BUT IMMUNIZATION NEGATES VIRULENCE HOST-CENTRIC VIEW (IMMUNOLOGISTS) MICROBE + SUSCEPTIBLE HOST = PATHOGEN BUT SUSCEPTIILITY GENERALLY HAS SPECIFICITY SINCE SUSCEPTIBLE HOSTS ARE NOT VULNERABLE TO ALL MICROBES TO RECONCILE BOTH VIEWS ONE NEEDS A GENERAL THEORY THAT ACCOUNTS FOR THE CONTIBUTION OF THE MICROBE AND HOST TO PATHOGENESIS WRONG QUESTION! ASSUMES THAT IS PATHOGENICITY IS AN INDEPENDENT MICROBIAL CHARACTERISTIC

8 THERE ARE NO PATHOGENS THE CONCEPT OF PATHOGEN IS FLAWED BECAUSE IT ASSUMES THAT PATHOGENITY IS AN INDEPENDENT CHARACTERISTIC THAT CAN BE ASSIGNED TO A MICROBE HOWEVER PATHOGENICITY AND VIRULENCE ARE MICROBIAL CHARACTERISTICS THAT ARE EXPRESSED ONLY IN A SUSCEPTIBLE HOST HENCE PATHOGENICITY AND VIRULENCE CANNOT BE INDEPENDENT MICROBIAL PROPERTIES AND CALLING A MICROBE A PATHOGEN ENDOWS IT WITH PROPERTIES THAT ARE NOT ITS OWN THERE ARE ONLY MICROBES AND HOSTS AND WHAT WE CARE ABOUT IT THE OUTCOME OF THE INTERACTION

9 THE FOUR OUTCOMES OF HOST- MICROBE INTERACTIONS SYMBIOSIS AND MUTUALISM EFFECTIVE IMMUNE RESPONSES HEALTH HOST MICROBE HOST MICROBE DISEASE HOST MICROBE HOST MICROBE INFECTIOUS DISEASES DEAD END HOST INFECTIONS AUTOIMMUNITY

10 DAMAGE 1. TWO ENTITIES DAMAGE-RESPONSE FRAMEWORK BASIC TENETS (OBVIOUS AND INCONTROVERTIBLE) HOST MICROBE MOLECULE VIRUS PROKARYOTE EUKARYOTE INTERACTION 2. RELEVANT OUTCOME = HOST DAMAGE Dr. Liise-anne Pirofski PROFESSOR CHIEF, ID DIVISION ALBERT EINSTEIN/MONTEFIORE? HOST RESPONSE 3. DAMAGE CAN COME FROM HOST, MICROBE OR BOTH Casadevall & Pirofski, Infect Immun 1999 Infect Immun 2000 Nature Micro Rev. 2003

11 DAMAGE VIRULENCE VIRULENCE IS A MICROBIAL PROPERTY THAT IS EXPRESSED ONLY IN A SUSCEPTIBLE HOST VIRULENCE = f(host IMMUNITY) J. Infect Dis AND IF VIRULENCE IS THE RELATIVE CAPACITY OF A MICROBE TO CAUSE DAMAGE IN A HOST THEN DAMAGE = f(host IMMUNITY) NATURE MICRO REVIEWS 2003 IMMUNE RESPONSE

12 BASIC RELATIONSHIP FOR DAMAGE-RESPONSE FRAMEWORK Casadevall & Pirofski, Nature Micro Rev DISEASE THRESHOLD HOST MICROBE HOST MICROBE DISEASE THRESHOLD HOST MICROBE HOST MICROBE WEAK STRONG WEAK STRONG HOST RESPONSE HOST RESPONSE

13 CONSIDER THE CASE OF S. CEREVISIAE AIDS PATIENT NORMAL WOMEN WITH VAGINITIS? BAKER WITH LUNG NODULE Saccharomyces cerevisiae IMMUNE RESPONSE OPPORTUNISTIC MASSIVE INFLAMMATION PRIMARY PATHOGEN THRESHOLD FOR DISEASE S. CEREVISIAE CANNOT BE DEFINED AS FOOD, COMMENSAL, OPPORTUNISTIC OR PRIMARY PATHOGEN WITHOUT TAKING INTO ACCOUNT HOST

14 A DEFINITION IS AN ACCOUNT (logos) THAT SIGNIFIES THE ESSENCE, Aristotle PATHOGEN PATHOGENICITY VIRULENCE A MICROBE CAPABLE OF CAUSING HOST DAMAGE THE CAPACITY OF A MICROBE TO CAUSE DAMAGE IN A HOST THE RELATIVE CAPACITY OF A MICROBE TO CAUSE DAMAGE IN A HOST Infect Immun 1999

15 VIRULENCE VIRULENCE THE RELATIVE CAPACITY OF A MICROBE TO CAUSE DAMAGE IN A HOST RELATIVE BECAUSE THERE IS NO ABSOLUTE MEASUREMENT OF VIRULENCE

16 HOST- VS. ENVIROMENT-ACQUIRED PATHOGENIC MICROBES HOST ACQUIRED ALL VIRUSES, MANY PARASITES, MOST BACTERIA, FEW FUNGI COMMUNICABLE HOST RANGE LIMITED NOT FREE LIVING OFTEN PRESSURE ON MICROBE NOT TO KILL HOST ENVIRONMENTALLY ACQUIRED PRIMARILY BACTERIA, FUNGI, SOME PARASITES NOT COMMUNICABLE HOST RANGE BROAD FREE LIVING SELECTION PRESSURES FOR CAUSING DISEASE UNKNOWN CAN CAUSE EXTINCTION!

17 PATHOGENIC FUNGI HOST-ACQUIRED ENVIROMENT-ACQUIRED Candida albicans es: Candida albicans Clinical Presentation C. albicans Tinea pedis Slide Reference #: GK 061 also Pneumocystis spp. Disease(s): Candidiasis DISEASE = DISRUPTION OF HOST-MICROBE RELATIONSHIP Aspergillus spp. Blastomyces dermatitidis Cryptococcus neoformans Coccidioides spp. Histoplama capsulatum Sporothrix schenkii DISEASE = HOST WITH IMPAIRED IMMUNITY OR LARGE INOCULUM

18 FOCUS ON C. NEOFORMANS: A MICROBE WITH WELL-DEFINED VIRULENCE FACTORS

19 FcR Ab C C. neoformans Phagosome CR3 GXMR PNAS 2001 Lysosomes Phagolysosome Binding to PFK Immunomodulation NC Leaky phagolysosome GXM vesicles Lateral Transfer Capsule growth, antioxidant enzymes GXM NC Survival and Intracellular replication Extrusion/ Vomocytosis/ Non-lytic exocytosis Macrophage division (1) Free living yeasts NC Macrophage separation NC NC NC Macrophage lysis Macrophage division (2) Free living yeasts Yeast between two macrophages NC NC Macrophage fusion NC NC

20 C. NEOFORMANS INTERACTIONS BACTERIA OTHER FUNGI SLIME MOLD AMOEBAE VIRUSES AIRBORNE PARTICLES INSECTS REPTILES RESOLUTION WORMS LATENCY DISEASE MAMMALS

21 VIRULENCE IS AN EMERGENT PROPERTY DEFINITION OF EMERGENT PROPERTY: any unique property that "emerges" when component objects are joined together in constraining relations to "construct" a higher-level aggregate object, a novel property that unpredictably comes from a combination of two simpler constituents COMPONENTS NOVELTY HOST + MICROBE VIRULENCE PATHOGENICITY DISEASE MUTUALISM COMMENSALISM DEATH OF EITHER PARTY

22 EXAMPLES OF EMERGENT PROPERTIES SURFACE TENSION FISH SCHOOL SAND DUNES BIRD FLOCKS

23 C. NEOFORMANS CAPSULE AND MELANIN ARE MOST IMPORTANT VIRULENCE FACTORS POLYSACCHARIDE CAPSULE ~26% ~14% MELANIN IN CELL WALL

24 Galleria mellonella MODEL

25 RELATIVE VIRULENCE OF THREE CRYPTOCOCCAL SPECIES IN GALLERIA PHOSPHOLIPASE + UREASE +

26 IS VIRULENCE A CHAOTIC SYSTEM? CHAOTIC SYSTEMS 1. MUST BE SENSITIVE TO THE INITIAL CONDITIONS 2. TOPOLOGICALLY MIXING 3. ORBITS MUST BE DENSE

27 LOOKING FOR EVIDENCE OF CHAOS IN UNCONVENTIONAL PLACES

28 CLOSING THOUGHTS VIRULENCE MEETS CRITERIA FOR CATEGORIZATION AS AN EMERGENT PROPERTY IF VIRULENCE IS AN EMERGENT PROPERTY DETERMINISM IS NOT ACHIEVABLE FORWARD LOOKING ANALYSIS SHOULD FOCUS ON DEVELOPING PROBABILISTIC MODELS WHETHER VIRULENCE IS A CHAOTIC SYSTEM IS CURRENTLY UNKNOWN THERE ARE LIMITS TO WHAT WE CAN KNOW AND PREDICT THROUGH REDUCTIONISM

29 BUT DO NOT DESPAIR DESPITE EMERGENCE AND MAYBE CHAOS HUMAN VICTORIES ARE POSSIBLE VIRTUAL ERADICATION OF MANY INFECTIOUS DISEASES FROM DEVELOPED AREAS SANITATION HAS VASTLY IMPROVED HUMAN HEALTH DOZENS OF VACCINES NOW AVAILABLE DRUGS NOW AVAILABLE AGAINST MANY BACTERIA, FUNGI, PARASITES AND VIRUSES SOME RECENT VICTORIES SARS CORONAVIRUS CONTAINED IN 2003 ANTIRETROVIRAL THERAPY