Microbiology Module 16

  1. Plague (Yersinia Pestis) (Slide 2)
    Claimed >200 million deaths througout history

    Bubonic form 50-75% mortality (Spread by fleas)

    Pneumonic form >90% mortality and highly contagious (person to person)

    Still exists as of 2003. >2000 cases worldwide (97 in US)

    Currently antibiotics successfully treat 90% of reported cases, but R plasmids now found in some infections
  2. Plague (Cont.) (Slide 3)
    Y. Pestis: Causative agent, Gram (-) rod. Obligative parasite. 3 plasmids encode virulence factors

    Reservoirs are primarily rodents in wild, in whome fleas find preferred host

    Wild rodents interact w/domestic populations and felas can hop onto new hosts (Less preferred)

    When domestic hosts become scarce, fleas hop onto and feed off humans but do not reproduce (dead-end host)
  3. Plague in the Flea (Slide 4)
    In Flea: At 26-28 degrees, flea-specific virulence factors are made that plug flea's digestive path from mouth to stomach, causing flea to starve and bite many hosts, spreading the pathogen

    Some scientists hypothesize that "little ice age" (1250-1850) contributed to spread of plague and the subsequent warm climatic conditions contribute to its disappearance
  4. Plague Pathogenesis in Human Host (Slide 5)
    2 stages of infection inside the human being (intra- and extracellular growth)

    Intracellular: Unencapsulated Y.Pestis are initially engulfed by macrophages

    Y. Pestis grow intracellularly, travel to and spread w/in lymph nodes and develop capsules

    Extracellular: Bacteria w/capsule lyse host cells, are released into blood and travel throughout body causing lung infection, sepsis, and systemic infections
  5. Plague: Y. Pestis Virulence Factors (Slide 6)
    Capsule (F1 protein) only produced at 37 degrees (not made in flea)

    Capsule inhibits phagocytosis by both ()PMNs and M(Phi). Is an adhesin therefore it binds to the macrophage

    Type III secretion system, injects 6 proteins (Apoptotic) into bound APC. Wipes out macrophage

    PLA (plasminogen Activator) is produced. A protease that inactivates complement

    Siderophores bind tightly to and transport iron into the pathogen

    Exotoxins, endotoxins, and fast growth all contribute to septicemia
  6. Treatments for Plagues (Slide 7)
    Antibiotics successfully treat most cases of bubonic plague, but only 50% of cases of pneumonic plague

    Vaccine was available but was taken off market because of toxicity

    Recombinant vaccines against F1 and V antigens currently being developed
  7. Anthrax--Bacillus anthracis (Slide 8)
    Ubiquitous facultave Gram positive anaerobe. Endospore forming

    Found naturally in soil

    Herbivores are infected while grazing, carnivores are exposed to spored from direct soil exposure or by exposure to infected animals

    20,000-100,000 cases each year world wide

    Pulmonary Anthrax (Spore inhalation) mortality rates nearly 100% if not treated right away

    Cutaneous or Gastrointestinal forms less lethal

    Vaccine is available to those at high risk
  8. Bacillus anthracis pathogenesis (slide 9)
    Spores are taken up by macrophages (spores are infectious form, no spread of bacteria from person to person)

    Pathogenic strains of B. Anthracis sporulate and multiply w/in macrophages, develop capsules (poly-glu) and lyse cells

    Encapsulated strains resist further phagocytosis and release toxins which lead to patient's death
  9. Anthrax Toxins (Slide 10)
    Anthrax toxin is comprised of 3 plasmid-encoded gene products (PA, LF and EF)

    PA (Protective Agent) acts to get LF (Lethal factor) and EF (Edema Factor) toxins into cells

    LF kills WBCs as well as many other kidns of cells. It is a protease that inhibits major signaling pathways, including master regulator NFkB

    EF elevates cAMP (adenylate cyclase), causing edema

    Endothelial cells become leaky, causing shock and death
  10. Anthrax as a Weapon (Slide 11)
    Refers to small size particles and electrical charges of endospores that keep them aloft

    No person-person spread

    Antibiotics readily available, but often administered too late

    In 1979 Russia, 1 gram of spores was release causing 77 cases and 66 deaths

    2001 USA, 22 cases, 5/11 pulmonary cases were fatal
  11. Pathogenic E.Coli (Slide 12)
    Usually strains are enteric commensals and cause no problems

    There are 200 known pathogenic strains that cause diarrheal disease or UTIs

    Enterotogigenic strains (ETEC) cause water (traveler's) diarrhea via 2 plasmid-encoded enterotoxins. LT and ST ( L--> heat-labile, S--> heat stable)

    Enterohemorrhagic strains (EHEC) produce verotoxins (kidney) that cause blody diarrhea and kidney failure

    73,000 cases and 60 deaths yearly in the US
  12. E. Coli 0157H7 (Slide 13)
    Verotoxins (Stx-1, -2) (Shiga like toxins ). probably from shigella

    Stx: AB toxins that bind to vascular and renal epithelial cells (A inhibits protein synthesis, is an endoglycosidase)

    Stx genes carried on (lambda prophage)

    Cows do not have receptors for the B component, they can harbor and disseminate 0157H7 without any side-effects
  13. Salmonella Sp. (Slide 14)
    1 species of salmonella w/many diff. strains

    Over 2000 strains. 1/3 of all chicken eggs are contaminated

    Reptile pets are frequent carriers

    Virulence factors include Type III secretion system that injects sip proteins (recognize actin in host cell to cause it to endocytose bound salmonella)

    S. typhi (strain) causes typhoid fever: Bacteria invade and then pass thru intestinal wall. Are phagocytosed but not killed in blood, are carried to liver, spleen, gall bladder

    Carriers (Typhoid Mary) often maintain bacteria in gall bladder
  14. Ulcers--The H. Pylori Connection (Slide 15)
    Most peptic ulcers are caused by a bacteria Helicobacter pylori

    Very Common: 40-50% of people have it world-wide, ut usually doesn't make ulcers

    Fimbriae/pili attach to mucous-producing cells in intestines

    Secrete enzymes (Urease) that neutralize acid and high levels of SOD (Superoxide Dismutase) and catalase to help inhibit phagocytic death

    Disruption of mucoid covering and inflammation cause stomach acid to erode stomach lining, allowing bacteria to invade deep into tissues

    Treatment is antibiotics
  15. Smallpox (Variola) Virus (Slide 17)
    dsDNA, eveloped, large, genome stable and whole sequence is known

    Highly contagious, stable in aerosol form for 24hrs

    Arose around 10,000BC and circulated continuously until eradicated in 1980

    Estimations are that 300-500 million died in 20th century

    50 million cases each year w/30-50% mortality

    No effective anti-virals for variola viruses
  16. Eradication of Smallpox (Slide 18)
    Eradication due in part to effective vaccination (DNA viral genome very stable). The only infectious disease ever to be eradicated

    Vaccine is from closely related live vaccinia virus ( genetically related to cowpox and smallpox viruses

    Only human hosts (No animal reservoirs)

    Obvious signs of infection and no human carriers

    World-wide commitment was needed to eradicate disease
  17. Reasons that smallpox is considered a bioweapon (Slide 19)
    Highly contagious and stable in aerosol form for 24hrs

    Russian bioweapons program made trillions of doses of smallpox virus and genome can be synthesized

    Currently good antiviral smallpox treatment are not identified, but vaccination w/in several days of exposure can ameliorate effects
  18. Smallpox as BioWeapon: The Bright Side (Slide 20)
    Vaccination w/live vaccinia gives long-term immunity and many people are still partially immune

    Most infected persons are infectious primarily after symptoms become visible, so spread of smallpox from infected bioterrorists would not be efficient

    Because of large, stable genome of pox viruses, the # of potential targets for rapid development of therapeutics is high
  19. Retroviruses in General (Slide 21)
    All are (+) strand RNA viruses containing reverse transcriptases that convert ssRNA into dsDNA as well as integrases that cause dsDNA to integrate into host chromosome

    Lentiviruses (HIV) are immunosupressive

    Deltaretroviruses (e.g. HTLV-1) cause leukemia
  20. HIV Entry into Host Cells (Slide 22)
    HIV virions contain 2 genomes of +ssRNA, RT, HIV protease, tRNA primer and integrase

    HIV envelope contains glycoprotein120 which binds to CD4 on immune cells

    Chemokine receptor, CCR5 (macrophage) of CXCR4 ( T (h) cells) removes gp120-CD4

    gp41, now exposed, binds to CM and causes HIV envelope to fuse to CM
  21. More of the Live Cycle of HIV (Slide 23)
    After uncoating, RT makes DS-DNA from RNA genome and integrase inserts it into chromosome of host cell

    HIV gene expression controlled by NFkB activation in host cell, causing rounds of virion production that bud out of cells

    Virions can bud out of the cell or via syncitia formation (gp41-mediated). Fusion of HIV-infected cell to non-infected cells allowing it to go from cell to cell

    Host immune system and HIV wipe out CD4+ cells (macrophage-like cells, T (h) cells), leading to AIDS
  22. AIDS (Slide 24)
    Death from AIDS is from a variety of opportunistic infections including viral, fungal, and bacterial infections.

    AIDS pandemic has led to widespread resistance to antibiotics of many microbial pathogens, as patients are contantly on antibiotic therapy

    Cancers also arise as immune surveillance breaks down
  23. Distribution and Prognosis ( Slide 25)
    HIV-1 probably around from SIV found in chimpanzees. spread throughout the globe today. 2 types HIV-1 and HIV-2

    RT are very error prone. Makes 1 mistake/genome, therefore strains are constantly mutating, making vaccine development problematic

    Current therapies use cocktails that separate gene products to limit formation of drug resistance (Must simultaneously develop resistance to all drugs)

    Combinations of vaccines are being put together and being tested.
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Card Set
Microbiology Module 16
Module 16