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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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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