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Human Diseases Worldwide

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most severe diarrheal disease is cholera ... Grim urban conditions fueled cholera spread ... Mapped cholera outbreaks in London to discern how the disease spread ... – PowerPoint PPT presentation

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Title: Human Diseases Worldwide


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Human Diseases Worldwide
  • Diarrheal diseases account for 16 of human
    illness
  • 2-4 billion cases/yr 3-5 million deaths/yr
    (mostly children lt5 yrs)
  • 50 of diarrheal disease caused by bacteria
  • most severe diarrheal disease is cholera
  • most common diarrheal disease caused by
    enterotoxigenic E. coli
  • one billion cases/yr 300,000-500,000 deaths/yr
    (young children)

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Vibrio cholerae and Enterotoxingenic E. coli
(ETEC)
  • Organism similarities
  • Gram negative organisms
  • Adhere to small intestine (uppermost 20 of gut)
  • Gastrointestinal pathogens contracted by
    consumption of contaminated water (fecal oral
    route)
  • Cause diarrheal disease
  • Similar virulence strategy and factors
  • Neither organism induces histological changes in
    gut epithelium

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V. Cholerae and ETEC Disease
  • V. cholerae causative agent of cholera
  • severe diarrhea only observed in humans
  • massive fluid loss (up to 20L/day)
  • 30 mortality without supportive therapy (rapid
    dehydration resulting in hypovolemic shock)
  • epidemic disease (7 pandemics)
  • first reported in India, 1817
  • current pandemic began 40 years ago in
    Bangladesh
  • endemic in areas with poor sanitation
  • ETEC causes cholera-like disease
  • causes disease in humans, calves and piglets
  • diarrheal disease less severe than cholera
  • not associated with epidemics
  • primarily observed in impoverished children
  • number one cause of bacterial diarrheal disease
    worldwide


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Cholera and the Birth of Epidemiology
  • Grim urban conditions fueled cholera spread
  • industrial revolution attracted and concentrated
    people in cities
  • cities lacked infrastructure to support ever
    growing masses
  • Pestilential odors rose from over 200K cesspools
    and accumulated sewage piled up in every ditch
    and alleyway sewage overflowed from storm-water
    sewers during rainstorms and Thames's high tides
  • Rivers viewed as a waste-disposal system Thames
    became a reeking brown sewer scenario pervasive
    across Europe
  • 1858, London wrapped in "The Great Stink" due to
    Thames contamination
  • Cholera outbreak kills hundreds of thousands
  • Germ theory of disease not established
  • disease caused by supernatural forces or miasma
    (bad air)
  • public health efforts focused on locating bad
    air source
  • pleasant or strong smelling odors protective
  • herbs, alcohol, smoke

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Cholera and the Birth of Epidemiology (cont.)
  • John Snow, English anesthesiologist
  • Argued that cholera transmitted by contaminated
    food or water
  • couldn't be airborne because it didn't affect
    the lungs
  • theory was ignored because he couldn't identify
    the "poison" in the water
  • Mapped cholera outbreaks in London to discern
    how the disease spread

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Cholera and the Birth of Epidemiology (cont.)
  • Mapped outbreaks to a water pump on Broad Street
  • most infected people had drank water from pump
  • those who did not live in area came to this pump
    for water because it tasted better than other
    city water
  • Snow recommended that the Broad Street pump
    decommission
  • pump handle removed
  • number of new cholera cases decreased
    dramatically
  • Medical community not convinced cholera was
    spread by contaminated water

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Cholera and the Birth of Epidemiology (cont.)
  • Two London water companies supplied one area of
    city
  • both provided water directly from the Thames
  • Southwark and Vauxhall company water from within
    city limits
  • Lambeth company water acquired upstream of
    London
  • Snow documented number of deaths/water company
  • Southwark and Vauxhall water 70/10,000 deaths
  • Lambeth company water 5/10,000 deaths
  • Findings sparked massive public concern
  • sanitary reform followed
  • Final London cholera epidemic in 1866
  • 2200 deaths

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Cholera Remains a Serious Threat
  • Inadequate sanitation and access to clean water
    fuel endemic and pandemic disease

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Vibrio cholerae Virulence Factors
  • Evolution
  • V. cholerae are non-pathogenic marine organisms
    present in all oceans
  • Virulence consequence of infection of 2
    serotypes (O1 and O139) with bacteriophages that
    encode elements essential for disease
  • Adhesions
  • Toxin co-regulated pilus (Tcp)
  • hair-like appendages extend from bacteria,
    contact host cell
  • Encoded within the Vibrio pathogenicity island
    (VPI) maybe phage genome
  • Essential for adhesion to upper 20 of intestine
  • Only known to cause disease in humans
  • Toxin
  • Encoded on a filamentous bacteriophage genome
    (separate from VPI)
  • Disrupts electrolyte balance resulting in fluid
    secretion
  • Infects V. cholerae through TCP
  • Virulence factor regulation
  • Tightly regulated expression governed by sensors
    of 2 environmental cues
  • Cell density dependent signal (Quorum sensing)


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ETEC Virulence Factors
  • Evolution
  • ETEC likely derived from gt70 different commensal
    E. coli strains
  • Virulence consequence of acquisition of
    plasmid(s)
  • Adhesions
  • Plasmid encoded
  • Attachment fimbriae termed colonization factor
    antigens (CFA)
  • gt20 different CFA variants identified
  • Adhesions likely associated with host
    specificity (humans, calves, piglets)
  • Toxins (strains may express 1 or more toxins)
  • Heat-labile toxin (LT)
  • Plasmid encoded
  • Identical to Cholera toxin (CT)
  • ETEC strains do not secrete LT/CT as efficiently
    as V. cholerae
  • V. cholerae CT secretion mediated by dedicated
    T2SS
  • ETEC genome does not encode dedicated T2SS
  • diminished toxin secretion (10) maybe
    associated with less severe disease
  • Heat-stabile toxins A and B (STa and STb)


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ETEC Heat Stabile (ST) Toxins
  • STa toxins
  • encoded within a composite transposon located on
    plasmids
  • small peptides (11-18 amino acids)
  • associated with porcine, bovine, and human ETEC
    strains
  • stimulates guanylate cyclase system
  • cGMP accumulation diminished water and
    electrolyte absorption
  • STb toxins
  • encoded within a composite transposon
  • small peptide (48 amino acids)
  • associated with porcine ETEC strains
  • does not increase cyclic nucleotide accumulation
    (mechanism not established)

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Cholera Toxin
  • CTX phage lysogenic filamentous virus buds from
    cell (no lysis)
  • CT produced in gut lumen following attachment to
    enterocytes
  • Pentomeric CT subunit B (CTB) binds toxin to
    host cell GM1 ganglioside receptors on enterocyte
    apical membrane surface CT internalized into
    cell inside membrane bound vesicle
  • CT escapes into host cell cytosol
  • CT subunit A (CTA)
  • synthesized as single protein
  • cleaved into 2 subunits (CTA1 and CTA2) by V.
    cholerae protease A subunits are joined via
    disulfide bond
  • CTA1 subunit is an ADP ribosylating enzyme
    (toxic activity)
  • CTA2 mediates insertion into CTB pentamer
  • CTA2 subunit KDEL C-terminus mediates CTA escape
    into cytosol


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Cholera Toxin A 1 Enzyme Activity
  • ADP ribosylates the heterotrimeric Gsalpha
    subunit of Adenylate Cyclase

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  • ON ADP-ribosyl adenylate cyclase increases
    cellular cAMP
  • cAMP activates PKA and PO4 (activation) of major
    intestinal chloride channel (CFTR)
  • CFTR activation increases Cl- secretion
  • change in osmotic balance leads to fluid
    secretion

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Vibrio cholerae Ecology
  • V. cholerae are marine organisms present in all
    oceans
  • Organism is sensitive to stomach acid
  • Relatively high infectious dose
  • Inconsistent with ability to cause epidemics
  • Oceanic V. cholerae present in viable
    non-culturable state
  • Organisms shed in cholera rice water stools are
    more infective than those cultured in lab
  • Microscopic analyses demonstrated stool and
    oceanic viable non-culturable V. cholerae present
    in biofilms


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Vibrio cholerae Bioflims
  • V. cholerae biofilms bind marine organisms
    (copepods) and phytoplankton
  • Biofilm V. cholerae in quiescent state
  • resistant to environmental stresses including
    acid

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Infectivity of V. cholerae Bioflims
  • Observations influencing anti-cholera practices
    and policies

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Ocean Climate Influences V. cholerae Outbreaks
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New Methods to Monitor Oceanic V. cholerae
  • Satillite surveillance of ocean temperatures
  • Monitoring of copepod and phytoplankton blooms
  • Monitoring of oceanic phages that kill V.
    cholerae
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