What is cholera
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What is Cholera?. Cholera. A life-threatening secretory diarrhea induced by enterotoxin secreted by V. cholerae Water-borne illness caused by ingesting water/food contaminated by copepods infected by V. cholerae An enterotoxic enteropathy (a non-invasive diarrheal disease)

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What is Cholera?

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What is cholera

What is Cholera?


Cholera

Cholera

  • A life-threatening secretory diarrhea induced by enterotoxin secreted by V. cholerae

  • Water-borne illness caused by ingesting water/food contaminated by copepods infected by V. cholerae

  • An enterotoxic enteropathy (a non-invasive diarrheal disease)

  • A major epidemic disease


What is cholera

Recent Cholera Pandemics

  • 1-6th pandemic:

    • V. cholerae O1 biotype classical

    • 1817-1923, Asia, Africa, Europe, America and Australia

  • 7th pandemic:

    • V. cholerae O1 biotype El Tor

    • Began in Asia in 1961

    • Spread to other continents in 1970s and 1980s

    • Spread to Peru in 1991 and then to most of South & Central America and to U.S. & Canada

    • By 1995 in the Americas, >106 cases; 104 dead

  • 1993: Cholera in Bengal caused by O139

    may be cause of 8th pandemic


What is cholera

Vibrio

  • Vibrio cholerae--gastroenteritis

  • Vibrio parahaemolyticus -- gastroenteritis, wound infection, bacteremia

  • Vibrio vulnificus -- wound infection, bacteremia


V cholerae

V. cholerae

  • Grows in salt and fresh water

  • Endemic in areas of poor sanitation (India and Bangladesh ), transmitted by fecal-oral route

  • Can survive and multiply in brackish water by infecting copepods

  • Has over 150 identified serotypes based on O-antigen

  • Only O1 and O139 are toxigenic and cause Cholera disease


Classification o1 antigen

小川型 稻叶型 彦岛型

Classification: O1 Antigen


Classification other antigens

O139 Serogroup

In 1993, an entirely new serogroup (O139) cause an epidemic in Bangladesh.

O139 organisms produce a polysaccharide capsule but do not produce O1 LPS or O1 antigen.

Non-O1, Non-O139 Serogroup

Most are CT (cholera toxin) negative and are not associated with epidemic disease.

Classification: Other antigens


Profile of vibrio cholerae

Profile of vibrio cholerae

  • G-, curved or comma-shaped rods

  • Highly motile; polar flagellum

  • Sensitive to low pH and die rapidly in solutions below pH 6

  • Proliferate in summers

  • Cholera toxin

  • Pathogenic and nonpathogenic strains

    • 206 serogroups


What is cholera

Profile of vibrio cholerae

  • Similarities to Enterobacteriaceae

    • G-, Facultative anaerobes

    • Fermentative bacilli

  • Differences from Enterobacteriaceae

    • Polar flagella

    • Oxidase positive

  • Formerly classified together as Vibrionaceae

    • Primarily found in water sources

    • Cause gastrointestinal disease

    • Shown not closely related by molecular methods


What is cholera

Physiology of Vibrio

  • Broad temperature & pH range for growth on media

    • 18-37C

    • pH 7.0 - 9.0 (useful for enrichment)

  • Grow on variety of simple media including:

    • MacConkey’s agar

    • TCBS (Thiosulfate Citrate Bile salts Sucrose) agar

  • V. cholerae grow without salt

    • Most other vibrios are halophilic


People most at risk

People Most at Risk

People with low gastric acid levels (103 -105 CFU )

Children: 10 × more susceptible than adults

Elderly

Blood types

O>> B > A > AB


Period of communicability

Period of Communicability

During acute stage

A few days after recovery

By end of week, 70% of patients non-infectious

By end of third week, 98% non-infectious


Symptoms

Symptoms

  • Occur 2-3 days after consumption of contaminated food/water

  • Usually mild, or no symptoms at all

    • 75% asymptomatic

    • 20% mild disease

    • 2-5% severe

  • Vomiting

  • Cramps

  • Watery diarrhea (1L/h)

  • Without treatment, death in 18 h-several days


  • Cholera gravis

    Cholera Gravis (霍乱肌无力)

    More severe symptoms

    Rapid loss of body fluids

    6 liters/hour

    107 vibrios/mL

    Rapidly lose more than 10% of bodyweight

    Dehydration and shock

    Death within 12 hours or less

    Death can occur within 2-3 hours


    Virulent factors

    Pathogenesis of V. cholerae

    Virulent factors

    • Toxins and enzymes

      - heat stable endotoxin

      - enterotoxin (exotoxin [cholera toxin CT])

      CT is antigenically and pharmacologically identical in all sero and bio types


    Cholera toxin ct structure

    Cholera Toxin (CT) Structure

    • The A subunit contains an intracellular ADP-ribosyltransferase activity.

    • The mature A subunit is proteolytically cleaved to produce an A1 polypeptide, which contains the intracellular enzymatic activity, and an A2 polypeptide.

    • CT is a prototype A/B subunit toxin, 1A+5B

    • The B subunit form a pentameric ring, which binds the holotoxin to a eukaryotic cell surface receptor.


    Cholera toxin ct structure1

    Cholera Toxin (CT) Structure

    • After cleavage, the A1 and A2 polypeptides remain linked by a disulphide bond.

    • A and B subunits are connected through the C-terminus of the A2 subunit, which is inserted through the central pore of the B pentamer.


    How does cholera toxin work

    How Does Cholera Toxin Work?

    • The biological activity of CT is dependent on binding of B pentamer to specific receptors GM1 ganglioside.

    • Internalization is initiated once CT-GM1 complexes cluster which then invaginate to form apical endocytic vesicles.


    How does cholera toxin work1

    How Does Cholera Toxin Work?

    • These vesicles enter cellular trafficking pathways leading to the trans-Golgi network (TGN).

    • The toxin then moves retrograde via the Golgi cistern to the ER.

    • Once in the ER, CT is processed to activate the A1 peptide, which then targets the basolateral membrane (heterotrimeric GTPase and adenylate cyclase (AC)).


    How does cholera toxin work2

    How Does Cholera Toxin Work?

    • Adenylate cyclase (AC) is activated normally by a regulatory protein (GS) and GTP; however activation is normally brief because another regulatory protein (Gi), hydrolyzes GTP.

    NORMAL CONDITION


    How does cholera toxin work3

    CHOLERA

    How Does Cholera Toxin Work?

    • A1 fragment catalyzes the attachment of ADP-Ribose (ADPR) to the regulatory protein forming Gs-ADPR from which GTP cannot be hydrolyzed.

    • Since GTP hydrolysis is the event that inactivates the adenylate cyclase, the enzyme remains continually activated.


    How does cholera toxin work4

    How Does Cholera Toxin Work?

    • Thus, the net effect of the toxin is to cause cAMP to be produced at an abnormally high rate which stimulates mucosal cells to pump large amounts of Cl- into the intestinal contents.


    How does cholera toxin work5

    H2O, Na+ and other electrolytes follow due to the osmotic and electrical gradients caused by the loss of Cl-.

    The lost H2O and electrolytes in mucosal cells are replaced from the blood.

    Thus, the toxin-damaged cells become pumps for water and electrolytes causing the diarrhea, loss of electrolytes, and dehydration that are characteristic of cholera. 

    How Does Cholera Toxin Work?


    How does cholera toxin work6

    How Does Cholera Toxin Work?

    • Inactivates GTPase function of G-protein coupled receptors in intestinal cells

    • G proteins stuck in “On” position

    • 100 fold increase in cAMP

    • Activation of ion channels

    • Ions flow out and water follows


    Diagnosis

    Diagnosis

    • Cholera should be suspected when patients present with watery diarrhea, severe dehydration

    • Based on clinical presentation and confirmed by isolation of vibrio cholera from stool

    • No clinical manifestations help distinguish

      cholera from other causes of severe diarrhea:

      Enterotoxigenic E. coli

      Viral gastroenteritis

      Bacterial food poisoning


    Diagnosis visible symptoms

    Diagnosis: Visible Symptoms

    • Decreased skin turgor

    • Sunken eyes, cheeks

    • Almost no urine production

    • Dry mucous membranes

    • Watery diarrhea consists of:

      • fluid without RBC, proteins

      • electrolytes

      • enormous numbers of vibrio cholera

        (107 vibrios/mL)


    Laboratory diagnosis

    Laboratory Diagnosis

    • Visualization by dark field or phase microscopy

      • Look like “shooting stars”

  • Gram Stain

    • Red, curved rods of bacteria

  • Isolate V. cholerae from patient’s stool

    • Plate on sucrose agar

    • Yellow colonies form


  • Vibrio prevention control

    VibrioPrevention & Control

    • Disrupt fecal-oral transmission

      Improved sanitation

    • Fluid and electrolyte replacement

    • Antibiotic prophylaxis

    • Improved food handling


    Vibrio parahemolyticus

    Vibrio parahemolyticus

    • One kind of halophilic vibrios;

    • optimal NaCl concentration contained in culture media is 3.5%;

    • hemolysin related to its pathogenicity, can be detected by human or rabbit RBC test (Kanagawa test);

    • cause food poisoning in human beings.

    • raw sea-food


    Vibrio parahemolyticus1

    Vibrio parahemolyticus

    • Clinical manifestations

      • Self-limiting diarrhea to mild cholera-like illness

      • 24 hours after ingestion-explosive water diarrhea

        • Headache, abdominal cramps, nausea, vomiting, low grade fever for 72 hours or more

        • Uneventful recovery

        • Wound infections in people exposed to seawater-containing vibrios


    What is cholera

    Helicobacter pylori


    What is cholera

    Helicobacter pylori

    • G- with S or spiral-shaped

    • Very Motile ---corkscrew motion

    • 2~6 flagella at one end of HP

    • 5% O2+10% CO2 at 37 oC

    • Reaction of urea hydrolysis and creates an ammonia cloud


    Pathogenesis of hp

    Pathogenesis of Hp

    CagA (Cytotoxin associated)

    VacA (vacuolationg associated)

    LPS also play great importance

    Flagellum and urease is necessary for its adhesion and inhabitation

    Adhesin


    What is cholera

    Duodenal Ulcer (DU)

    Gastric Ulcer (GU)


    What is cholera

    Campylobacter jejuni

    • G- rods with comma, S, or “gull-wing” shapes.

    • Motive, with a single polar flagellum

    • No spore & no capsule

    • 5% O2+10% CO2

    • Two types of colonies:

       watery and spreading

      round and convex


    What is cholera

    Pathogenesis of Campylobacter

    • Produces a toxin called Cytolethal Distending Toxin (CDT).

    • CDT activity requires activation of three genes: cdtA, cdtB, and cdtC.

    • CdtB is nuclease that damages DNA and causes cell cycle arrest.

    • Causes cell death.


    What are the symptoms

    What Are the Symptoms?

    • Diarrhea

      • Usually watery and sticky

      • Can contain blood and fecal leucocytes

    • Fever

    • Abdominal pain

    • Nausea and vomiting

    • Headache

    • Muscle pain


    Who is affected

    Who is affected?

    • All warm-blooded animals can become affected. Some animals carry the disease without exhibiting symptoms.

    • Any person can become infected.

    • Children under 5 and young adults ages 15-29 are most often affected.

    • Most deaths occur among the elderly and the immune-suppressed.


    Summary

    Summary

    • Properties of Vibrio (stain, culture, biochemical reaction, antigens and virulence factors)

    • Pathogenesis of V. parahemolyticus, H. pylori, C. jejuni


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