Question

. A male student that attends a 4 year College majoring in Arts and music felt sick for a day with diarrhea he took some medication and felt fine. 8 days later he had a second round of diarrhea this time it was much worse and lasted most of the day. Again with somewhat more medication he was fine. 5 days later he had a 3rd round of diarrhea that was much worse and included vomiting. He was bed ridden the next day his symptoms continued with fever. 1. What disease does he have? Name the causative agent. 2. How did he become infected with this microbe? Explain the pathogenesis of this disease. 3. What is the virulence factor and how would you treat this disease? 4. How would the immune system deal with this case and why? 5. Why Doctors could only treat the symptoms before and not the disease and why death may result from it?

Answer 1

He is suffering from Cholera. The causative agent is Vibrio cholerae

He must have consumed unsafe water or unsafe food, most likely contaminated by human faeces bacteria. Other possibility is consumption of uncooked seafood.

Pathogenicity: V.cholerae release cholera toxin into the intestinal lumen by piston-like molecular pumps, soon after colonizing the small intestine. Cholera toxin belongs to AB toxin family and has a toxigenic A subgroup and an adhesive B subgroup. Each CT(B) monomer can have non-covalent interaction with GM1 ganglioside which associates the toxin with lipid rafts. This is critical to cholera toxicity. After this binding has taken place, CT enters the cell by endocytosis and reaches Endoplasmic reticulum (ER) by retrograde transport pathway. In the ER lumen, CTA1 chain activates ER associated degradation pathway. In this, disulphide linkage between two subunits of A chain is reduced, protein disulphide isomerase binds CTA1 causing monomeric chain to unfold and releases it to ER lumen. CT1 now exits into cytosol from ER where endogenous ERAD substrates are ubiquitinated and degraded by proteasome. CTA1 that escapes degradation, refolds with the help of ADP ribosylation factor 6 (ARF6). The properly folded CTA1 is activated by binding to ARF6, which acts to inhibit GTPase activity of the G subunit and constitutively activating adenylyl cyclase to increase intracellular cAMP concentration. cAMP activates protein kinase A instead, which activates cystic fibrosis conductance regulator (CFTR). Phosphorylation brings about conformational change which opens ion channels and allow chloride ion flow down the chemical gradient. Extracellular chloride concentration increases and chemiosmotic imbalance occurs in the system. Thus, sodium outflow occurs from enterocytes and water secretion increases so as to compensate for high amount of extracellular electrolyte. This causes excessive fluid loss from the intestine and leads to symptomatic cholera.

Virulence of V.cholerae is due to its enterotoxin. Treatment of cholera can be made by:

Fluids: successfully treated with oral rehydration therapy, rice-based solutions and ringer’s lactate with added potassium can be administered as well

Electrolytes: consuming food high in potassium contents will be good, to avoid condition of sudden depletion of potassium as dehydration is corrected

Antibiotics: Doxycycline, cotrimoxazole, erythromycin, tetracycline, chloramphenicol

Zinc supplementation can be done, but in cases of children, not in the current situation

Intravenous or oral route of administering drug is done. This induces effective priming and boosting of mucosal antibodies which helps in synthesis of IgA in intestine. This acts as an antitoxin.

5. Death occurs mostly due to profuse diarrhea and dehydration.