1 / 20

MECHANISM, TREATMENT AND PREVENTION FOR CHOLERA

PHM142 Fall 2019 Instructor : Chesa Dojo Soeandy Coordinator: Jeffrey Henderson. MECHANISM, TREATMENT AND PREVENTION FOR CHOLERA. By: NAVDEEP MANGAT SHAHRUKH RAHMAN GEORGE CHEN PARVINDER SAHOTA Presented on: OCT 1, 2019. CONTENTS. OVERVIEW OF CHOLERA GPCR MECHANISM

bjorn
Télécharger la présentation

MECHANISM, TREATMENT AND PREVENTION FOR CHOLERA

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. PHM142 Fall 2019 Instructor: Chesa Dojo Soeandy Coordinator: Jeffrey Henderson MECHANISM, TREATMENT AND PREVENTION FOR CHOLERA By: NAVDEEP MANGAT SHAHRUKH RAHMAN GEORGE CHEN PARVINDER SAHOTA Presented on: OCT 1, 2019

  2. CONTENTS • OVERVIEW OF CHOLERA • GPCR MECHANISM • EFFECT OF CHOLERA TOXIN ON GPCR MECHANISM • TREATMENT • PREVENTION

  3. CHOLERA What is Cholera? • Infectious disease that causes severe diarrhea and dehydration How is it caused? • Ingesting food and water that's contaminated by Vibrio cholerae Epidemiology • Developing countries with poor sanitation • Limited outbreaks in developed countries Vibrio cholerae

  4. Cholera Epidemiology History - Around 1850 John Snow looked into the cholera epidemic in London- He had a theory that waste dumped into rivers near waterwellswould contaminate drinking water and spread disease- John mapped out infected victims and found almost all near the Broad Street Pump - He convinced town officials to remove the handle off the pump to prevent people from using it- As a result the cholera epidemic immediately came to an end- This was strong evidence that the contaminated water caused cholera, but people were still skeptical of his theory

  5. Discovery of Vibrio Cholerae - In 1854 cholera had reached Florence Italy - Filippo Pacini was interested in cholera and performed autopsies on cholera patients- With his microscope he observed the intestinal mucosa- He found a rod shaped bacteria and categorized it as water born (Vibrio), which we now refer to as Vibrio Cholerae

  6. GPCR MECHANISM

  7. GPCR is in the dormant state • Ligand binds to receptor and causes a conformational change • Receptor binds to the Gα subunitand alters the conformation of the coupled G-protein

  8. Conformational change promotes the release of GDP and binding of GTP to the Gα subunit • Leads to the separation of the Gα subunit and the Gβ-γ complex.

  9. Gα subunit binds to adenylate cyclase (transmembrane protein) and activates the production of cyclic AMP (cAMP) • In intestinal epithelial cells, ↑in [cAMP] -> activates Protein Kinase A (PKA) -> activates CFTR -> ↑ [Cl-] in lumen

  10. GTP is hydrolysed by GTPase to form GDP • Gα subunit dissociates from adenylate cyclase • Gα subunit and the Gβ-γ complex reassemble • GPCR is inactive

  11. Cholera Toxin

  12. Cholera toxin binds to GM1 via B subunit • Taken up by endocytosis • Travels in retrograde fashion to the endoplasmic reticulum

  13. Protein disulfide isomerase (PDI) cleaves A subunit into A1 and A2 peptides • Mimics a misfolded protein, causing cell machinery to send it to cytosol for degradation • A1 peptide associates with Sec61 transporter and goes to G proteins

  14. A1 peptide causes Gsα subunit to undergo ADP-ribosylation • Modified Gsα has internal GTPase activity inhibited • Locked in “on” state • Increased cAMP production

  15. Increased cAMP production → Increased PKA activity→ Increased activation of CFTR channels • Excess Cl- secreted into the intestinal lumen • Electrolyte imbalance • Cell responds by secreting excess water into the lumen • Cell absorption can’t keep up with excess secretion • Results in Cholera disease state

  16. TREATMENT • Minor: Oral rehydration solution • Severe: Intravenous fluids • Antibiotics (eg. Doxycycline), in conjunction with hydration • Chlorpromazine

  17. PREVENTION • Cook food thoroughly, and avoid raw foods • Build improved water filtration systems • Ensure proper hygiene rules are followed • Vaccinations (Shanchol, Dukoral)

  18. SUMMARY • Cholera is an infectious disease that causes severe diarrhea, dehydration, metabolic acidosis • Cholera toxins bind to plasma membrane of intestinal epithelial cells and lock the G-proteins in their GTP-bound active state • Results in: ↑ in intracellular [cAMP] -> activate Protein Kinase A (PKA) -> activate CFTR channels -> ↑ [Cl-] in lumen -> ↑ water and electrolytes in intestinal lumen -> eliminated in feces • The body loses high levels of water, electrolytes, bicarbonate • Treatment: Oral rehydration solution (minor ailment) or IV hydration (serious ailment) • Antibiotics can help treat severe symptoms • Prevention: Cook food well, improve water systems, vaccinations, proper hygiene

  19. REFERENCES Alhadeff, R., Vorobyov, I., Wool Yoon, H. and Warshel, A. (2018). Exploring the free-energy landscape of GPCR activation. [online] PNAS. Available at: https://www.pnas.org/content/115/41/10327 [Accessed 27 Sep. 2019]. DOI: 10.1073/pnas.1810316115 Finkelstein, R. (2019). Cholera, Vibrio cholerae O1 and O139, and Other Pathogenic Vibrios. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK8407/ [Accessed 25 Sep. 2019]. Frerichs, R.R. (n.d.). John Snow And The Broad Street Pump On The Trail Of An Epidemic. Retrieved from https://www.ph.ucla.edu/epi/snow/snowcricketarticle.html Holmgren J. Actions of cholera toxin and the prevention and treatment of cholera. Nature. 1981 July;292(1):413-417. Kaper J, Morris J, Levine M. Cholera. Clinical Microbiology Reviews. 1995 Jan;8(1):46, 56-59. Lodish, H., Berk, A., Zipursky, S., Matsudaira, P., Baltimore, D. and Darnell, J. (2019). G Protein –Coupled Receptors and Their Effectors. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK21718/ [Accessed 27 Sep. 2019]. The biology behind cholera. (n.d.). Retrieved from https://bigpictureeducation.com/biology-behind-cholera

More Related