Mahrukh Naqvi #17 Cholera
Self Introduction
Mahrukh Naqvi, Dublin Jerome, 2018
The Ohio State University, University of Michigan, University of Cincinnati, majoring in Pre-med with a second minor in either Business, Journalism, Political Science
Senior at Dublin Jerome High School, President of Key Club, Work at a pizza shop, volunteers at clinic. I enjoy helping others and hope to one day save lives.
Cholera affects numerous individuals in Pakistan, the country i am from, because the deficiency in education and funding prevents proper filtration. Want to research to look for methods of countering.
Cholera is an infectious bacterial disease that is often fatal if no treatment is provided. It is common in third-world countries with an estimated 3-5 million cases yearly.
Thesis Statement
Cholera is an extremely virulent disease which is caused by consuming water and food contaminated with Vibrio Cholerae. The methods of treatment include proper water filtration.
Low level
Filtered water
Vibrio Cholerae is bacteria which comes into food / water and can make people sick. Cholera has existed for a long time, but it began to affect more people when trading and communication between different countries increased. There have been 7 pandemics of this disease.
Unfiltered water/Countries with bad sanitation systems/Water has poop or from someone else with cholera.
A stranger uses a key to get into a bakery. They break in and go through each room, looking for things to steal. Usually, when a cupcake isn’t baked right, it is thrown away. The stranger doesn’t discard the bad cupcakes, and actually gives them to people, which makes the people sick too. The sick people start a rebellion and burn the city down, and start breaking into bakeries too.
Replacing the normal level of liquids and salts as soon as possible.
Med Level
Description
b/c Vibrio Cholerae is a virus, it is difficult to directly place its origin. The first recorded cases of an illness with symptoms similar to Cholera was in India in 1583. Cholera did undergo massive amplification during the Industrial Revolution of the mid-19th Century, where it traveled from the Ganges River. There have been 7 pandemics of this disease. People get the disease by drinking water contaminated with Vibrio Cholerae.
Mechanism
Cholera toxin binds to enterocytes. This process triggers endocytosis of toxin. The A and B fragments of Cholera are cleaved. A1 fragment of the Cholera toxin enters cytosol/activates the G protein, locks the G protein in its GTP bound form. Continuously stimulating adenylate cyclase to produce cAMP, which activate cystic fibrosis transmembrane, causing release of ions and water from infected enterocytes.
Analogy
In bakery, 2 robbers enter. Robber A (A1 fragment) locks manager G (G protein) into the kitchen. Robber A forces manager G to be in their yelling mode. Manager G yells at bakers (adenylate cyclase) to produce cupcakes that are poisoned. The cupcakes are sold to the people, and they are poisoned so everyone pukes and pees.
Professional
Epidemiology
Impoverished areas with lack of filtration system.Haiti, India, Pakistan, Syria. Lack of sewage infrastructure
Has existed for centuries, and the Pandemics have killed numerous individuals. Cases have decreased with modernization in filtration systems and sewage systems
3-5 Million
7 pandemics. 100,000-120,000 die annually
Symptoms
Diarrhea, Nausea, Vomiting, Irritability, Lethargy, dry mouth, extreme thirst, sunken eyes and skin
Diagnosis: Stool Samples, rapid immunochromatic dipstick testing blood for antibodies
Cholera toxin has 6 protein subunits. 1 copy of A subunit and 5 copies of B subunit, which are connected by disulfide bond.
When cholera toxin is released from bacteria, it binds to enterocytes (intestinal cells) because the pentameric B subunit of Cholera binds with the GM1 ganglioside receptor on the intestinal cell.
This binding causes the endocytosis of toxin
Lipid raft/caveolae mediated endocytic pathway
Clathrin mediated endocytic pathway
ARF6 associated associated endocytic pathway
Cholera travels to endoplasmic reticulum. A subunit dissociates from B subunit of Cholera
The KDEL signal is transported to ER in retrograde fashion and serves to retrieve the Cholera subunit A from the golgi apparatus to the ER.
This subunit has ADP ribosylation activity of CT. Entry of CTA1 into cytosol is avoided because the ER associated degradation pathway (degradation of misfolded proteins) is avoided because CTA1 has low lysine content which is a signal for ubiquitination
CTA1 unfolds and refolds during degradosome reduction by protein disulphide isomerase and re oxidation by Ero1 also occurs.
CTA1 catalyzes ADP ribosylation of trimeric Gsa component of AC. This causes AC to remain in GTP state, which is a form that continuously activates adenylate cyclase to produces cAMP. cAMP in high concentrations activate cystic fibrosis transmembrane conductance regulator, which causes water and ions to efflux from infected enterocytes. This causes the water release in patients with Cholera.
Key Molecules/Proteins
Subunit A: ADP ribosylation activity of CT resides in CTA1. CTA is surrounded by the peripheral B units, as Subunit A is the enzyme. This allows the dissociation of the Subunit A and the SUbunit B to occur rapidly.
KDEL Signal: serves for the retrieval of the dissociated CTA from the Golgi apparatus to the ER. It is a peptide sequence. KDEL stands for the amino acid sequence of lysine, aspartic acid, glutamic acid, leucine. As a result, the deficiency in CTA1’s content for lysine causes the degradation pathway linked to the ER to be broken
GM1 ganglioside is the intestinal binding receptor for cholera toxin.
Adenylyl cyclase is an enzyme which catalyzes the cyclization of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP)
cAMP is a derivative of adenosine triphosphate (ATP and is used for intracellular signal transduction, like transferring hormones into cell. It is also involved in the activation of protein kinases. cAMP binds to and regulates the function of ion channels such as the HCN channels and a few other cyclic nucleotide-binding proteins. High levels of this molecule activates the cystic fibrosis transmembrane conductance regulator.
CFTR is as an ATP powered anion channel, which increasing the conductance for certain anions to flow down their electrochemical gradient. ATP-driven conformational changes in CFTR open and close a gate to allow transmembrane flow of anions down their electrochemical gradient. This allows the water and ions to efflux from the membrane, and also causes the massive loss of water in cholera patients.
Symptoms molecular mechanism
Diarrhea is caused by the efflux of water and ions from the CFTR membrane which is caused by the high levels of cAMP. This change results in prolonged opening of the chloride channels that are instrumental in secretion of water from the crypts, uncontrolled secretion of water. Additionally, cholera toxin affects the enteric nervous system, resulting in an independent stimulus of secretion. The excessive levels of water which are delivered to the small intestinal lumen cannot be absorbed.
The deficiency of water causes the extreme dehydration. Since electrolyte imbalance, which is often associated with diarrhea because the sodium absorption capabilities of the villi are damaged. The loss of electrolytes can lead to muscle cramps due to lack of salts in muscle tissue and shock. This drop of blood pressure and oxygen in the body will lead to hypovolemic shock and subsequently death in a matter of minutes.
Treatment:
There is a vaccine against cholera, but it does not necessarily protect over half the people who consume the vaccine and provides protection for only a couple of months. The main treatment or cholera is rehydration, in order to replace the lost fluids. Antibiotics can kill the bacteria, therefore shortening the duration of the disease by half and reduce the excretion of the bacteria. Since cholera is transmitted through fecal matter, antibiotics help diminish the transmission of the bacteria.
Vaxhora is the vaccine which is a live, weakened vaccine that consists of an orally taken liquid dose of 3 ounces.Other antibiotics include noroxin, azithromycin, erythromycin. Trimethoprim.
Doxycycline inhibits protein synthesis which therefore inhibits Cholera bacterial growth. Tetracycline inhibits bacterial protein synthesis through the binding of 30s and 50s subunits. Azithromycin acts by binding to 50s ribosomes and blocks dissociation of peptidyl tRNA from ribosomes. Trimethoprim is a dihydrofolate reductase inhibitor that prevents tetrahydrofolic acid production in bacteria.
Pubmed
Dr. Paul Farmer in Massachusetts is a major driving force for the increase of treatment in Haiti and other developed areas for Cholera.
Professor Oded Lewinson at the Technion-Israel Institute of Technology combined organic acids and metals at a low concentration finding that the combination is effective in eradicating pathogenic bacteria such as cholera from news-medical.net
Dr. Clemens completed research on the consummation of a BS/whole cell vaccine for cholera in Bangladesh
Dr. Eric Mintz is cholera expert at the Centers for Disease Control and Prevention and is studying vaccine options from Atlanta
Trials
Dr. Clemens from the United States initiated the trial. Sponsored by the University of Chicago in 1988.
Dr. Mintz from the United States began a trial which was funded by the Bill and Melinda Gates Foundations and assisted by Partners in Health. The vaccine was developed in 1990 in South Korea, but has been altered and improved since. Clinical trials for the newest version commenced in 2016.
There is not research on Cholera in Nationwide Children’s
I researched the information through various online sources, including:
I found that Cholera vaccine has not been widely provided to most patients of Cholera and populations at risk, however the risk
I would consider the most effective methods to distribute the vaccine, and I would also consider the general costs of water purification systems, since the contaminated water most likely is linked to other health complications and Cholera can be treated with rehydration if found early enough. I would also consider the costs of the vaccine, and perhaps work with other international organizations to maximize publicity.
My interest in the disease comes from the fact that Cholera is an incredibly prominent disease internationally, yet it can be combatted with water purification. I do think that the treatment for Cholera can be improved internationally, and I do not think that all the necessary steps are being taken to eliminate the disease.
I would continue to teach the importance of education the masses on water purification, as well as providing methods to purify water with few materials and equipment. I also would develop vaccines and increase the accessibility of antibiotics to decrease the amount of cases internationally
I would potentially collaborate with other researchers to alter their research into a feasible vaccine. I also believe that the efforts to create a complete vaccine are scattered, so I would work to unify the branches to create the optimal product.
I would do so by networking with various organizations and research universities, as well as requesting grants.
I would prepare by accumulating as much research as possible on the disease, as well as explaining the worldwide prevalence of the disease in order to convey the absolute necessity for a reevaluation of current prevention methods.
I would apply to the National Institute of Environmental Health Sciences (NIEHS) because Cholera is deeply rooted in factors dependent upon the environment
I would apply to the NIH Exploratory/Developmental Research Grant Award (R21) in order to maximize the variety of research and treatments which are used. I believe that much of the research which can be completed on cholera could be used to treat other bacterial diseases, which is why a common, innovative research grant which would be provided by the Exploratory Research Grant would be incredibly beneficial to all bacterial diseases. I do think that a 2 year span would be a bit short, but I feel that the united efforts of all global institutions which are in the process of fighting cholera could effectively develop a solution in that time frame.
Globally, a new health solution would only be effective if actually given to the patients. Since majority of those affected are underprivileged, impoverished individuals, their capabilities for affording treatment are limited as well. As a result, the only proper way for a global change to truly occur would be to provide a low-cost solution coupled with filtration treatments and educational resources to prevent the spread of Vibrio Cholerae. If this is done effectively, then the illnesses and health deficiencies associated with consuming contaminated water would also diminish, thereby decreasing the number of deaths with a common illness.