Diarrheal Diseases in Developing Countries

Diarrheal Diseases in Developing CountriesKathleen HannanBiol402

http://www.treehugger.com/files/2009/10/one-million-children-die-diarrhea-unsafe-drinking-water-no-handwashing-to-blame.phpIt is most commonly caused by gastrointestinal infections which kill around 2.2 million people globally each year, mostly children in developing countries

1OutlineWhat are diarrheal diseases?Causes & transmissionWorldwide impactRotavirusBiology and how it makes you sickSolutionsORTVaccinesWhat are diarrheal diseases?http://www.ncbi.nlm.nih.gov/books/bookres.fcgi/dcp2/ch19.pdfDef: when three or more stools are passed in 24 hours that are sufficiently liquid to take the shape of the container in which they are placed

3Syndromic DiagnosisAcute watery diarrheaPersistent diarrheaBloody diarrheahttp://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dcp2&part=A2526Syndromic diagnosis provides important clues to optimal management and is both programmatically and epidemiologically relevant.

They are acute watery diarrhea, which results in varying degrees of dehydration; persistent diarrhea, which lasts 14 days or longer, manifested by malabsorption, nutrient losses, and wasting; and bloody diarrhea, which is a sign of the intestinal damage caused by inflammation

Pakistan, persistent diarrhea accounted for 8 to 18 percent of episodes but 54 percent of deaths (Khan and others 1993). In Bangladesh, persistent diarrhea associated with malnutrition was responsible for nearly half of diarrhea deaths, and the relative risk for death among infants with persistent diarrhea and severe malnutrition was 17 times greater than for those with mild malnutrition (Fauveau and others 1992).4CausesViruses BacteriaProtozoaHelminths (intestinal parasite)http://www.nlm.nih.gov/medlineplus/ency/imagepages/1003.htm

Diarrhea is caused by infectious organisms, including viruses, bacteria, protozoa, and helminths, that are transmitted from the stool of one individual to the mouth of another, termed fecaloral transmission.

Pic: hookworms attached to intestinal mucosa5TransmissionFecal-oral transmissionAmong bacteria survival in stomach

http://www.genomenewsnetwork.org/articles/11_02/shigella.shtmlExample of another necessity for transmission is in bacteria:

Shigella bacteria are resistant to low pH, and a few thousand organisms suffice, which are readily transferred by direct person-to-person contact or through contamination of inanimate objects, such as a cup. In contrast, bacteria readily killed by acid, such as Vibrio cholerae, require millions of organisms to cause illness, and therefore must first multiply in food or water to an infectious dose. Some Salmonella bacteria selectively infect humans or animals, but most are not adapted to a specific host

Pic: Highly infectious microbe Shigella flexneri. 6ExamplesRotavirusSalmonellaShigellaeCampylobacter jejuniVibrio CholeraeEscherichia coliGiardiaEntamoebahttp://dcc2.bumc.bu.edu/IH887/presentatons99/Diarrh/prevention_and_control_of_diarrh.htm

http://www.skyhighway.com/~multispecies/about.htmlLast two are protozoan pathogens

Pic: Salmonella typhimurium7Impact on Developing CountriesKills ~1.7 million children annuallyMalnutrition4,500 deaths every single day

http://www.isaartrust.com/Pediatric death toll > AIDS, tuberculosis, and malaria combinedMalnutrition and diarrheal diseases are linked in a complex, vicious cycleRepeated bouts of diarrhea and persistent diarrheal diseasetypically 2 to 10 episodes of diarrhea annually per childradically impairs gut function, which is the single greatest contributor to childhood malnutrition and growth retardation.In poor countries, diarrheal disease is second only to pneumonia in causing the deaths of children under five years old. Every week, 31,000 children in low-income countries die from diarrheal diseases approximately 4,500 deaths every single day.

8Worldwide distribution of deaths caused by diarrhea in children under 5 in 2000

http://www.jci.org/articles/view/34005/files/JCI0834005.f1/mediumA closer look at rotavirus

http://web.ebscohost.com.libproxy.lib.unc.edu/ehost/pdf?vid=2&hid=9&sid=77f6bf31-d409-4038-ba94-0753e4b88e39%40sessionmgr10Rotavirus is estimated to cause 6% of diarrhea episodes and 20% of deaths due to diarrhea in developing countries in children under 5Although mortality due to rotavirus infections is much higher in developing than in developed countries, frequency of infection is remarkably similar

Because rotaviruses play such an important role in severe dehydrating gastroenteritis AND because even advanced levels of hygiene appear unable to control the spread of rotavirus infections, there has been considerable interest in developing effective vaccination and therapeutic strategies.11Rotavirus Particlehttp://www.sciencedirect.com.libproxy.lib.unc.edu/science?_ob=MiamiCaptionURL&_method=retrieve&_udi=B6VNM-46R67HV-7&_image=fig1&_ba=1&_user=130907&_coverDate=08%2F31%2F2002&_rdoc=1&_fmt=full&_orig=search&_cdi=6182&_issn=01884409&_pii=S0188440902003740&view=c&_acct=C000004198&_version=1&_urlVersion=0&_userid=130907&md5=acfbb149e9396472a6e49c7fa17fbbbb

Three-dimensional reconstruction of a mature, triple-layered rotavirus particle. Image obtained by cryoelectron microscopy. Part of the middle and outer protein layers were cut away to show the inner structure of the virus

Non-enveloped virusesThe mature virion is formed by three concentric layers of protein that enclose a genome composed of 11 segments of double-stranded RNAInnermost layer: VP2 protein dimmersSurround viral genome and 12 copies of both RNA polymerase and guanylyltransferase Intermediate layer: VP6 trimersOutermost layer: VP4 and VP7Smooth external surface (from VP7)May interact with cell surface molecules after initial attachment60 spike-like structures of VP4 dimersVP4 essential in life cycle of virusInvolved in receptor binding and cell penetration

Rotaviruses have a very specific cell tropism, infecting only enterocytes (intestinal absorptive cells) on the tip of the intestinal villi, which suggests that specific host receptors must exist not specifically known

12How does it make you sick?How does it make you sick?We dont really know, but there are some general ideas!How does it make you sick?Enterocyte KillingMaldigestion of carbohydratesEnterotoxin NSP4rotavirus infection kills off most of the mature enterocytes (intestinal absorptive cells), causing a decrease in the digestive and absorptive capacities of the intestinehence generating a malabsorption type of diarrhea

Rotavirus infection induces maldigestion of carbohydrates and their accumulation in the intestinal lumen And malabsorption of nutrients and also inhibition of water reabsorption

Enterotoxin NSP4Enterotoxin= protein toxin released by a microorganism in the intestinewhile NSP4 induces diarrhea in young mice, its importance in chloride secretion remains unresolvednot the same as bacterial enterotoxinsCa2+-dependent transepithelial Cl- secretionrotavirus has been shown to impair Na+-solute symport activities, hence contributing to massive water loss all along the small intestinal crypt-villus axisNSP4 was also able to directly and specifically inhibit SGLT1

15What needs to be done to address this problem?Gates Foundation ApproachVaccinationOral rehydration therapy (ORT)Nutrition, sanitation, water, and hygiene

Research biomarkers / host mechanisms

Existing vaccines for rotavirus, cholera, and typhoid could address approximately 25 percent of child deaths due to enteric and diarrheal diseasesdevelop low-cost versions of these vaccinesalso supporting the development of new vaccines against Escherichia coli (ETEC) and Shigella.

Biomarkers are elements in the body that can be detected and measured to detect disease (for example, measuring body temperature for fever).identify biomarkers for diarrheal-related conditions, which will help the development of new vaccines and better nutritional and drug treatments.

deliver oral rehydration therapy (ORT) one of the most effective treatments for diarrheain combination with zinc to decrease the length of time children suffer from diarrhea

17Looking specifically at ORTA simple mixture of sugar and electrolytes costs as little as 10 cents and can be given in the home to rehydrate children who have lost fluids due to diarrhea.

Oral rehydration therapy (ORT) also focuses on replacing lost fluids through breast milk, rice water mixed wit salt, soups, and cereals.18

Normally, the high extracellular Na+ concentration drives the influx of glucose via symportSodium-glucose cotransport across apical surface of intestinal epithelial cells accumulates glucose in cell against its concentration gradient

take up dietary sugars and amino acids from the lumen of the intestine. The uptake of glucose is carried out by a transporter that coordinately transports two Na+ and one glucose into the cellThe flow of Na+ down its electrochemical gradient provides the energy required to take up dietary glucose and to accumulate high intracellular glucose concentrations.

19Using Oral Rehydration Treatment.

http://rehydrate.org/ors/ort-how-it-works.htmHowever, when someone is suffering from diarrhea, the Na+ is leaving the body too quickly to be used to drive the symport

Thus, a Simple a saline solution (water plus Na+) by mouth has no beneficial effect because the normal mechanism by which Na+ is absorbed by the healthy intestinal wall is impaired in the diarrheal stateif the Na+ is not absorbed neither can the water be absorbed Actually, excess Na+ in the lumen of the intestine causes increased secretion of water and the diarrhea worsens.

If glucose is added to a saline solution, now glucose molecules are absorbed through the intestinal wall - unaffected by the diarrheal disease statein conjunction sodium is carried through by a co-transport coupling mechanism opposite of how it usually occurs

co-transport of sodium and glucose which the Lancet described as "potentially the most important medical advance this century"

glucose does not co-transport water - rather it is the now increased relative concentration of Na+ across the intestinal wall which pulls water through after it.

other molecules apart from glucose have a similar capacity to co-transport Na+ including: aminoacids (e.g. glycine), dipeptides, tripeptides

absorption of these molecules may occur independently of each other at different sites effect=additive. Research is currently being carried on to utilize these additive effects to develop a multi-component "Super ORS".

20SGLT (Na+/glucose cotransport)

http://bcsb.lbl.gov/wiki/index.php/Scientific_Highlightshttp://www.jbc.org/content/269/21/15204.long

Intestinal uptake of dietary glucose and galactose is mediated by the SGLTl Na+/glucose cotransporter of the brush border. An SGLTl missense mutation underlies hereditary glucose/galactose malabsorption, characterized by potentially fatal diarrhea; conversely, oral rehydration therapy exploits normal transport to alleviate life-threatening diarrhea of infectious origin

21

http://rehydrate.org/ors/ort.htmFinal thoughtsDiarrheal Disease is a serious problem facing the developing world!Disparities in care account for the deaths of thousands each yearSomething we get frequently and dont die of is causing too many deathsWorks CitedArias, Carlos F. et al "Molecular Biology of Rotavirus Cell Entry." Archives of Medical Research 33.4 (2002): 356-361. ScienceDirect. Web. 15 Mar. 2010. .Lorrot, Mathie, and Monique Vasseur "How Do the Rotavirus NSP4 and Bacterial Enterotoxins Lead Differently to Diarrhea?" Virology Journal 4.31 (2007): 1. Web. 15 Mar. 2010. .Keusch, Gerald T. et al"Diarrheal Diseases." Disease Control Priorities in Developing Countries. Ed. Dean T. Jamison. Washington, D.C.: IBRD/The World Bank and Oxford UP, 2006. 371-388. Online: . Parashar, Umesh D. et al "Rotavirus." Emerging Infectious Diseases 4.4 (1998): 561-571. Web. 15 Mar. 2010. .