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Case 4 – PATH 417A Signs and Symptoms: There are several signs and symptoms present in Ronnie’s medical history that could reveal the nature of the bacteria infecting him. The signs include the low grade fever, the results of the stool sample and the bloodwork. The symptoms Ronnie experiences include the abdominal cramps, bloody diarrhea, fever, and peri-umbilical tenderness. Although many of the symptoms and signs listed above are non-specific, in combination, they hint towards two individual bacterial species. The first of which is the enteric illness causing Campylobacter. Jejuni. C. jejuni, infection usually manifests within 2-5 days after consumption of undercooked meat contaminated with animal feces, primarily poultry. Illness is associated with bloody diarrhea, fever, abdominal cramps and peri-umbilical pain1 fitting well with Ronnie’s case. The second putative cause of the patient’s symptoms could be E. coli O157:H7. This strain of E.coli causes gastritis 3-4 days after exposure to undercooked meat/beef hence it is commonly called the “hamburger disease”. Infection commonly presents with bloody diarrhea, low grade or no fever, and abdominal cramps2. Anatomy and Function of Affected Areas The primary site of infection for both C. jejuni and E. coli O157:H7 is the gastrointestinal tract. The specific cell type infected by the bacterium is the epithelial cell layer or gut enterocytes3. The bacteria are both ingested via the mouth and pass through the esophagus and stomach to the small intestine. Here the bacteria can attach to epithelial cells, invade, and initiate various apoptotic and inflammatory effects leading to the symptoms of gastroenteritis. The Anatomy of the GI Tract4 Component Mouth Pharynx and Esophagus Function + Anatomy The mouth serves as the external opening to the GI tract. The smell/taste/thought of food triggers salivary glands inside it to secrete saliva. The mouth possesses teeth which aid in the mechanical digestion of food. The bacteria present on the hamburger enters the body in this way. The pharynx/throat receives food from the mouth and branches off to the esophagus. Food enters the pharynx and via movement of a flap called the epiglottis during the process of swallowing. Depression of the epiglottis prevents food from entering the trachea and the lungs. During swallowing the tongue and soft palate (roof of mouth) push food into the pharynx and cause closure of the epiglottis. The food and bacteria now enter the esophagus. Muscular contractions called peristalsis pushes the food through the esophagus. Near the end of the esophagus, the lower esophageal sphincter controls food entry into the stomach. The LES prevents stomach acid from entering the esophagus and causing heartburn. Stomach Small and Large Intestine Rectum/anus The stomach is a muscular sac that serves to mix and grind food mechanically and to break down food products chemically through the secretion of several enzymes as well as hydrochloric acid. The stomach wall like the entire GI tract is covered with mucous and protective factors to prevent auto-digestion (ulcers). The small intestine is made up of 3 segments the duodenum, jejunum, and ileum. The duodenum secretes several digestive enzymes as well as accepting enzymes released from the gall bladder to further chemical breakdown of food. The small intestine serves as the primary site of nutrient/water absorption and the large intestine acts to reabsorb any remaining water. Food moves through the small intestine both via peristalsis and segmentation and through the large intestine via mass movements as well. The rectum is a short chamber that connects the LI to the anus and stores fecal matter before defecation. The anus serves as the exit site for food ingested through the mouth and completes the GI tract. Impaired Physiology of the GI Tract C. jejuni Intestinal epithelial cells or gut enterocytes are normally covered in a thick mucous layer that prevents entry of intestinal bacteria into underlying cells. The flagellum of C. jejuni is able to corkscrew through this layer and adhere to or invade enterocytes5. The entry is mediated by the stimulation of normal host protein kinases by bacterial effectors. C. jejuni secretes both hemolysins and a cytolethal distending toxin which causes certain cell types to become distended resulting in cell death. CDT also disturbs the survival and maturation of crypt cells into functional villus cells and, as a result, impairs the absorptive functions of the small intestine5. CDT is also thought to cause immunosuppression therefore preventing the body from effectively dealing with intestinal bacteria7. The bacterium also expresses several iron-acquisition systems that impair the normal sequestration and storage of iron in enterocytes and bound to proteins in blood. The release of iron can result in the proliferation of gut bacteria that were previously limited by iron scarcity. The bacteria are also able to convert ROS like superoxides into peroxide and as such circumvent the normal defense strategies of the gut cells. The bacterium also induces changes in the conformation of polarized epithelial cells leading to impaired barrier function and increased permeability. This can cause water leakage back into the gut lumen and subsequent diarrhea6. Dehydration results as the reabsorption of water in the gut is impaired. The many mechanisms by which C. jejuni induces cell death including toxins, induction of cytotoxic Tcells, and inflammatory mediators, causes destruction of the intestinal wall. This leads to a loss of the structural integrity of the gut barrier allowing entry of commensals into the blood and intestinal cells which can initiate their own infection. Additionally, loss of villi again reduces the absorptive capacity of the intestine. E. coli O157:H7 One of the major E. coli virulence factors is the cytotoxic Shiga toxin which induces cell death by inhibition of protein synthesis9. The toxin directly damages mucosal cells and vascular endothelial cells in the gut wall8. The bacteria also cause effacement of the intestinal microvilli causing decreased surface area for absorption. This is done via a bacterial Stx2 holotoxin which causes miss-targeting of important brush border proteins such as villin. Additionally, E. coli decreases ion reabsorption via secretion of effectors through a T3SS. This can cause increased osmolality in the gut lumen leading to diarrhea. The build up of water in the intestinal lumen also results in villus cell death leading to reduced nutrient reabsorption10. Secondary Sites of Infection C. jejuni Infection of C. jejuni typically resolves within a week, however Guillain-Barre syndrome is a common following infection. This is due to the fact that C. jejuni causes autoimmune disease through molecular micmicry. Campylobacter contains ganglioside like epitopes that cause formation of autoantibodies that react with peripheral nerves leading to acute flaccid paralysis due to demyelination11. Another autoimmune syndrome linked to spread of C.jejuni to joints is reactive arthritis which can in time lead to chronic arthritis. In immunocompromised patients, infection may spread to other parts of the body including the heart, bloodstream, appendix, gall bladder, central nervous system, colon, urinary tract, and abdominal cavity12. Spread of the bacteria to the blood (bacteremia) can cause hemolytic anemia or hemolytic uremic syndrome in response to bacterial hemotoxins, endotoxins, and the effect of the immunocomplex on the vascular endothelium13,14. Carditis, encephalopathy, osteromyelitis, and uveitis are also postinfectious extra-intestinal complications that are possible. The bacteria are able to spread to these sites via apoptotic effects on the intestinal and vascular epithelium. The bacterium first adheres to intestinal enterocytes, invades, causes cell lysis and moves into the underlying tissue and blood vessels. The bacteria migrate to other body sites via the blood network and via expression of endotoxins that cause lysis of vascular cell walls. In this way C. jejuni enters distant tissues and establishes secondary infection. In most cases, C. jejuni only causes a localized infection in the gut and does not spread systemically, however highly virulent C. jejuni strains may be able to penetrate the epithelial barrier and spread to extraintestinal sites, such as the liver, gallbladder, pancreas, uterus, and fetal tissues20. The spread is heavily dependent on flagellar motility as well as chemotaxic ability mediated by agglutination, attachment, and biofilm formation. Bacteremia is highly uncommon in the case of C. jejuni infection but has been known to occur in immunocompromised individuals and has increased prevalence in those > 6519. Years of age. Systemic infection with the bacteria such as those described above does not occur with most diarrheal strains and requires specific variants possessing persistence genes and mechanisms that allow survival in the bloodstream18. E. coli O157:H7 After infection with E.coli the bacteria rapidly multiply in the intestine and secrete Shiga toxin. Bacteria stimulate macropinocytosis of the toxin via actin remodeling. After absorption of the toxin into the intestinal capillaries, transcytosis occurs to the basolateral environment21. Once Shiga toxin has escaped into systemic circulation via intestinal capillaries, it binds weakly to receptors on white blood cells. On the WBC’s the bacteria travel to the kidneys where they are transferred via strong binding to Gb3 receptors. These receptors are also present on other organs such as the brain or pancreas and site of secondary infection depends primarily on the density of receptor expression in each tissue type. The toxin enters glomerular endothelial cells, podocytes, and tubular epithelia cells in the kidney, causing kidney damage9. The toxin shuts down protein synthesis causing cell death and injury. The injury activates blood platelets causing a coagulation cascade that leads to formation of clots in the kidney and subsequent kidney failure and hemolytic uremic syndrome15. E. coli can also travel through the small intestine to the colon where they invade and destroy colonic epithelial cells or cholangiocytes. The bacteria utilize host actin to navigate the host cell, spread to adjacent cells, and multiple in the cytoplasm. The resultant epithelial cell destruction can lead to colonic ulceration22. Routine Bloodwork Routine bloodwork for suspected gastroenteritis includes a complete blood count (CBC), electrolyte counts, renal function tests, and blood urea nitrogen tests among others16. The CBC tests for RBC’s, WBC’s, hemoglobin, hematocrit, and platelets. C. jejuni infection could result in a high WBC and platelet count as well as a low hemoglobin, hematocrit, and RBC count17. Renal function and blood urea nitrogen tests will be abnormal if the E. coli infection has caused kidney or liver damage. Works Cited: 1) "Pediatric Campylobacter Infections Clinical Presentation." Pediatric Campylobacter Infections Clinical Presentation: History, Physical, Causes. Web. 20 Mar. 2016. 2) "Department of Health." E. Coli 0157:H7 Infection. Web. 20 Mar. 2016. 3) "Campylobacter Jejuni - MicrobeWiki - Kenyon College." Web. 20 Mar. 2016. 4) "The Digestive System Diagram, Organs, Function, and More." WebMD. WebMD. Web. 20 Mar. 2016. 5) Vliet, A.h.m. Van, and J.m. Ketley. "Pathogenesis of Enteric Campylobacter Infection." J Appl Microbiol Journal of Applied Microbiology 90.S6 (2001). Web. 6) Wine, Eytan, Voon L. Chan, and Philip M. Sherman. "Campylobacter Jejuni Mediated Disruption of Polarized Epithelial Monolayers Is Cell-Type Specific, Time Dependent, and Correlates With Bacterial Invasion." Pediatr Res Pediatric Research 64.6 (2008): 599-604. Web. 7) "Campylobacter Jejuni - MicrobeWiki - Kenyon College." Web. 20 Mar. 2016. 8) "Escherichia Coli Infections." Merck Manuals Professional Edition. Web. 20 Mar. 2016. 9) "Enterohaemorrhagic Escherichia Coli (EHEC)." World Health Organization. Web. 20 Mar. 2016. 10) Hodges, Kim, and Ravinder Gill. “Infectious Diarrhea: Cellular and Molecular Mechanisms.” Gut Microbes 1.1 (2010): 4–21. PMC. Web. 20 Mar. 2016. 11) Nachamkin, Irving, Ban Mishu Allos, and Tony Ho. “Campylobacter Species and GuillainBarré Syndrome.” Clinical Microbiology Reviews 11.3 (1998): 555–567. Print. 12) "Campylobacter Jejuni." Government of Canada, Health Canada and the Public Health Agency of Canada. Web. 20 Mar. 2016. 13) Smith, Malcolm A., Narayan R. Shah, Jeffrey S. Lobel, and Wade Hamilton. "Methemoglobinemia and Hemolytic Anemia Associated with Campylobacter Jejuni Enteritis." Journal of Pediatric Hematology/Oncology 10.1 (1988): 35-38. Web. 14) "Hemolytic Uremic Syndrome After Campylobacter-Induced Diarrhea in an Adult." JAMA Network. Web. 20 Mar. 2016. 15) "Hemolytic Uremic Syndrome (HUS)." Hemolytic Uremic Syndrome (HUS). Web. 20 Mar. 2016. 16) "Emergent Treatment of Gastroenteritis Workup." Emergent Treatment of Gastroenteritis Workup: Laboratory Studies, Imaging Studies, Procedures. Web. 20 Mar. 2016. 17) "Campylobacter Jejuni Gastroenteritis Complicated by Pancytopenia." Campylobacter Jejuni Gastroenteritis Complicated by Pancytopenia. Web. 20 Mar. 2016. 18) Blaser, M. J., G. P. Perez, P. F. Smith, C. Patton, F. C. Tenover, A. J. Lastovica, and W. I. Wang. 1986. Extraintestinal Campylobacter jejuni and Campylobacter coli infections: host factors and strain characteristics. J. Infect. Dis. 153:552-559. 19) Skirrow, M. B., D. M. Jones, E. Sutcliffe, and J. Benjamin. 1993. Campylobacter bacteraemia in England and Wales, 1981-91. Epidemiol. Infect. 110:567-573. 20) Smith, J. L. 2002. Campylobacter jejuni infection during pregnancy: Long-term consequences of associated bacteremia, Guillain-Barre syndrome, and reactive arthritist. J. Food Prot. 65:696-708. 21) Lukyanenko, Valeriy et al. “Enterohemorrhagic Escherichia Coli Infection Stimulates Shiga Toxin 1 Macropinocytosis and Transcytosis across Intestinal Epithelial Cells.” American Journal of Physiology - Cell Physiology 301.5 (2011): C1140–C1149. PMC. Web. 20 Mar. 2016. 22) "Infections of the Large Intestine." Infections of the Large Intestine. Web. 20 Mar. 2016.