Clostridia Notes.docx

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Department
Microbiology and Immunology
Course
Microbiology and Immunology 2500A/B
Professor
John Mc Cormick
Semester
Winter

Description
Clostridia  Gram positive  Rod shaped  Strict anaerobes Clostridia form endospores and vegetative cells are killed by oxygen. They are generally found in soil and intestinal tracts of animals. Clostridia are responsible for several unrelated diseases, as there are over 80 species of Clostridia (most which are not pathogenic). The important human pathogens are: Clostridium difficile: pseudomembranous colitis Clostridium tetani: tetanus Clostridium botulinum: botulism Clostridium perfringens: food-borne illness and gas gangrene The above can cause life-threatening diseases mediated by exotoxins. Endospore formation “Endo” means within, and endospores are highly resistant to heat, drying, harsh chemicals, and nutrient depletion. They function as “survival structures” and are also used for dispersal through air, water, and intestinal tracts. Clostridia produce terminal endospores. Endospore formation is best studied in Bacillus and Clostridium species. Sporulation occurs due to a lack of nutrients and stress  Development of endospores. Endospores are considered a dormant stage in the bacterial life cycle and can remain dormant for years, but revert back to vegetative cells rapidly. Endospore formation occurs through c complex series of events:  The exosporium and spore coat are composed of protein  The core wall is peptidoglycan  The cortex contains DNA, cytoplasm, ribosomes, etc… Dipicolinic acid complex with calcium helps to dehydrate the cortex, keeping it at the consistency of a gel and allowing it to be very resistant to heat, chemicals etc. Pasteurization (63-72°C) will not kill endospores (through a machine) but autoclaving at 121°C will kill endospores. The pathogen: C. difficile C. difficile causes pseudomembranous colitis aka antibiotic-associated diarrhea. It can exist as:  Asymptomatic carrier state  not causing disease  Cause of mild to moderate diarrhea  Cause of life-threatening pseudomembranous colitis C. difficile can be harbored in the large intestine in low numbers, and ~3% of healthy adults are colonized, but this doesn’t necessarily mean that they are diseased. It is a nosocomial pathogen often found in nursing homes and hospitals. Under harsh conditions, it reverts to highly resistant spores, which are very difficult to eradicate from the environment. The mode of transmission is through the spore (fecal-oral route). Most symptomatic patients have recently received an antimicrobial agent  this is the single most important risk factor. Antibiotics are used to cure infections, but they also kill normal microbiota, which leads to suppression of normal flora and the persistence of C. difficile endospores. In response to the antibiotic, C. difficle enters the endospore state. After the antibiotic is stopped, spores germinate, and overgrowth of C. difficile occurs with the production of toxins. C. difficile does not invade, but the toxins damage the intestinal lining of the large intestine  the toxins cause the damage. C. difficile produces A-B toxins called the large clostridial cytotoxins. The “A-B” serves to designate two domains:  A domain: denotes the active portion of the toxin that carries enzymatic activity  does the damage (toxin portion) by inactivating key regulatory G- proteins of host cells  B domain: denotes the portion of the toxin molecule responsible for binding and uptake by the host cell  allows the A portion to get inside Note: the A-domain has to get inside to be toxic. These toxins cause disregulation of multiple cell processes including cytoskeletal rearrangements  cell death and inflammation. C. difficile spores and vegetative cells are ingested possibly with food and pass through the esophagus into the stomach. They are able to germinate in the SI. In the LI, they adhere to some of the tissue and some of these cells are able to form endospores and some aren’t. A broad-spectrum antibiotic comes along and wipes out a large amount of microbiota, and endospores survive. When you stop the antibiotic, C. difficile is able to germinate and form toxins. The toxins target epithelial cells, damage the epithelium, and cause inflammatory problems  eventually forming the pseudomembrane. The disease: Pseudomembranous colitis Pseudomembranous colitis is an inflammatory condition of the large intestine. It results in offensive smelling diarrhea, abdominal pain, fever, nausea, and dehydration. Patients usually have “constitutional” symptoms. Symptoms may occur 1-2 days after antibiotics, or several weeks after the antibiotic is discontinued. In serious cases, it can lead to low blood pressure, kidney failure, perforated colon, and a toxic megacolon. Endoscopy can show characteristic yellow lesions, and these lesions can enlarge to cover substantial portions of inflamed mucosa and can be stripped off  pseudomembrane. Diagnosis and treatment of Pseudomembranous colitis It can be diagnosed through history (antibiotic use), symptoms, laboratory tests, endoscopy, and toxin detection assays. If you’re using a broad-spectrum antibiotic and the patient develops pseudomembranous colitis, you must discontinue the antibiotic. Antibiotics more specific for C. difficile are oral vancomycin or IV metronidazole. You also want to avoid antidiarrheal agents because you don’t want colonic stasis and decreased toxin clearance. Fecal Microbiota Transplantation Take feces from a healthy donor and transplant them into the infected individual. 1. Healthy individual 2. Given a broad-spectrum antibiotic: reduced gut microbial species and diversity 3. Ingestion of C. difficile spores from the environment: spores germinate, gut microbiota are reduced 4. Development of C. difficile infection: can cause pseudomembranous colitis by inducing inflammation and cell death 5a. Antibiotics continued and C. difficile killed but spores remain  recurrent infection 5b. Donor fecal sample restores stable, healthy gut microbiota They ran a clinical trial, where they compared this FMT with vancomyacin treatment. They had to stop the trial quickly, because the people receiving the FMT were doing so well (81% responded to FMT) in comparison to the other groups (vancomyacin; response of 30%), that it was not ethical to continue the trials for the other groups. Some of the problems are that you need to find a donor (screen the donor to see if they have other diseases etc…). One idea is a universal donor (containing good
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