Researchers at Virginia Bioinformatics Institute at Virginia Tech have discovered how an common diarrhea-causing bacterium sends one’s body’s natural defenses into overdrive, actually intensifying illness while fighting infection.
The invention, recently published in PLOS One, may lead to new medications for Clostridium difficile, a standard germ in medical care- associated infections often referred to as C. diff. Many experts have linked to the death of 14,000 Americans annually, using the Centers for Disease Control and Prevention.
Researchers with the Center for Modeling Immunity to Enteric Pathogens at Virginia Tech applied computational and mathematical modeling in conjunction with RNA-sequencing and mouse studies to recognise a significant regulatory pathway during Clostridium difficile infection.
“We have found that tissue damage and disease severity in C. difficile infection is a member of a disruption from the peroxisome proliferator-activated receptor gamma (PPARγ) pathway,” said Josep Bassaganya-Riera, a professor of immunology, director of the Nutritional Immunology and Molecular Medicine Laboratory and the principal investigator with the Center for Modeling Immunity to Enteric Pathogens.
A person’s intestine must peacefully coexist with trillions of beneficial bacteria while swiftly answering and adjusting pathogens like C. difficile. Sometimes the disease fighting capability is going into overdrive when giving an answer to pathogens, causing more damage to try to pay off the infection.
Scientists studying mice bowels found the PPARγ pathway keeps the immune reaction in balance, allowing our bodies to heal as the immune cells that fight infection do their work in the controlled manner. When PPARγ was absent or inactive, disease was more rampant and colonic lesions from C. difficile were much worse.
Also, researchers found the protective mechanism can be activated along with the severity of the C. difficile infection is usually reduced through the use of an existing diabetes drug. More studies will be needed before the drug could be tested against C. difficile.
“These studies demonstrates how the integration of powerful computer simulations of host responses with immunology experimentation not simply plays a role in an improved perception of the immunoregulatory processes from the gut mucosa during C. difficile infection, it also advances the discovery of broad-based therapeutic targets inside the host for infectious diseases,” said Raquel Hontecillas, an assistant professor of immunology at Virginia Tech, co-director with the Nutritional Immunology and Molecular Medicine Laboratory and leader from the immunology part of the guts for Modeling Immunity to Enteric Pathogens.
This research builds on previous work from your Nutritional Immunology and Molecular Medicine Laboratory, which demonstrates PPARγ is very important to reducing disease brought on by enteric pathogens and regulating autoimmune diseases for instance inflammatory bowel disease.
“With continued research, new drugs targeting this pathway are going to be developed that can have fewer uncomfortable side effects and greater efficacy as opposed to runners currently available,” Bassaganya-Riera said.
C. difficile has become a widespread problem in hospitals with patients who have received heavy doses of multiple antibiotics and it is spreading locally. Symptoms include persistent diarrhea, fever, gut inflammation, and weight reduction. Though such potentially life-threatening intestinal infections occur among very young, elderly or immune-compromised individuals, C. difficile has increasingly been seen in patients who traditionally wouldn’t be subject to this bacterium.
Current strains of C. difficile are becoming all the more virulent and anti-microbial resistant lately which emphasizes the value of developing broad-based, host-targeted ways to control the ailment rather than just relying upon anti-microbial therapies that concentrate on the bacterium and will stimulate multiplication of resistance.
The abstract of this article is as following.
Clostridium difficile is an anaerobic bacterium that has re-emerged as a facultative pathogen and can cause nosocomial diarrhea, colitis or even death. Peroxisome proliferator-activated receptor (PPAR) γ has been implicated in the prevention of inflammation in autoimmune and infectious diseases; however, its role in the immunoregulatory mechanisms modulating host responses to C. difficile and its toxins remains largely unknown. To characterize the role of PPARγ in C. difficile-associated disease (CDAD), immunity and gut pathology, we used a mouse model of C. difficileinfection in wild-type and T cell-specific PPARγ null mice. The loss of PPARγ in T cells increased disease activity and colonic inflammatory lesions following C. difficile infection. Colonic expression of IL-17 was upregulated and IL-10 downregulated in colons of T cell-specific PPARγ null mice. Also, both the loss of PPARγ in T cells and C. difficile infection favored Th17 responses in spleen and colonic lamina propria of mice with CDAD. MicroRNA (miRNA)-sequencing analysis and RT-PCR validation indicated that miR-146b was significantly overexpressed and nuclear receptor co-activator 4 (NCOA4) suppressed in colons of C. difficile-infected mice. We next developed a computational model that predicts the upregulation of miR-146b, downregulation of the PPARγ co-activator NCOA4, and PPARγ, leading to upregulation of IL-17. Oral treatment of C. difficile-infected mice with the PPARγ agonist pioglitazone ameliorated colitis and suppressed pro-inflammatory gene expression. In conclusion, our data indicates that miRNA-146b and PPARγ activation may be implicated in the regulation of Th17 responses and colitis in C. difficile-infected mice.
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Viladomiu M, Hontecillas R, Pedragosa M, Carbo A, Hoops S, et al. (2012) Modeling the Role of Peroxisome Proliferator-Activated Receptor γ and MicroRNA-146 in Mucosal Immune Responses toClostridium difficile. PLoS ONE 7(10): e47525. doi:10.1371/journal.pone.0047525
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