Clostridium difficile is a leading cause of diarrhea in hospitalized patients and infection is acquired by ingestion of spores that germinate into toxin-producing vegetative forms that destroy colonic epithelial integrity. Intestinal inflammation induced by C. difficile requires spore germination within the GI tract, bacterial proliferation and toxin production leading to intestinal epithelial damage. C. difficile growth in the colon occurs when the composition of the commensal bacterial flora is damaged by antibiotic treatment. Specific members of the commensal flora inhibit C. difficile growth, in part by converting primary to secondary bile salts. Once C. difficile infection has damaged the colonic epithelial layer, the host?s immune system is activated and, while essential for host survival, also contributes to intestinal pathology. Inflammatory monocytes, neutrophils, innate lymphocytes (ILCs) and a range of inflammatory cytokines have been implicated in defense against C. difficile infection (CDI) and in inflammatory pathology. The goal of our studies is to identify and characterize microbiota and immune-mediated protective mechanisms and to test our discoveries on microbiologically and clinically diverse C. difficile strains.
Our specific aims are: 1.) To assemble minimal-complexity commensal bacterial consortia derived from human fecal samples that provide high-level resistance against CDI. 2.) To characterize microbiota-mediated mechanisms that promote ILC1-mediated resistance against C. difficile and to test the hypothesis that the residual microbiota determines the balance of ILC1 versus ILC3 differentiation. 3.) To determine whether microbiota or ILC1 mediated defenses against CDI differ for distinct C. difficile strains. The proposed studies will provide novel insights into microbiota-mediated defenses against CDI and will also identify immune mechanisms that ameliorate adverse inflammatory responses during early CDI. These insights will facilitate the development of therapies to prevent and treat C. difficile infections.
Infections caused by Clostridium difficile are an increasing problem in the US, with an alarming frequency in elderly and immunocompromised patients requiring hospitalization for cancer treatment. Recent studies show normal commensal bacteria in the intestine can provide a remarkable degree of resistance to infection and that cells of the innate immune system also contribute to recovery from infection. The experiments described in this application will identify commensal bacterial strains that confer high-level resistance to C. difficile and characterize their impact on immune cells, with the goal of reducing infections and colonic inflammation.
|Haak, Bastiaan W; Littmann, Eric R; Chaubard, Jean-Luc et al. (2018) Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT. Blood 131:2978-2986|
|Kim, Sohn; Covington, April; Pamer, Eric G (2017) The intestinal microbiota: Antibiotics, colonization resistance, and enteric pathogens. Immunol Rev 279:90-105|
|Becattini, Simone; Pamer, Eric G (2017) Multifaceted Defense against Listeria monocytogenes in the Gastro-Intestinal Lumen. Pathogens 7:|
|Lewis, Brittany B; Carter, Rebecca A; Ling, Lilan et al. (2017) Pathogenicity Locus, Core Genome, and Accessory Gene Contributions to Clostridium difficile Virulence. MBio 8:|
|Caballero, Silvia; Kim, Sohn; Carter, Rebecca A et al. (2017) Cooperating Commensals Restore Colonization Resistance to Vancomycin-Resistant Enterococcus faecium. Cell Host Microbe 21:592-602.e4|
|Pamer, Eric G (2017) Microbial Tuning of the Mammalian Immune System. Trends Mol Med 23:379-380|
|Lewis, Brittany B; Carter, Rebecca A; Pamer, Eric G (2016) Bile acid sensitivity and in vivo virulence of clinical Clostridium difficile isolates. Anaerobe 41:32-36|
|Abt, Michael C; McKenney, Peter T; Pamer, Eric G (2016) Clostridium difficile colitis: pathogenesis and host defence. Nat Rev Microbiol 14:609-20|
|Becattini, Simone; Taur, Ying; Pamer, Eric G (2016) Antibiotic-Induced Changes in the Intestinal Microbiota and Disease. Trends Mol Med 22:458-478|
|Pamer, Eric G (2016) Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. Science 352:535-8|
Showing the most recent 10 out of 32 publications