Clostridium difficile causes colitis following antibiotic-mediated perturbation of the intestinal microbiota. C. difficile causes over 500,000 infections per year, with an estimated 15,000 deaths annually in the United States. Ingestion of infectious spores from contaminated environments represents the major route by which this infection is acquired. Very little is known about interactions between C. difficile and the normal intestinal microbiota or with the host innate immune system. Our laboratory has investigated C. difficile infection in antibiotic treated mice and demonstrated that stimulating TLR-5 with bacterial flagellin or TLR7/8 with resiquimod markedly enhances resistance to C. difficile infection. We have also demonstrated that a single dose of clindamycin results in prolonged susceptibility to C. difficile infection. The goal of this project is to characterize innate immune defenses, includig those induced by the commensal microbial flora, in protection against C. difficile infection.
The first aim i s to characterize the mechanism by which stimulation of TLR5 by flagellin or TLR7/8 by resiquimod enhances resistance to C. difficile infection. We will investigate the role IL22, the arl hydrocarbon receptor and primary and secondary bile salts in TLR-mediated defense against C. difficile infection.
The second aim i s to determine whether intestinal dendritic cells or inflammatory monocytes contribute to resistance to C. difficile infection. We will use CCR2-reporter and CCR2-depletor mice that were generated in our laboratory to determine the impact of inflammatory monocytes on the pathogenesis of C. difficile colitis.
The third aim i s to determine the effect of different antibiotic treatments on the composition of the intestinal microbial flora. We will use the Roche 454 massively parallel pyrosequencing platform to determine microbial complexity in the GI tract, and to correlate changes in the flora with susceptibility to C. difficile infection. Mice will be reconstituted with fractionated intestinal microbiota and resistance to C. difficile infection will be measured. These studies will identify microbial populations that inhibit germination and/or vegetative growth of C. difficile. Our ultimate goal is to identify the in vivo mechanisms protecting the host from C. difficile infection and to discover practicable approaches, such as selective TLR or cytokine receptor stimulation or microbiota manipulation, to re-induce these mechanisms in vulnerable patients.
Colitis caused by Clostridium difficile is a major complication of antibiotic treatment. Antibiotics destroy normal commensal bacteria in the intestine and thus enable C. difficile to cause disease. The only preventive strategies are to avoid antibiotic use or contact with C. difficile. Our studies will identify immune mechanisms that prevent the development of C. difficile colitis in vulnerable patients.
|Pamer, Eric G (2017) Microbial Tuning of the Mammalian Immune System. Trends Mol Med 23:379-380|
|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|
|Lee, Yeon Joo; Arguello, Esther P; Jenq, Robert R et al. (2017) Protective Factors in the Intestinal Microbiome Against Clostridium difficile infection in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation. J Infect Dis :|
|Weber, Daniela; Jenq, Robert R; Peled, Jonathan U et al. (2017) Microbiota Disruption Induced by Early Use of Broad-Spectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant 23:845-852|
|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:|
|Westblade, Lars F; van Belkum, Alex; Grundhoff, Adam et al. (2016) Role of Clinicogenomics in Infectious Disease Diagnostics and Public Health Microbiology. J Clin Microbiol 54:1686-93|
|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|
|Pamer, Eric G (2016) Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. Science 352:535-8|
|Becattini, Simone; Taur, Ying; Pamer, Eric G (2016) Antibiotic-Induced Changes in the Intestinal Microbiota and Disease. Trends Mol Med 22:458-78|
Showing the most recent 10 out of 31 publications