Clostridium Difficile Infection

Clostridium difficile is a Gram positive, spore-forming rod that causes a spectrum of intestinal diseases extending from relatively mild diarrhea to toxic megacolon and is a frequent cause of hospital-acquired enteric infection. C. difficile associated disease (CDAD) generally occurs in hospitalized patients and almost always follows antibiotic treatment for unrelated infections. The incidence of CDAD has increased dramatically and C. difficile colitis has become one of the most important and expensive health-care associated infections. Recurrence rates after treatment are high. The role of the immune system in defense against this infection or in the pathogenesis of C. difficile-associated disease is poorly defined.

We are investigating a murine model of antibiotic-induced C. difficile colitis and are focusing on novel approaches to ameliorate infection and to decrease the intestinal pathology associated with CDAD. We find that flagellin treatment markedly increases survival of mice infected with C. difficile (Jarchum et al. Infection and Immunity 2011). Ongoing studies in the laboratory are determining the range of TLR agonists that can enhance resistance to C. difficile infection. We have also discovered that innate lymphocytes that produce interferon-gamma play an important role in early defense against acute C. difficile infection (Abt et al. Cell Host & Microbe 2015).

Figure 1

Clostridium difficile produces toxins A and B, which result in a loss of intestinal epithelial integrity.  Innate lymphocytes (ILC) in the lamina propria are activated by infection and enhance early innate immune defense against C. difficile infection (Abt et al.  Cell Host & Microbe  2015).

Ongoing studies in our laboratory are also identifying commensal bacterial species that confer resistance to C. difficile infection.  We have recently identified Clostridium scindens, an obligate anaerobic bacterium that converts primary to secondary bile salts, as a major contributor to resistance against C. difficile colitis (Buffie et al.  Nature  2015).  Ongoing studies are focusing on identifying optimal commensal bacterial populations to maximize resistance to C. difficile infection. 

Jarchum I, Liu M, Lipuma L, Pamer EG. Toll-Like Receptor 5 Stimulation Protects Mice from Acute Clostridium difficile Colitis. Infect Immun. 2011; 79(4):1498-503.

Buffie CG, Jarchum I, Equinda M, Lipuma L, Gobourne A, Viale A, Ubeda-Morant C, Xavier J, Pamer EG. Profound alterations of intestinal microbiota following a single dose of Clindamycin results in sustained susceptibility to C. difficile-induced colitis. Infect Immun. 2012; 80(1):62-73.

Jarchum I, Liu M, Shi C, Equinda M, Pamer EG. Critical role for MyD88-mediated neutrophil recruitment during C. difficile colitis. Infect Immun. 2012 Jun 11.

Kinnebrew MA, Lee YJ, Jenq RR, Lipuma L, Littmann ER, Gobourne A, No D, van den Brink M, Pamer EG, Taur Y. Early Clostridium difficile infection during allogeneic hematopoietic stem cell transplantation. PLoS One. 2014 Mar 24; 9(3): e90158.

Geiger TL, Abt MC, Gasteiger G, Firth MA, O’Connor MH, Geary CD, O’Sullivan TE, van den Brink MR, Pamer EG, Hanash AM, Sun JC. Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J Exp Med. 2014 Aug 25; 211(9): 1723-31.

Taur Y, Pamer EG. Harnessing microbiota to kill a pathogen: Fixing the microbiota to treat Clostridium difficile infections. Nature Medicine. 2014 Mar; 20(3):246-247.

Buffie CG, Bucci V, Stein RR, McKenney PT, Ling L, Gobourne A, No D, Liu H, Kinnebrew M, Viale A, Littmann E, van den Brink MR, Jenq RR, Taur Y, Sander C, Cross J, Toussaint NC, Xavier JB, Pamer EG. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature. 2015 Jan 8; 517(7533):205-208.

Lewis BB, Buffie CG, Carter RA, Leiner I, Toussaint NC, Miller LC, Gobourne A, Ling L, Pamer EG. Loss of microbiota-mediated colonization resistance to Clostridium difficile infection with oral vancomycin compared with metronidazole. Journal of Infectious Diseases. 2015 Apr 28; Epub ahead of print.

Abt MC, Lewis BB, Caballero S, Xiong H, Carter RA, Susac B, Ling L, Leiner I, Pamer EG. Innate immune defenses mediated by two ILC subsets are critical for protection against acute Clostridium difficile infection. Cell Host & Microbe. 2015 In Press.