Toll-like receptor 5 stimulation protects mice from acute Clostridium difficile colitis.
Clostridium difficile is a spore-forming bacterium that infects the lower intestinal tract of humans and is the most common known cause of diarrhea among hospitalized patients. Clostridium difficile colitis is mediated by toxins and develops during or following antibiotic administration. We have used a murine model of C. difficile infection, which reproduces the major features of the human disease, to study the effect of innate immune activation on resistance to C. difficile infection. We found that administration of purified Salmonella-derived flagellin, a Toll-like receptor 5 (TLR5) agonist, protects mice from C. difficile colitis by delaying C. difficile growth and toxin production in the colon and cecum. TLR5 stimulation significantly improves pathological changes in the cecum and colon of C. difficile-infected mice and reduces epithelial cell loss. Flagellin treatment reduces epithelial apoptosis in the large intestine, thereby protecting the integrity of the intestinal epithelial barrier during C. difficile infection. We demonstrate that restoring intestinal innate immune tone by TLR stimulation in antibiotic-treated mice ameliorates intestinal inflammation and prevents death from C. difficile colitis, potentially providing an approach to prevent C. difficile-induced pathology.
MImmunology Program, Department of Medicine (Division of Infectious Disease),Memorial Sloan-Kettering Cancer Center, New York, New York, USA. jarchumi@mskcc.org
Irene
I
Jarchum
Mingyu
M
Liu
Lauren
L
Lipuma
Eric G
EG
Pamer
D000208:Acute Disease; D000818:Animals; D016360:Clostridioides difficile / Q000276:immunology*; D004195:Disease Models, Animal; D004761:Enterocolitis, Pseudomembranous / Q000276:immunology* / Q000473:pathology; D005260:Female; D005408:Flagellin / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051198:Toll-Like Receptor 5 / Q000819:agonists* / Q000276:immunology*
D051198:Toll-Like Receptor 5; D005408:Flagellin
J Immunol. 2008 Jun 15;180(12):8280-5
18523294
J Clin Invest. 2000 Apr;105(8):1147-56
10772660
Infect Immun. 2001 Mar;69(3):1329-36
11179295
Infect Immun. 1991 Oct;59(10):3659-66
1910012
Microbiology (Reading). 2000 Apr;146 ( Pt 4):957-966
10784054
Cell. 2004 Jul 23;118(2):229-41
15260992
J Immunol. 2001 Aug 15;167(4):1882-5
11489966
Nature. 2008 Oct 9;455(7214):804-7
18724361
N Engl J Med. 2008 Oct 30;359(18):1932-40
18971494
Gut. 1980 Jun;21(6):493-9
6776012
Infect Immun. 2010 Oct;78(10):4226-33
20643849
Immunity. 2009 Oct 16;31(4):677-89
19833089
J Immunol. 2010 Jul 15;185(2):1142-9
20566829
Nat Med. 2008 Mar;14(3):282-9
18264109
Microb Pathog. 2009 Jun;46(6):298-305
19324080
Nat Immunol. 2006 Aug;7(8):868-74
16829963
Infect Immun. 1998 Nov;66(11):5462-9
9784558
Nature. 2010 Oct 7;467(7316):711-3
20844489
J Exp Med. 2009 Jul 6;206(7):1465-72
19564350
J Clin Invest. 1994 Mar;93(3):1257-65
7907603
J Immunol. 2004 Apr 15;172(8):5056-62
15067088
Gastroenterology. 2008 Dec;135(6):1984-92
18848941
Nat Rev Microbiol. 2009 Jul;7(7):526-36
19528959
Science. 2008 Apr 11;320(5873):226-30
18403709
Clin Infect Dis. 2002 Feb 1;34(3):346-53
11774082
Annu Rev Immunol. 2010;28:623-67
20192812
PLoS One. 2009 Jun 29;4(6):e6073
19562033
Infect Immun. 2009 Sep;77(9):3661-9
19564382
J Exp Med. 2007 Aug 6;204(8):1891-900
17635956
Gastroenterology. 2010 Aug;139(2):542-52, 552.e1-3
20398664
Curr Protoc Microbiol. 2009 Feb;Chapter 9:Unit9A.1
19235151
J Infect Dis. 2010 Feb 15;201(4):534-43
20064069
J Immunol. 2007 Jul 1;179(1):566-77
17579078
PLoS One. 2010 May 17;5(5):e10673
20498856
J Immunol. 2001 Jan 15;166(2):1248-60
11145708
J Immunol. 2010 Jul 15;185(2):1177-85
20566828
Cell. 2009 Oct 30;139(3):485-98
19836068