Download PDF
Clin Colon Rectal Surg 2020; 33(02): 067-072
DOI: 10.1055/s-0040-1701231
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Inflammasome and Type-2 Immunity in Clostridium difficile Infection

Alexandra Donlan
1   Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia
2   Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia
3   Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia
,
William A. Petri Jr.
1   Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia
2   Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia
3   Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia
› Author Affiliations
Further Information

Publication History

Publication Date:
25 February 2020 (online)

    Permissions and Reprints

Abstract

Clostridium difficile (reclassified as “Clostridioides”) is the leading cause of hospital-acquired infections in the United States, and is associated with high-patient mortality and high rates of recurrence. Inflammasome priming and activation by the bacterial toxins, TcdA, TcdB, and C. difficile transferase (CDT), initiates a potent immune response that is characterized by interleukin- (IL) 8, IL-1β, and neutrophil recruitment, and is required for pathogen killing. However, it is becoming clearer that a strong inflammatory response during C. difficile infection can result in host tissue damage, and is associated with worse patient outcome. Recent work has begun to show that a type-2 immune response, most often associated with helminth infections, allergy, and asthma, may be protective during C. difficile infection. While the mechanisms through how this response protect are still unclear, there is evidence that it is mediated through eosinophil activity. This chapter will review the immune response to C. difficile, how the inflammasome signaling during infection can deleterious to the host, as well as the current understanding of a protective type-2 immunity. Understanding the host immune response may help to provide insight into novel approaches to prognosis markers, as well as how treat patient C. difficile infection without, or in addition to, antibiotics.

Keywords

Clostridium difficle - diarrhea - inflammasome - type-2 immunity
 

  • References

  • 1 Abou Chakra CN, Pepin J, Sirard S, Valiquette L. Risk factors for recurrence, complications and mortality in Clostridium difficile infection: a systematic review. PLoS One 2014; 9 (06) e98400
    CrossrefPubMedGoogle Scholar
  • 2 El Feghaly RE, Stauber JL, Deych E, Gonzalez C, Tarr PI, Haslam DB. Markers of intestinal inflammation, not bacterial burden, correlate with clinical outcomes in Clostridium difficile infection. Clin Infect Dis 2013; 56 (12) 1713-1721
    CrossrefPubMedGoogle Scholar
  • 3 Pothoulakis C. Effects of Clostridium difficile toxins on epithelial cell barrier. Ann N Y Acad Sci 2000; 915 (01) 347-356
    PubMedGoogle Scholar
  • 4 Cowardin CA, Kuehne SA, Buonomo EL, Marie CS, Minton NP, Petri Jr WA. Inflammasome activation contributes to interleukin-23 production in response to Clostridium difficile . MBio 2015; 6 (01) e02386-14
    CrossrefPubMedGoogle Scholar
  • 5 Barbut F, Mastrantonio P, Delmée M, Brazier J, Kuijper E, Poxton I. ; European Study Group on Clostridium difficile (ESGCD). Prospective study of Clostridium difficile infections in Europe with phenotypic and genotypic characterisation of the isolates. Clin Microbiol Infect 2007; 13 (11) 1048-1057
    CrossrefPubMedGoogle Scholar
  • 6 Bauer MP, Notermans DW, van Benthem BH. , et al; ECDIS Study Group. Clostridium difficile infection in Europe: a hospital-based survey. Lancet 2011; 377 (9759): 63-73
    CrossrefPubMedGoogle Scholar
  • 7 Cohen NA, Miller T, Na’aminh W. , et al. Clostridium difficile fecal toxin level is associated with disease severity and prognosis. United European Gastroenterol J 2018; 6 (05) 773-780 . doi:10.1177/2050640617750809
    CrossrefPubMedGoogle Scholar
  • 8 Gerding DN, Johnson S, Rupnik M, Aktories K. Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance. Gut Microbes 2014; 5 (01) 15-27
    CrossrefPubMedGoogle Scholar
  • 9 Cowardin CA, Buonomo EL, Saleh MM. , et al. The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. Nat Microbiol 2016; 1 (08) 16108
    CrossrefPubMedGoogle Scholar
  • 10 Péchiné S, Collignon A. Immune responses induced by Clostridium difficile . Anaerobe 2016; 41: 68-78
    CrossrefPubMedGoogle Scholar
  • 11 Buonomo EL, Cowardin CA, Wilson MG, Saleh MM, Pramoonjago P, Petri Jr WA. Microbiota-regulated IL-25 increases eosinophil number to provide protection during Clostridium difficile infection. Cell Reports 2016; 16 (02) 432-443
    CrossrefPubMedGoogle Scholar
  • 12 Kulaylat AS, Buonomo EL, Scully KW. , et al. Development and validation of a prediction model for mortality and adverse outcomes among patients with peripheral eosinopenia on admission for Clostridium difficile infection. JAMA Surg 2018; 153 (12) 1127-1133
    CrossrefPubMedGoogle Scholar
  • 13 Spencer LA, Weller PF. Eosinophils and Th2 immunity: contemporary insights. Immunol Cell Biol 2010; 88 (03) 250-256
    CrossrefPubMedGoogle Scholar
  • 14 Voehringer D, Shinkai K, Locksley RM. Type 2 immunity reflects orchestrated recruitment of cells committed to IL-4 production. Immunity 2004; 20 (03) 267-277
    CrossrefPubMedGoogle Scholar
  • 15 Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol 2015; 15 (01) 57-65
    CrossrefPubMedGoogle Scholar
  • 16 Buonomo EL, Petri Jr WA. The microbiota and immune response during Clostridium difficile infection. Anaerobe 2016; 41: 79-84
    CrossrefPubMedGoogle Scholar
  • 17 Netea MG, Nold-Petry CA, Nold MF. , et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1β in monocytes and macrophages. Blood 2009; 113 (10) 2324-2335
    CrossrefPubMedGoogle Scholar
  • 18 Kelly CP, Kyne L. The host immune response to Clostridium difficile . J Med Microbiol 2011; 60 (Pt 8): 1070-1079
    CrossrefPubMedGoogle Scholar
  • 19 Jarchum I, Liu M, Shi C, Equinda M, Pamer EG. Critical role for MyD88-mediated neutrophil recruitment during Clostridium difficile colitis. Infect Immun 2012; 80 (09) 2989-2996
    CrossrefPubMedGoogle Scholar
  • 20 Díaz A, Allen JE. Mapping immune response profiles: the emerging scenario from helminth immunology. Eur J Immunol 2007; 37 (12) 3319-3326
    CrossrefPubMedGoogle Scholar
  • 21 Allen JE, Wynn TA. Evolution of Th2 immunity: a rapid repair response to tissue destructive pathogens. PLoS Pathog 2011; 7 (05) e1002003
    CrossrefPubMedGoogle Scholar
  • 22 Yazdanbakhsh M, Kremsner PG, van Ree R. Allergy, parasites, and the hygiene hypothesis. Science 2002; 296 (5567): 490-494
    CrossrefPubMedGoogle Scholar
  • 23 Woodruff PG, Modrek B, Choy DF. , et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009; 180 (05) 388-395
    CrossrefPubMedGoogle Scholar
  • 24 Sorg JA, Sonenshein AL. Inhibiting the initiation of Clostridium difficile spore germination using analogs of chenodeoxycholic acid, a bile acid. J Bacteriol 2010; 192 (19) 4983-4990
    CrossrefPubMedGoogle Scholar
  • 25 Theriot CM, Bowman AA, Young VB. Antibiotic-induced alterations of the gut microbiota alter secondary bile acid production and allow for Clostridium difficile spore germination and outgrowth in the large intestine. MSphere 2016; 1 (01) e00045-15
    CrossrefPubMedGoogle Scholar
  • 26 Francis MB, Allen CA, Shrestha R, Sorg JA. Bile acid recognition by the Clostridium difficile germinant receptor, CspC, is important for establishing infection. PLoS Pathog 2013; 9 (05) e1003356
    CrossrefPubMedGoogle Scholar
  • 27 von Moltke J, Ji M, Liang H-E, Locksley RM. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 2016; 529 (7585): 221-225
    PubMedGoogle Scholar
  • 28 Owyang AM, Zaph C, Wilson EH. , et al. Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract. J Exp Med 2006; 203 (04) 843-849
    CrossrefPubMedGoogle Scholar
  • 29 Fort MM, Cheung J, Yen D. , et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 2001; 15 (06) 985-995
    CrossrefPubMedGoogle Scholar
  • 30 Zaph C, Du Y, Saenz SA. , et al. Commensal-dependent expression of IL-25 regulates the IL-23-IL-17 axis in the intestine. J Exp Med 2008; 205 (10) 2191-2198
    CrossrefPubMedGoogle Scholar
  • 31 Chaves-Olarte E, Weidmann M, Eichel-Streiber C, Thelestam M. Toxins A and B from Clostridium difficile differ with respect to enzymatic potencies, cellular substrate specificities, and surface binding to cultured cells. J Clin Invest 1997; 100 (07) 1734-1741
    CrossrefPubMedGoogle Scholar
  • 32 Bobo LD, El Feghaly RE, Chen Y-S. , et al. MAPK-activated protein kinase 2 contributes to Clostridium difficile-associated inflammation. Infect Immun 2013; 81 (03) 713-722
    CrossrefPubMedGoogle Scholar
  • 33 Xu H, Yang J, Gao W. , et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 2014; 513 (7517): 237-241
    PubMedGoogle Scholar
  • 34 Jafari NV, Kuehne SA, Bryant CE. , et al. Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s). PLoS One 2013; 8 (07) e69846
    CrossrefPubMedGoogle Scholar
  • 35 Ng J, Hirota SA, Gross O. , et al. Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome. Gastroenterology 2010; 139 (02) 542-552 , 552.e1–552.e3
    CrossrefPubMedGoogle Scholar
  • 36 Ghonime MG, Shamaa OR, Das S. , et al. Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function. J Immunol 2014; 192 (08) 3881-3888
    CrossrefPubMedGoogle Scholar
  • 37 Vanaja SK, Rathinam VA, Fitzgerald KA. Mechanisms of inflammasome activation: recent advances and novel insights. Trends Cell Biol 2015; 25 (05) 308-315
    CrossrefPubMedGoogle Scholar
  • 38 Langrish CL, McKenzie BS, Wilson NJ, de Waal Malefyt R, Kastelein RA, Cua DJ. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol Rev 2004; 202: 96-105
    CrossrefPubMedGoogle Scholar
  • 39 Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest 2006; 116 (05) 1218-1222
    CrossrefPubMedGoogle Scholar
  • 40 Kuehne SA, Collery MM, Kelly ML, Cartman ST, Cockayne A, Minton NP. Importance of toxin A, toxin B, and CDT in virulence of an epidemic Clostridium difficile strain. J Infect Dis 2014; 209 (01) 83-86
    CrossrefPubMedGoogle Scholar
  • 41 Buckley AM, Spencer J, Candlish D, Irvine JJ, Douce GR. Infection of hamsters with the UK Clostridium difficile ribotype 027 outbreak strain R20291. J Med Microbiol 2011; 60 (Pt 8): 1174-1180
    CrossrefPubMedGoogle Scholar
  • 42 Carter GP, Chakravorty A, Pham Nguyen TA. , et al. Defining the roles of TcdA and TcdB in localized gastrointestinal disease, systemic organ damage, and the host response during Clostridium difficile infections. MBio 2015; 6 (03) e00551
    PubMedGoogle Scholar
  • 43 Stiles BG, Pradhan K, Fleming JM, Samy RP, Barth H, Popoff MR. Clostridium and bacillus binary enterotoxins: bad for the bowels, and eukaryotic being. Toxins (Basel) 2014; 6 (09) 2626-2656
    CrossrefPubMedGoogle Scholar
  • 44 Papatheodorou P, Carette JE, Bell GW. , et al. Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). Proc Natl Acad Sci U S A 2011; 108 (39) 16422-16427
    CrossrefPubMedGoogle Scholar
  • 45 Hemmasi S, Czulkies BA, Schorch B, Veit A, Aktories K, Papatheodorou P. Interaction of the Clostridium difficile binary toxin CDT and its host cell receptor, lipolysis-stimulated lipoprotein receptor (LSR). J Biol Chem 2015; 290 (22) 14031-14044
    CrossrefPubMedGoogle Scholar
  • 46 Liu W, Ouyang X, Yang J. , et al. AP-1 activated by toll-like receptors regulates expression of IL-23 p19. J Biol Chem 2009; 284 (36) 24006-24016
    CrossrefPubMedGoogle Scholar
  • 47 Chen X, Katchar K, Goldsmith JD. , et al. A mouse model of Clostridium difficile-associated disease. Gastroenterology 2008; 135 (06) 1984-1992
    CrossrefPubMedGoogle Scholar
  • 48 Pulendran B, Artis D. New paradigms in type 2 immunity. Science 2012; 337 (6093): 431-435
    CrossrefPubMedGoogle Scholar
  • 49 Eng SS, DeFelice ML. The role and immunobiology of eosinophils in the respiratory system: a comprehensive review. Clin Rev Allergy Immunol 2016; 50 (02) 140-158
    CrossrefPubMedGoogle Scholar
  • 50 Klion AD, Nutman TB. The role of eosinophils in host defense against helminth parasites. J Allergy Clin Immunol 2004; 113 (01) 30-37
    CrossrefPubMedGoogle Scholar