Nucleotide-binding oligomerization domain 1 mediates recognition of Clostridium difficile and induces neutrophil recruitment and protection against the pathogen

Mizuho Hasegawa, Takashi Yamazaki, Nobuhiko Kamada, Kazuki Tawaratsumida, Yungi Kim, Gabriel Núñez, Naohiro Inohara

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Clostridium difficile is a Gram-positive obligate anaerobic pathogen that causes pseudomembranous colitis in antibiotics-treated individuals. However, host immune protective mechanisms against C. difficile are largely unknown. In this study, we show that C. difficile possesses potent stimulatory activity for nucleotide-binding oligomerization domain 1 (Nod1), an intracellular pattern recognition molecule that senses bacterial peptidoglycan-related molecules. Nod1-/-, but not Nod2-/-, mice exhibited increased lethality in response to C. difficile intestinal infection despite comparable levels of intestinal damage and epithelial permeability in Nod1-/- and control mice. The enhanced lethality was accompanied by impaired C. difficile clearance, increased bacterial translocation, and elevated levels of endotoxin and IL-1β in the serum of Nod1-/- mice. Histological and flow cytometric analyses revealed that Nod1-/- mice had defective recruitment of neutrophils, but not macrophages, to the intestine after C. difficile infection. The reduced recruitment of neutrophils correlated with impaired production of CXCL1, but not CCL2, XCL1, and other cytokines/ chemokines, in infected Nod1-/- mice. The influx of neutrophils also was reduced when C. difficile was administered i.p., suggesting that Nod1 directly recognizes C. difficile to induce the recruitment of neutrophils to the infected site. These results indicate that Nod1 regulates host susceptibility to C. difficile and suggest that Nod1-mediated neutrophil recruitment is an important immune response against the enteric pathogen.

Original languageEnglish
Pages (from-to)4872-4880
Number of pages9
JournalJournal of Immunology
Volume186
Issue number8
DOIs
Publication statusPublished - 2011 Apr 15
Externally publishedYes

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Clostridium difficile
Neutrophil Infiltration
Nucleotides
Pseudomembranous Enterocolitis
Bacterial Translocation
Clostridium Infections
Peptidoglycan
Interleukin-1
Chemokines
Endotoxins
Intestines
Permeability
Neutrophils
Macrophages
Cytokines
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Immunology

Cite this

Nucleotide-binding oligomerization domain 1 mediates recognition of Clostridium difficile and induces neutrophil recruitment and protection against the pathogen. / Hasegawa, Mizuho; Yamazaki, Takashi; Kamada, Nobuhiko; Tawaratsumida, Kazuki; Kim, Yungi; Núñez, Gabriel; Inohara, Naohiro.

In: Journal of Immunology, Vol. 186, No. 8, 15.04.2011, p. 4872-4880.

Research output: Contribution to journalArticle

Hasegawa, Mizuho ; Yamazaki, Takashi ; Kamada, Nobuhiko ; Tawaratsumida, Kazuki ; Kim, Yungi ; Núñez, Gabriel ; Inohara, Naohiro. / Nucleotide-binding oligomerization domain 1 mediates recognition of Clostridium difficile and induces neutrophil recruitment and protection against the pathogen. In: Journal of Immunology. 2011 ; Vol. 186, No. 8. pp. 4872-4880.
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