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

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.
AuthorsMizuho Hasegawa, Takashi Yamazaki, Nobuhiko Kamada, Kazuki Tawaratsumida, Yun-Gi Kim, Gabriel Núñez, Naohiro Inohara
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 186 Issue 8 Pg. 4872-80 (Apr 15 2011) ISSN: 1550-6606 [Electronic] United States
PMID21411735 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Chemokine CXCL1
  • Interleukin-6
  • Nod1 Signaling Adaptor Protein
  • Receptors, Pattern Recognition
Topics
  • Animals
  • Bacterial Translocation
  • Cecum (immunology, metabolism, microbiology)
  • Chemokine CXCL1 (immunology, metabolism)
  • Clostridioides difficile (immunology, physiology)
  • Colon (immunology, metabolism, microbiology)
  • Enterocolitis, Pseudomembranous (genetics, immunology, microbiology)
  • Female
  • Flow Cytometry
  • Genetic Predisposition to Disease (genetics)
  • HEK293 Cells
  • Host-Pathogen Interactions (immunology)
  • Humans
  • Immunohistochemistry
  • Interleukin-6 (immunology, metabolism)
  • Intestine, Small (immunology, metabolism, microbiology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration (immunology)
  • Neutrophils (immunology, metabolism)
  • Nod1 Signaling Adaptor Protein (genetics, immunology, metabolism)
  • Receptors, Pattern Recognition (genetics, immunology, metabolism)

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