Leptin receptor q223r polymorphism influences neutrophil mobilization after Clostridium difficile infection

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Abstract

Clostridium difficile is the leading cause of nosocomial infections in the United States. Clinical disease outcomes after C. difficile infection (CDI) are dependent on intensity of host inflammatory responses. Specifically, peak peripheral white blood cell (WBC) count >20 × 10 9 l '1 is an indicator of adverse outcomes in CDI patients, and is associated with higher 30-day mortality. We show that homozygosity for a common single nucleotide polymorphism (Q to R mutation in leptin receptor that is present in up to 50% of people), significantly increases the risk of having peak peripheral WBC count >20 × 10 9 l '1 (odds ratio=5.41; P=0.0023) in CDI patients. In a murine model of CDI, we demonstrate that mice homozygous for the same single nucleotide polymorphism (RR mice) have more blood and tissue leukocytes (specifically neutrophils), exaggerated tissue inflammation, and higher mortality as compared with control mice, despite similar pathogen burden. Further, we show that neutrophilia in RR mice is mediated by gut microbiota-directed expression of CXC chemokine receptor 2 (CXCR2), which promotes the release of neutrophils from bone marrow reservoir. Overall these studies provide novel mechanistic insights into the role of human genetic polymorphisms and gut microbiota in regulating the fundamental biological process of CDI-induced neutrophilia.

Original languageEnglish (US)
Pages (from-to)947-957
Number of pages11
JournalMucosal Immunology
Volume11
Issue number3
DOIs
Publication statusPublished - May 1 2018
Externally publishedYes

Cite this

Jose, S., Abhyankar, M. M., Mukherjee, A., Xue, J., Andersen, H., Haslam, D. B., & Madan, R. (2018). Leptin receptor q223r polymorphism influences neutrophil mobilization after Clostridium difficile infection. Mucosal Immunology, 11(3), 947-957. https://doi.org/10.1038/mi.2017.119