Escherichia coli heme oxygenase modulates host innate immune responses

Nitsan Maharshak*, Hyungjin Sally Ryu, Ting Jia Fan, Joseph C. Onyiah, Stephanie Schulz, Sherrie L. Otterbein, Ron Wong, Jonathan J. Hansen, Leo E. Otterbein, Ian M. Carroll, Scott E. Plevy

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Induction of mammalian heme oxygenase (HO)-1 and exposure of animals to carbon monoxide (CO) ameliorates experimental colitis. When enteric bacteria, including Escherichia coli, are exposed to low iron conditions, they express an HO-like enzyme, chuS, and metabolize heme into iron, biliverdin and CO. Given the abundance of enteric bacteria residing in the intestinal lumen, our postulate was that commensal intestinal bacteria may be a significant source of CO and those that express chuS and other Ho-like molecules suppress inflammatory immune responses through release of CO. According to real-time PCR, exposure of mice to CO results in changes in enteric bacterial composition and increases E. coli 16S and chuS DNA. Moreover, the severity of experimental colitis correlates positively with E. coli chuS expression in IL-10 deficient mice. To explore functional roles, E. coli were genetically modified to overexpress chuS or the chuS gene was deleted. Co-culture of chuS-overexpressing E. coli with bone marrow-derived macrophages resulted in less IL-12p40 and greater IL-10 secretion than in wild-type or chuS-deficient E. coli. Mice infected with chuS-overexpressing E. coli have more hepatic CO and less serum IL-12 p40 than mice infected with chuS-deficient E. coli. Thus, CO alters the composition of the commensal intestinal microbiota and expands populations of E. coli that harbor the chuS gene. These bacteria are capable of attenuating innate immune responses through expression of chuS. Bacterial HO-like molecules and bacteria-derived CO may represent novel targets for therapeutic intervention in inflammatory conditions.

Original languageEnglish
Pages (from-to)452-465
Number of pages14
JournalMicrobiology and Immunology
Volume59
Issue number8
DOIs
StatePublished - 1 Aug 2015

Funding

FundersFunder number
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney DiseasesR01DK054452
National Institute of Diabetes and Digestive and Kidney Diseases

    Keywords

    • Carbon monoxide
    • ChuS
    • Enteric microbiota
    • Heme oxygenase

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