Subtilase cytotoxin from Shiga-toxigenic Escherichia coli impairs the inflammasome and exacerbates enteropathogenic bacterial infection

Hiroyasu Tsutsuki; Tianli Zhang; Kinnosuke Yahiro; Katsuhiko Ono; Yukio Fujiwara; Sunao Iyoda; Fan-Yan Wei; Kazuaki Monde; Kazuko Seto; Makoto Ohnishi; Hiroyuki Oshiumi; Takaaki Akaike; Tomohiro Sawa

doi:10.1016/j.isci.2022.104050

Subtilase cytotoxin from Shiga-toxigenic Escherichia coli impairs the inflammasome and exacerbates enteropathogenic bacterial infection

iScience. 2022 Mar 10;25(4):104050. doi: 10.1016/j.isci.2022.104050. eCollection 2022 Apr 15.

Authors

Affiliations

¹ Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
² Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, 5 Misasagi-Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan.
³ Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
⁴ Department of Bacteriology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
⁵ Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
⁶ Quality Assurance Unit, Division of Planning, Osaka Institute of Public Health, 1-3-69 Nakamichi, Higashinari-ku, Osaka 537-0025, Japan.
⁷ Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
⁸ Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.

Abstract

Subtilase cytotoxin (SubAB) is an AB₅ toxin mainly produced by the locus of enterocyte effacement-negative Shiga-toxigenic Escherichia coli (STEC) strain such as O113:H21, yet the contribution of SubAB to STEC infectious disease is unclear. We found that SubAB reduced activation of the STEC O113:H21 infection-induced non-canonical NLRP3 inflammasome and interleukin (IL)-1β and IL-18 production in murine macrophages. Downstream of lipopolysaccharide signaling, SubAB suppressed caspase-11 expression by inhibiting interferon-β/STAT1 signaling, followed by disrupting formation of the NLRP3/caspase-1 assembly. These inhibitions were regulated by PERK/IRE1α-dependent endoplasmic reticulum (ER) stress signaling initiated by cleavage of the host ER chaperone BiP by SubAB. Our murine model of SubAB-producing Citrobacter rodentium demonstrated that SubAB promoted C. rodentium proliferation and worsened symptoms such as intestinal hyperplasia and diarrhea. These findings highlight the inhibitory effect of SubAB on the NLRP3 inflammasome via ER stress, which may be associated with STEC survival and infectious disease pathogenicity in hosts.

Keywords: Bacteriology; Biochemistry; Microbiology; Protein.