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Hepatitis E virus infection activates NOD‐like receptor family pyrin domain‐containing 3 inflammasome antagonizing interferon response but therapeutically targetable
Author(s) -
Li Yang,
Yu Peifa,
Kessler Amy L.,
Shu Jingyi,
Liu Xiaoyan,
Liang Zhaochao,
Liu Jiaye,
Li Yunlong,
Li Pengfei,
Wang Ling,
Wang Yining,
Ma Zhongren,
Liu Aixia,
Wang Ling,
Bruno Marco J.,
Man Robert A.,
Peppelenbosch Maikel P.,
Buschow Sonja I.,
Wang Lin,
Wang Yijin,
Pan Qiuwei
Publication year - 2022
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.32114
Subject(s) - inflammasome , pyrin domain , immunology , interferon , innate immune system , virology , macrophage , biology , nod , inflammation , immune system , in vivo , biochemistry , microbiology and biotechnology , in vitro
Background and Aims HEV infection is the most common cause of liver inflammation, but the pathogenic mechanisms remain largely unclear. We aim to explore whether HEV infection activates inflammasomes, crosstalk with antiviral interferon response, and the potential of therapeutic targeting. Approach and Results We measured IL‐1β secretion, the hallmark of inflammasome activation, in serum of HEV‐infected patients and rabbits, and in cultured macrophage cell lines and primary monocyte‐derived macrophages. We found that genotypes 3 and 4 HEV infection in rabbits elevated IL‐1β production. A profound increase of IL‐1β secretion was further observed in HEV‐infected patients (1,733 ± 1,234 pg/mL; n = 70) compared to healthy persons (731 ± 701 pg/mL; n = 70). Given that macrophages are the drivers of inflammatory response, we found that inoculation with infectious HEV particles robustly triggered NOD‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome activation in primary macrophages and macrophage cell lines. We further revealed that the ORF2 capsid protein and the formed integral viral particles are responsible for activating inflammasome response. We also identified NF‐κB signaling activation as a key upstream event of HEV‐induced NLRP3 inflammasome response. Interestingly, inflammasome activation antagonizes interferon response to facilitate viral replication in macrophages. Pharmacological inhibitors and clinically used steroids can effectively target inflammasome activation. Combining steroids with ribavirin simultaneously inhibits HEV and inflammasome response without cross‐interference. Conclusions HEV infection strongly activates NLRP3 inflammasome activation in macrophages, which regulates host innate defense and pathogenesis. Therapeutic targeting of NLRP3, in particular when combined with antiviral agents, represents a viable option for treating severe HEV infection.