Hepatitis E virus infection activates NOD-like receptor family pyrin domain-containing 3 inflammasome antagonizing interferon response but therapeutically targetable

Yang Li, Peifa Yu, Amy L. Kessler, Jingyi Shu, Xiaoyan Liu, Zhaochao Liang, Jiaye Liu, Yunlong Li, Pengfei Li, Ling Wang, Yining Wang, Zhongren Ma, Aixia Liu, Ling Wang, Marco J. Bruno, Robert A. de Man, Maikel P. Peppelenbosch, Sonja I. Buschow, Lin Wang*, Yijin Wang*Qiuwei Pan*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Pages (from-to)196-212
Number of pages17
JournalHepatology
Volume75
Issue number1
Early online date15 Aug 2021
DOIs
Publication statusPublished - Jan 2022

Bibliographical note

Funding Information:
Supported by a VIDI grant (No. 91719300) from the Netherlands Organisation for Scientific Research (NWO; to Q. Pan) and the China Scholarship Council for funding Ph.D. fellowship (to Yang Li; No. 201703250073) We thank Dr. Ruud Delwel (Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands) for generously providing THP-1 and U937 cell lines and Dr. Gwenny Fuhler (Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands) for providing the HL60 cell line. We also thank Dr. Suzanne U. Emerson (National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA) for generously providing GT1 and GT3 HEV plasmids to generate subgenomic and full-length HEV genomic RNA; Dr. Tian-Cheng Li (National Institute of Infectious Diseases, Tokyo, Japan) for providing the plasmid containing the full-length dromedary camel HEV genome (GenBank Accession: KJ496144); and Dr. Rasa Petraityt?-Burneikien? (Vilnius University, Lithuania) and Dr. Rainer G?nter Ulrich (Federal Research Institute for Animal Health, Greifswald, Germany) for providing purified recombinant HEV ORF2 protein.

Funding Information:
Supported by a VIDI grant (No. 91719300) from the Netherlands Organisation for Scientific Research (NWO; to Q. Pan) and the China Scholarship Council for funding Ph.D. fellowship (to Yang Li; No. 201703250073)

Publisher Copyright:
© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

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