Hepatitis E virus infection activates NOD-like receptor family pyrin domain-containing 3 inflammasome antagonizing interferon response but therapeutically targetable
| Autor: | 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, Marco J. Bruno, Robert A. de Man, Maikel P. Peppelenbosch, Sonja I. Buschow, Lin Wang, Yijin Wang, Qiuwei Pan |
|---|---|
| Přispěvatelé: | Gastroenterology & Hepatology |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Inflammasomes
THP-1 Cells viruses Interleukin-1beta Primary Cell Culture Inflammation medicine.disease_cause Antiviral Agents Pathogenesis chemistry.chemical_compound Hepatitis E virus SDG 3 - Good Health and Well-being Interferon NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Humans Secretion Hepatology business.industry Macrophages Ribavirin NF-kappa B virus diseases Inflammasome Hepatitis E Disease Models Animal chemistry Viral replication Host-Pathogen Interactions Immunology Interferons Rabbits medicine.symptom business Signal Transduction medicine.drug |
| Zdroj: | Hepatology, 75(1), 196-212. John Wiley & Sons Ltd. |
| ISSN: | 0270-9139 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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