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

Abstract

Background & Aims: Hepatitis E virus (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, the crosstalk with antiviral interferon response and potential of therapeutic targeting. Approach & 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 (1733 pg/mL ± 1234; n = 70) compared with healthy individuals (731 pg/mL ± 701; n = 70). As macrophages are the drivers of inflammatory response, we found inoculation with infectious HEV particles robustly triggered 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 inhibit 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 NLRP3, in particular when combined with antiviral agents, represents a viable option for treating severe HEV infection.

Chronic hepatitis E: Advancing research and patient care

“…A recent study showed that macrophages effectively initiate NLRP3 inflammasome activation in response to active HEV infection but also inactivated viral particles. 100 This study provided further in vivo evidence of inflammasome activation in rabbits and patients acutely infected with HEV. 100 Future investigation in chronically infected animals and patients is highly relevant.…”

“…100 This study provided further in vivo evidence of inflammasome activation in rabbits and patients acutely infected with HEV. 100 Future investigation in chronically infected animals and patients is highly relevant. Interestingly, pharmacological targeting of NLRP3 by steroids can inhibit HEV-triggered inflammasome activation.…”

Placenta as a site of HEV replication and inflammatory cytokines modulating the immunopathogenesis of HEV in pregnant women

“…In addition, the statistically significant difference in the IL‐1β and IL‐18 cytokine levels in the serum of HEV‐infected pregnant women further contributed to the pathogenesis. NLRP3 inflammasome was found to be activated in macrophages leading to the elevation of IL‐1β secretion in HEV‐infected patients 18 . Our previous study showed that NLRP3 sensed the HEV infection and produced inflammatory cytokines IL‐1β and IL‐18, which further stimulated IFN‐γ production and initiated Th1 response 19 .…”

Review of clinical characteristics, immune responses and regulatory mechanisms of hepatitis E-associated liver failure

“…A recent study reported the critical role of an important inflammasome (NLRP3) in HEV infection, which can be activated by macrophages and then further regulate host defense. Further research suggests that therapeutic targeting of NLRP3 could benefit treatment of HEV-associated severe liver disease[ 9 ].…”

“…The changed numbers of monocyte-macrophage cells and dendritic cells and increased proinflammatory cytokines [interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-10, IL-18] in blood among HEV patients correlated with adverse outcomes. In addition, inflammasome activation in macrophages shows that immune response plays an important role in the development of HEV-associated LF[ 9 , 11 , 12 ], although the exact pathogenesis remains to be clarified.…”