Innate Immunity to Enteric Hepatitis Viruses

Abstract

Although hepatitis A virus (HAV) and hepatitis E virus (HEV) are both positive-strand RNA viruses that replicate in the cytoplasm of hepatocytes, there are important differences in the ways they induce and counteract host innate immune responses. HAV is remarkably stealthy because of its ability to evade and disrupt innate signaling pathways that lead to interferon production. In contrast, HEV does not block interferon production. Instead, it persists in the presence of an interferon response. These differences may provide insight into HEV persistence in immunocompromised patients, an emerging health problem in developed countries.

Co-Occurrence of Hepatitis A Infection and Chronic Liver Disease

“…These results suggest that HAV infection activates human immune systems and induces cytokines [ 115 , 116 , 117 , 118 , 119 ]. Innate immunity also seems to be involved in the pathogenesis of hepatitis A [ 120 , 121 ]. Hypergammaglobulinemia and a high occurrence of autoantibodies are observed in HAV infection [ 122 , 123 ].…”

Induction and Suppression of Innate Antiviral Responses by Hepatitis A Virus

“…Kupffer cells and monocytes express high levels of NLRs, which play important roles in mediating inflammatory responses and modulating liver injury (Dixon et al, 2013 ). Exposure to either eHAV or HAV neither initiates nor blocks NLRP3 inflammasome assembly or IL-1β secretion by THP-1 cells, a human monocyte cell line derived from an acute monocytic leukemia (Feng and Lemon, 2018 ). Nonetheless, NLRX1 positively regulates very early (3 h) RLR-induced cytokine responses to HAV in PH5CH8 cells, which are T antigen-transformed adult human hepatocytes.…”

“…Type I IFNs, but not type II IFNs, are a major barrier for cross-species infection by HAV. MAVS-dependent, RLR-induced IFN responses play a much more important role in restricting HAV replication than TLR3 in vivo , at least in mice, despite the fact that HAV targets adaptors in both signaling pathways for degradation (Feng and Lemon, 2018 ). Since the sequences targeted in human MAVS and TRIF are not conserved in small mammals, the failure of HAV to infect these species could derive from inability to disrupt IFN responses (Hirai-Yuki et al, 2016 ).…”

“…RLR signaling through MAVS in the mitochondria and mitochondria-associated membranes (MAM) results in the expression of both type I and type III interferons, whereas RLR signaling through MAVS in the peroxisome induces the expression of type III interferon alone (Odendall et al, 2014 ; Bender et al, 2015 ; Chow et al, 2018 ). Although type I IFNs clearly play a pivotal role in restricting HAV infection in mice (Hirai-Yuki et al, 2016 ), type III IFNs are predominantly detected in cultured human hepatocytes infected with HAV (Feng and Lemon, 2018 ). Human hepatocytes produce and respond robustly to type III interferon as noted above, but mouse hepatocytes express negligible amounts of the receptor for type III IFN and respond poorly to type III interferon (Hermant et al, 2014 ; Chow et al, 2018 ).…”

CD8+ lymphocytes but not B lymphocytes are required for protection against chronic hepatitis E virus infection in chickens

“…During chronic HEV infection, viral RNA and anti‐HEV antibodies are detected in the feces and serum respectively for more than 6 months . Long‐lasting immunoglobulin G (IgG) HEV antibodies are produced shortly after IgM anti‐HEV antibodies, and HEV persists in the presence of a type III interferon response . In a previous study, the reduction of IFN‐γ producing CD4 + T cells was associated with progression to chronic HEV infection in pigs; however, the role of antibodies and CD8 + T cells during HEV infections remains unknown.…”