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Pathogenesis, miR-122 gene-regulation, and protective immune responses after acute equine hepacivirus infection

ABSTRACT: Equine hepacivirus (EqHV) is phylogenetically the closest relative of hepatitis C virus (HCV) and shares genome organization, hepatotropism, transient or persistent infection outcome, and the ability to cause hepatitis. Thus, EqHV studies are important to understand equine liver disease, and further as an outbred surrogate animal model for HCV pathogenesis and protective immune responses. Here, we aimed to characterize the course of EqHV infection and associated protective immune responses. Approach & Results: Seven horses were experimentally inoculated with EqHV, monitored for 6 months, and rechallenged with the same, and subsequently a heterologous EqHV. Clearance was the primary outcome (6 of 7) and was associated with subclinical hepatitis characterized by lymphocytic infiltrate and individual hepatocyte necrosis. Seroconversion was delayed and antibody titers waned slowly. Clearance of primary infection conferred non-sterilizing immunity resulting in shortened duration of viremia after rechallenge. Peripheral blood mononuclear cell responses in horses were minimal, although EqHV specific T cells were identified. Additionally, an interferon stimulated gene signature was detected in the liver during EqHV infection, similar to acute HCV in humans. EqHV, as HCV, is stimulated by direct binding of the liver-specific microRNA, miR-122. Interestingly, we found that EqHV infection sequesters enough miR-122 to functionally affect gene regulation in the liver. This RNA-based mechanism thus could have consequences for pathology. Conclusions: EqHV infection in horses typically has an acute resolving course, and the protective immune response lasts for at least a year and broadly attenuates subsequent infections. This could have important implications to achieve the primary goal of an HCV vaccine; to prevent chronicity while accepting acute resolving infection after virus exposure.

ORGANISM(S): Equus caballus

PROVIDER: GSE167260 | GEO | 2021/06/01

REPOSITORIES: GEO

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Project description:Hepatitis A virus (HAV) is a hepatotropic human picornavirus that has been associated only with acute infection. Its pathogenesis is not well understood since there have been few recent studies in animal models using modern methodologies. We characterized HAV infections in three chimpanzees, quantifying viral RNA by qRT-PCR and examining critical aspects of the innate immune response including intrahepatic interferon-stimulated gene expression. We compared these infection profiles with similar studies of chimpanzees infected with hepatitis C virus (HCV), a hepatotropic flavivirus that frequently causes persistent infection. Surprisingly, HAV-infected animals exhibited very limited induction of type I interferon-stimulated genes in the liver compared to chimpanzees with acute resolving HCV infection, despite similar levels of viremia and 100-fold greater quantities of viral RNA in the liver. Minimal ISG15 and IFIT1 responses peaked 1-2 weeks after HAV challenge, then subsided despite continuing high hepatic viral loads. An acute inflammatory response at 3-4 weeks correlated with the appearance of virus-specific antibodies, and both apoptosis and proliferation of hepatocytes. Despite this, HAV RNA persisted in the liver for months, remaining present long after its clearance from serum and feces and revealing dramatic differences in the kinetics of clearance in the three compartments. Viral RNA was detected in the liver for significantly longer (35 to >48 weeks) than HCV RNA in animals with acute resolving HCV infection (10-20 weeks). Collectively, these findings suggest that early HAV infection is far stealthier than HCV infection and represents a distinctly different paradigm in viral-host interactions within the liver. Chimpanzee liver was biopsied during an acute HAV infection. Chimp 1 and 2 had two baseline samples. Chimp 3 used the baselines from chimps 1 and 2. Chimp 1 had 8 samples during the HAV acute infection. Chimp 2 had 9 samples during the HAV acute infection. Chimp 3 had 4 samples during the HAV acute infection.

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Pathogenesis, miR-122 gene-regulation, and protective immune responses after acute equine hepacivirus infection

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