Abstract
Hepatitis A virus (HAV) infection is a common cause of acute viral hepatitis worldwide. Despite decades of research, the pathogenic mechanisms of hepatitis A remain incompletely understood. As the replication of HAV is noncytopathic in vitro, a widely accepted concept has been that virus-specific cytotoxic T cells are responsible for liver injury. However, accumulating evidence suggests that natural killer (NK) cells, NKT cells, and even non-HAV-specific CD8+ T cells contribute to liver damage during HAV infection. In addition, intrinsic death of virus-infected hepatocytes has been implicated as a cause of liver injury in a murine model of hepatitis A. Furthermore, genetic variations in host factors such as T cell immunoglobulin-1 (TIM1) and IL-18 binding protein (IL-18BP) have been linked to hepatitis A severity. This review summarizes the current knowledge of the mechanisms of hepatocellular injury in hepatitis A. Different mechanisms may be involved under different conditions and they are not necessarily mutually exclusive. A better understanding of these mechanisms would aid in diagnosis and treatment of diseases associated with HAV infection.
Highlights
Hepatitis A virus (HAV) infection is a common cause of acute viral hepatitis worldwide
Studies with experimentally infected chimpanzees revealed a very limited induction of type I interferon-stimulated genes in the liver during the acute phase [9]. This blunted type I IFN response is attributable to HAV protease-mediated cleavage of the mitochondrial antiviral signaling protein (MAVS) and TIR-domain-containing adaptor-inducing interferon-β (TRIF) [32,33]
These initial studies provided the first evidence that virus-specific cytotoxic T lymphocytes (CTLs) are involved in mediating liver injury in acute hepatitis A (Figure 1A)
Summary
Hepatitis A virus (HAV) infection is a common cause of acute viral hepatitis worldwide. HAV infection is associated with a lengthy incubation period (4–6 weeks), during which large amounts of virus are shed into the feces [1]. HAV replicates very slowly and does not cause apparent cytopathic effects in cell culture [5]. This is in line with a relatively long incubation period of acute HAV infection in humans [1,4]. A murine model was established by Lemon and colleagues [10] Studies in these animal models have provided insights into the pathogensis of HAV infection in humans
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