Novel Mechanism of Arenavirus-Induced Liver Pathology

Abstract

Viral hemorrhagic fevers (VHFs) encompass a group of diseases with cardinal symptoms of fever, hemorrhage, and shock. The liver is a critical mediator of VHF disease pathogenesis and high levels of ALT/AST transaminases in plasma correlate with poor prognosis. In fact, Lassa Fever (LF), the most prevalent VHF in Africa, was initially clinically described as hepatitis. Previous studies in non-human primate (NHP) models also correlated LF pathogenesis with a robust proliferative response in the liver. The purpose of the current study was to gain insight into the mechanism of liver injury and to determine the potential role of proliferation in LF pathogenesis. C57Bl/6J mice were infected with either the pathogenic (for NHPs) strain of lymphocytic choriomeningitis virus (LCMV, the prototypic arenavirus), LCMV-WE, or with the non-pathogenic strain, LCMV-ARM. As expected, LCMV-WE, but not ARM, caused a hepatitis-like infection. LCMV-WE also induced a robust increase in the number of actively cycling hepatocytes. Despite this increase in proliferation, there was no significant difference in liver size between LCMV-WE and LCMV-ARM, suggesting that cell cycle was incomplete. Indeed, cells appeared arrested in the G1 phase and LCMV-WE infection increased the number of hepatocytes that were simultaneously stained for proliferation and apoptosis. LCMV-WE infection also induced expression of a non-conventional virus receptor, AXL-1, from the TAM (TYRO3/AXL/MERTK) family of receptor tyrosine kinases and this expression correlated with proliferation. Taken together, these results shed new light on the mechanism of liver involvement in VHF pathogenesis. Specifically, it is hypothesized that the induction of hepatocyte proliferation contributes to expansion of the infection to parenchymal cells. Elevated levels of plasma transaminases are likely explained, at least in part, by abortive cell cycle arrest induced by the infection. These results may lead to the development of new therapies to prevent VHF progression.

Pro-inflammatory cytokines promote viral replication and cell cycle mediators in arenavirus-induced hepatitis.

“…Our recent studies showed Axl to be upregulated at the gene and protein expression levels in the liver of LCMV-WE-infected mice [45]. As a potential viral entry factor into hepatocytes and a key player involved in inhibiting TLR-immune responses [75], we examined the impact of TNF-α and LCMV infection on gene expression of Axl in AML-12 hepatocytes ( Figure 5C).…”

“…[37,44,45]. Furthermore, although KCs or resident liver macrophages were targeted early, hepatitis developed when hepatocytes were targeted more exclusively later in infection [44].…”

“…Furthermore, although KCs or resident liver macrophages were targeted early, hepatitis developed when hepatocytes were targeted more exclusively later in infection [44]. We previously observed in mice that LCMV-WE caused transient hepatitis and liver pathology characterized by robust hepatocyte proliferation without hyperplasia, cell cycle arrest, and strong upregulation of hepatic tumor necrosis factor alpha (TNF-α) expression [45].…”

“…We focused on TNF-α specifically because this proinflammatory cytokine was upregulated in our results from LCMV-WE infection in mice [45]; therefore, we focused on this cytokine in our murine macrophages…”

“…Furthermore, liver hyperplasia was not evident in human LF cases nor in NHP or murine animal models of LF-like disease, suggesting hepatocyte cell cycle is incomplete [25,26,45]. Thus, we next investigated the effect of LCMV infection on cell cycle mediators in our proliferating AML-12 hepatocytes.…”