Genetic dissection of Rift Valley fever pathogenesis: Rfvs2 on mouse chromosome 11 enables survival to acute-onset hepatitis [article]

Leandro Batista, Grégory Jouvion, Dominique Simon-Chazottes, Denis Houzelstein, Odile Burlen-Defranoux, Magali Boissière, Satoko Tokuda, Tania Zaverucha do Valle, Ana Cumano, Marie Flamand, Xavier Montagutelli, Jean-Jacques Panthier
2019 bioRxiv   pre-print
The systemic inoculation of mice with Rift Valley fever virus (RVFV) reproduces major pathological features of severe human disease, notably the acute-onset hepatitis and delayed-onset encephalitis. We previously reported that a genomic interval (Rvfs2) derived from the susceptible MBT/Pas strain is associated with reduced survival time after RVFV infection. In this study, we investigated the pathophysiological mechanisms by which Rvfs2 confers increased susceptibility to BALB/c mice that are
more » ... ngenic for Rvfs2 (C.MBT Rvfs2) after infection with virulent RVFV. Clinical traits, biochemical parameters, and histopathological features indicated similar liver damage in BALB/c and C.MBT Rvfs2 mice between the third and fifth days after infection. However, C.MBT Rvfs2 mice died at that point from acute liver injury while most BALB/c mice recovered from this condition but eventually died of encephalitis. We observed that hepatocytes proliferated actively within the infected liver of BALB/c mice on the sixth day after infection, promoting organ regeneration on the eighth day after infection and recovery from liver damage. We found that the production of infectious virions was up to 100-fold lower in the peripheral blood and liver of BALB/c compared to C.MBT Rvfs2 mice. Likewise, RVFV protein amounts were much lower in BALB/c liver compared to C.MBT Rvfs2 liver. Primary cultured hepatocytes showed higher viral replication rate in C.MBT Rvfs2 which could contribute to the susceptibility conferred by Rvfs2. Using bone marrow chimera experiments, we uncovered that both hematopoietic and non-hematopoietic cells are required for the BALB/c allele of Rvfs2 to exert its protective effects against the RVFV-induced acute liver disease. Taken together, we have established that Rvfs2 acts as an important RVFV restriction factor by limiting virus multiplication in mice.
doi:10.1101/545129 fatcat:oyr4ezb2j5hmbdfqf2cwwu675u