Genetic dissection of Rift Valley fever pathogenesis:Rfvs2on mouse chromosome 11 enables survival to acute-onset hepatitis
Authors: Batista Leandro , Jouvion Gregory , Simon-Chazottes Dominique , Houzelstein Denis , Burlen-Defranoux Odile , Boissière Magali , Tokuda Satoko , Do Valle Tania Zaverucha , Cumano Ana , Flamand Marie , Montagutelli Xavier , Panthier Jean-Jacques 
Published: February 2019

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 whichRvfs2confers increased susceptibility to BALB/c mice that are congenic forRvfs2(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-Rvfs2mice between the third and fifth days after infection. However, C.MBT-Rvfs2mice 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-Rvfs2mice. Likewise, RVFV protein amounts were much lower in BALB/c liver compared to C.MBT-Rvfs2liver. Primary cultured hepatocytes showed higher viral replication rate in C.MBT-Rvfs2which could contribute to the susceptibility conferred byRvfs2. Using bone marrow chimera experiments, we uncovered that both hematopoietic and non-hematopoietic cells are required for the BALB/c allele ofRvfs2to exert its protective effects against the RVFV-induced acute liver disease. Taken together, we have established thatRvfs2acts as an important RVFV restriction factor by limiting virus multiplication in mice.

Author Summary

Rift Valley fever (RVF) is a mosquito-borne viral disease with potential to generate a public health emergency. The wide variation in RVF symptoms and severity observed within patient population suggests that natural host genetic determinants, among other factors, can influence the disease outcome. Infection of mice mimics several features of the pathology in humans, including acute-onset hepatitis and delayed-onset encephalitis. BALB/c inbred mice bearing the BALB/c haplotype at theRvfs2locus survive longer than those bearing the MBT haplotype. In this study, we investigated clinical traits, biochemical parameters, virological evidence, and histological features to characterize the pathogenesis of RVF in early and late susceptible mice. We show that animals of both groups develop acute liver disease shortly after infection. We demonstrate that, by comparison with early susceptible mice, BALB/c mice exhibit significantly reduced replication of RVF virusin vivoin the blood and liver andin vitroin primary cultured hepatocytes, and eventually self-recover from the liver damages. We use reciprocal transplantations of bone marrow cells between early and late susceptible mice to show that survival to severe liver disease requires both hematopoietic and non-hematopoietic cells. Taken together, we establishRvfs2as a single locus that enables mice to survive RVF virus-induced liver disease.