Genetic dissection of Rift Valley fever pathogenesis: Rvfs2 locus on mouse chromosome 11 enables survival to early-onset hepatitis

Abstract

Infection of mice with Rift Valley fever virus (RVFV) reproduces major pathological features of severe human disease, notably the early-onset hepatitis and delayed-onset encephalitis. We previously reported that the Rvfs2 locus from the susceptible MBT/Pas strain reduces survival time after RVFV infection. Here, we used BALB/cByJ (BALB) mice congenic for Rvfs2 (C.MBT-Rvfs2) to investigate the pathophysiological mechanisms impacted by Rvfs2. Clinical, biochemical and histopathological features indicated similar liver damage in BALB and C.MBT-Rvfs2 mice until day 5 after infection. However, while C.MBT-Rvfs2 mice succumbed from acute liver injury, most BALB mice recovered and died later of encephalitis. Hepatocytes of BALB infected liver proliferated actively on day 6, promoting organ regeneration and recovery from liver damage. By comparison with C.MBT-Rvfs2, BALB mice had up to 100-fold lower production of infectious virions in the peripheral blood and liver, strongly decreased RVFV protein in liver and reduced viral replication in primary cultured hepatocytes, suggesting that the BALB Rvfs2 haplotype limits RVFV pathogenicity through decreased virus replication. Moreover, bone marrow chimera experiments showed that both hematopoietic and non-hematopoietic cells are required for the protective effect of the BALB Rvfs2 haplotype. Altogether, these results indicate that Rvfs2 controls critical events which allow survival to RVFV-induced hepatitis.

The ring finger protein 213 gene (Rnf213) contributes to Rift Valley fever resistance in mice

“…The Rvfs2 locus was previously isolated in a congenic strain carrying a ~16.9 Mb segment of distal Chr 11 of the highy susceptible MBT strain in a BALB/c inbred background. We have previously shown that these congenic mice die earlier than BALB/c mice due to a higher susceptibility to the acute RVFVinduced hepatitis correlated with increased replication rate in hepatocytes (Batista et al 2020). This result provided some functional evidence for the specific effect of the Rvfs2 locus on the time to death in mice which develop a fatal infection.…”

“…In human RVFV patients, the liver is the primary site of RVFV replication and lipid droplet accumulation was reported in the liver of a man who died from RVFV (Shraim et al 2016). In the mouse model, a major consequence of RVFV infection is also the overwhelming infection of hepatocytes that subsequently undergo apoptosis resulting in early-onset death primarily attributed to severe hepatitis (Batista et al 2020;Smith et al 2010). The hepatocytes that maintain their viability amass cytoplasmic lipid droplets that persist during liver regeneration in the surviving mice (Reed et al 2012).…”

“…The characterization of the Rvfs2 locus was achieved using congenic mice. Indeed, while most BALB/c males die from 9 to 10 days after infection with signs of encephalitis (Batista et al 2020), C.MBT-Rvfs2 congenic males, that carry the Rvfs2 locus from the MBT strain on a BALB/c genetic background, generally die within 5 days of infection with signs of acute hepatitis. We have shown that the prolonged time to death in BALB/c mice could be explained by their capacity to overcome this acute hepatitis, emphasizing the pathophysiological relevance of the time to death as a parameter for suceptibility (Batista et al 2020).…”

Genetic diversity of collaborative cross mice enables identification of novel rift valley fever virus encephalitis model

“…BALB/c mice are the exception to this, displaying a split-phenotype where some BALB/c mice overcome the hepatic stage of infection to progress to death by late-onset encephalitis [ 6 ]. By using the inherent difference in hepatic disease susceptibility present in BALB/c and MBT mice (classically susceptible to hepatitis) three RVF susceptibility loci (Rvfs2, Rvfs11, and Rvfs5) were identified as affecting survival time [ 7 , 29 ]. To date, these are the only genetic loci that have been identified as affecting RVFV susceptibility in the mouse.…”

“…However, in up to 20% of cases people exhibit severe forms of disease including retinitis, hepatitis, hemorrhagic fever, or delayed-onset encephalitis [ 1 – 4 ]. Compared to the breadth of clinical outcomes in humans, inbred mouse strains challenged with wild-type (WT) RVFV are uniformly susceptible to infection and overwhelmingly develop a lethal acute hepatitis with occasional BALB/c mice surviving longer to display encephalitic manifestations [ 5 – 7 ]. There are no murine models that develop either hemorrhagic fever, retinitis, or uniform late-onset encephalitis.…”