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

Leandro Batista (1, 2) , Grégory Jouvion (3, 4) , Dominique Simon-Chazottes (1, 5) , Denis Houzelstein (1) , Odile Burlen-Defranoux (6) , Magali Boissière (7) , Satoko Tokuda (1) , Tânia Zaverucha Do Valle (1, 8) , Ana Cumano (6) , Marie Flamand (7) , Xavier Montagutelli (5, 1) , Jean-Jacques Panthier (1)

1 Génétique fonctionnelle de la Souris
2 SU - Sorbonne Université
3 Inserm U933 - Maladies génétiques d'expression pédiatrique [CHU Trousseau]
4 Neuropathologie expérimentale / Experimental neuropathology
5 Génétique de la souris - Mouse Genetics
6 Lymphopoïèse
7 Virologie Structurale - Structural Virology
8 FIOCRUZ - Fundação Oswaldo Cruz

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.

Domains: Life Sciences [q-bio]; Genetics

Leandro Batista, Grégory Jouvion, Dominique Simon-Chazottes, Denis Houzelstein, Odile Burlen-Defranoux, et al.. Genetic dissection of Rift Valley fever pathogenesis: Rvfs2 locus on mouse chromosome 11 enables survival to early-onset hepatitis. Scientific Reports, 2020, 10 (1), pp.8734. ⟨10.1038/s41598-020-65683-w⟩. ⟨pasteur-02868603⟩