The Dissemination of Rift Valley Fever Virus to the Eye and Sensory Neurons of Zebrafish Larvae Is Stat1-Dependent

The Rift Valley fever virus (RVFV) causes haemorrhagic fever, encephalitis, and permanent blindness and has been listed by the WHO as a priority pathogen. To study RVFV pathogenesis and identify small-molecule antivirals, we established a novel In Vivo model using zebrafish larvae. Pericardial injection of RVFV resulted in ~4 log₁₀ viral RNA copies/larva, which was inhibited by the antiviral 2'-fluoro-2'-deoxycytidine. The optical transparency of the larvae allowed detection of RVFV_eGFP in the liver and sensory nervous system, including the optic tectum and retina, but not the brain or spinal cord. Thus, RVFV-induced blindness likely occurs due to direct damage to the eye and peripheral neurons, rather than the brain. Treatment with the JAK-inhibitor ruxolitinib, as well as knockout of stat1a but not stat1b, enhanced RVFV replication to ~6 log₁₀ viral RNA copies/larva and ultra-bright livers, although without dissemination to sensory neurons or the eye, thereby confirming the critical role of stat1 in RVFV pathogenesis.