Development of a reverse genetics system for Sosuga virus allows rapid screening of antiviral compounds

Sosuga virus (SOSV) is a recently discovered zoonotic paramyxovirus isolated from a single human case in 2012; it has been ecologically and epidemiologically associated with transmission by the Egyptian rousette bat (Rousettus aegyptiacus). Bats have long been recognized as sources of novel zoonotic pathogens, including highly lethal paramyxoviruses like Nipah virus (NiV) and Hendra virus (HeV). The ability of SOSV to cause severe human disease supports the need for studies on SOSV pathogenesis to better understand the potential impact of this virus and to identify effective treatments. Here we describe a reverse genetics system for SOSV comprising a minigenome-based assay and a replication-competent infectious recombinant reporter SOSV that expresses the fluorescent protein ZsGreen1 in infected cells. First, we used the minigenome assay to rapidly screen for compounds inhibiting SOSV replication at biosafety level 2 (BSL-2). The antiviral activity of candidate compounds was then tested against authentic viral replication using the reporter SOSV at BSL-3. We identified several compounds with anti-SOSV activity, several of which also inhibit NiV and HeV. Alongside its utility in screening for potential SOSV therapeutics, the reverse genetics system described here is a powerful tool for analyzing mechanisms of SOSV pathogenesis, which will facilitate our understanding of how to combat the potential public health threats posed by emerging bat-borne paramyxoviruses.
Author summary Shortly after returning from a field trip to South Sudan and Uganda in 2012, a wildlife researcher presented to the emergency room with high fever and muscle and joint pain, that later progressed to severe disease. Sosuga virus (SOSV), a novel paramyxovirus, was identified as the etiological agent. Further epidemiological investigations identified bats as the probable reservoir of SOSV. Other related bat-borne paramyxoviruses, such as Nipah and Hendra viruses, have developed into major public health issues, raising concern that SOSV could represent an emerging threat. We developed a SOSV reverse genetics system to screen antiviral compounds and identify putative therapeutic interventions. Using this system, we generated a reporter virus capable of expressing a fluorescent protein in infected cells. By incorporating the reporter SOSV into a high-throughput screening assay, we identified several compounds that inhibit SOSV replication. In addition to antiviral screening, this rescue system can be used to investigate disease mechanisms, and to contribute to development of public health interventions for threats posed by emerging bat-transmitted paramyxoviruses.