Chikungunya virus (CHIKV) is a re-emerging arbovirus in the alphavirus genus. Upon infection, it can cause severe joint pain that can last years in some patients, significantly affecting their quality of life. Currently, there are no vaccines or anti-viral therapies available against CHIKV. Its spread to the Americas from the eastern continents has substantially increased the count of the infected by millions. Thus, there is an urgent need to identify therapeutic targets for CHIKV treatment. A potential point of intervention is the sphingosine-1-phosphate (S1P) pathway. Conversion of sphingosine to S1P is catalyzed by Sphingosine kinases (SKs), which we previously showed to be crucial pro-viral host factor during CHIKV infection. In this study, we screened inhibitors of SKs and identified a novel potent inhibitor of CHIKV infection—SLL3071511. We showed that the pre-treatment of cells with SLL3071511 in vitro effectively inhibited CHIKV infection with an EC₅₀ value of 2.91 µM under both prophylactic and therapeutic modes, significantly decreasing the viral gene expression and release of viral particles. Our studies suggest that targeting SKs is a viable approach for controlling CHIKV replication.

Sphingosine kinase 2 (SK2) is a lipid kinase that catalyzes the production of sphingosine-1-phosphate (S1P) from sphingosine. Previously, we have shown that SK2 is recruited to the viral replication complex (VRC) early during chikungunya virus (CHIKV) infection. In the present study, we demonstrate that SK2 is required for viral replication and protein production. Treatment with a SK2 inhibitor significantly impaired the function of a CHIKV replicon. Similarly, compound treatment or genetic targeting resulted in impaired viral protein production. Mechanistically, we demonstrate that CHIKV nsP3 binds to SK2. Association of nsP3 with SK2 was mediated, in part, through the FGDF motifs within the hypervariable domain (HVD) of nsP3. In a competition assay, SK2 competed with G3BP for binding to nsP3. Collectively, these results extend our previous findings and identify SK2 as a CHIKV host factor recruited by nsP3.

Alphaviruses have recently re-emerged as important disease-causing agents resulting in debilitating disease in humans and animals. To develop therapeutic strategies, it is important to identify host factors co-opted by viruses during infection. Sphingosine kinases (SKs) have been identified as important host factors for viruses. In this study, we extend on our previous findings and demonstrate a pattern to re-localization of sphingosine kinases during alphavirus infection. Specifically, we observed that encephalitic alphaviruses preferentially re-localize SK1, while arthritogenic alphaviruses re-localize SK2, during infection. Inhibition of SK1 specifically resulted in decreased encephalitic alphavirus infection. Thus, sphingosine kinases are differentially recruited by alphaviruses and represent a viable therapeutic target.

On January 9th, 2025, the California Council on Science and Technology (CCST), in partnership with the Department of Public and Ecosystem Health at Cornell University, brought together 30 interdisciplinary experts in Sacramento, California for the Wildland Fire Smoke and Public Health Convening. The event was held against the backdrop of the devastating Palisades and Eaton fires in Los Angeles, providing a somber reminder of the urgency of dealing with extreme fires. The convening aimed to connect the various disciplines working to respond to wildland fire smoke in California, particularly focusing on the roles of land managers and public health practitioners. Land management and public health experts participated in breakout sessions where they discussed current practices in their respective fields and identified gaps in research, policy, and practice that need to be addressed.