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bioRxiv · 10.64898/2026.07.02.736094

Mammarenavirus-Induced Remodeling of the Cellular Lipid Landscape Reveals Sphingolipid Metabolism as a Novel Target for Antiviral Intervention

Mingo-Casas, P.·Witwit, H.·Casasampere, M.·Blazquez, A. B.·Cubitt, B.·Martin-Acebes, M. A.·de la Torre, J. C.
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Abstract

Several mammarenaviruses (MaAv) cause severe and often life-threatening disease in humans and represent major public health threats in their endemic regions. Lassa (LASV) and Junin (JUNV) MaAv, endemic to Western Africa and the Argentine Pampas, respectively, are etiologic agents of viral hemorrhagic fevers associated with high morbidity and mortality. In addition, the globally distributed MaAv lymphocytic choriomeningitis virus (LCMV) is an underrecognized human pathogen capable of causing severe congenital disease and fatal infections in immunocompromised individuals. Despite their public health importance, no FDA-approved vaccines or virus-specific antiviral therapies exist to prevent and treat human MaAv infections. Current treatment relies on the off-label use of ribavirin whose therapeutic efficacy remains controversial. These findings underscore the urgent need to develop effective antiviral strategies against human pathogenic MaAv. Here, we investigated the impact of LCMV infection on host lipid metabolism using an integrated transcriptomic and lipidomic approach. Our data reveal extensive time-dependent remodeling of the cellular lipid landscape, with particularly prominent alterations in sphingolipid and fatty acid metabolic pathways. Functional interrogation of these pathways using pharmacological inhibitors identified acetyl-CoA carboxylase (ACC) and neutral sphingomyelinase 2 (nSMase2) as host factors contributing to efficient viral replication. Notably, inhibition of nSMase2 reduced infectious virus production by 2 logs of infectious virus. Our findings showed that LCMV reprograms host lipid metabolism to facilitate infection and identified sphingolipid turnover as a promising target for host-directed antiviral strategies against MaAv infections.

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Mingo-Casas, P., Witwit, H., Casasampere, M., Blazquez, A. B., Cubitt, B., Martin-Acebes, M. A., de la Torre, J. C.. 2026-07-03. Mammarenavirus-Induced Remodeling of the Cellular Lipid Landscape Reveals Sphingolipid Metabolism as a Novel Target for Antiviral Intervention. https://doi.org/10.64898/2026.07.02.736094

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