Species-specific gene programs define divergent antiviral responses in Marburg virus reservoir bats and humans

Bats tolerate viruses that cause severe disease in humans. Egyptian rousette bats, the natural reservoirs of Marburg virus (MARV), sustain asymptomatic infection, whereas humans develop severe and fatal disease. To define the basis of this divergence, we establish a comparative framework using primary and immortalized Egyptian rousette and human cells exposed to double-stranded RNA and interferon (IFN). Bat cells upregulate antiviral effectors while limiting inflammatory amplifiers, a pattern further supported by analysis of independent in vivo MARV infection datasets. In contrast, human cells activate antiviral programs and immune hyperactivation in response to MARV. Integrating transcriptomic and proteomic analyses, we identify species-specific immune programs encompassing differential IFN-stimulated gene regulation, apoptotic control, and cytokine signaling. Our findings establish an integrative framework for understanding species-specific antiviral responses associated with MARV reservoir biology, identify pathways linked to immunopathogenesis in humans, and provide a foundation for future studies of host responses to filovirus infection.