Molecular Insights into Alphavirus Host-Pathogen Interactions: A Focus on Immune Evasion

Alphaviruses are enveloped, positive-sense, single-stranded RNA viruses transmitted by mosquito vectors. These viruses, classified as arthritogenic or encephalitic, pose significant public health risks. Arthritogenic alphaviruses cause persistent arthritis, joint damage, and cardiomyopathy, while encephalitic strains can lead to severe neurological sequelae or death. Globalization and climate change have expanded the range of vector-competent mosquitoes, resulting in epidemics such as the 2 million cases of Chikungunya virus in the Western Hemisphere. Despite this burden, no effective antiviral therapies or licensed vaccines are available. To address this gap, our lab investigates the molecular mechanisms of alphavirus infection, focusing on immune evasion strategies. Through an innovated, unbiased biotin ligase approach, we identified a conserved interaction between the Sindbis virus (SINV) capsid protein (CP) and the host innate immune regulator Interleukin-1 Receptor-Associated Kinase 1 (IRAK1). Our objective is to define the molecular determinants and functional outcomes of this interaction to identify potential therapeutic targets. We hypothesize that the CP/IRAK1 interface is a critical immune evasion strategy that allows alphaviruses to subvert host defenses. Our comparative analyses indicate that the CP’s RII domain mediates the IRAK1 interaction, which is crucial for viral dissemination and neuroinvasion in vivo. Thus, the CP/IRAK1 interaction suppresses innate immune activation by masking viral Pathogen-Associated Molecular Patterns (PAMPs) from Toll-Like Receptors (TLRs), facilitating immune evasion. By elucidating how alphavirus capsid proteins modulate host immune pathways, we aim to inform the development of strategies to mitigate the physiological impacts of alphavirus infections. UofL Dept. of Microbiology and Immunology JHFE Competitive Enhancement Grant NIH-NIAID R01 AI153275 to KJS This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.