MXRA8 confers respiratory tropism and drives systemic dissemination of Chikungunya virus

Chikungunya virus (CHIKV) is a re-emerging alphavirus causing explosive urban outbreaks worldwide. Historically, its pathogenesis has been restricted to a canonical mosquito-host cycle wherein cutaneous inoculation drives systemic inflammation. However, the biological mechanisms sustaining its rapid transmission dynamics remain incompletely defined. Here, we identify the human respiratory tract as a highly permissive amplification niche. Patient nasopharyngeal swabs reveal high viral loads, while human nasal and airway organoids demonstrate robust replication and bidirectional release facilitating respiratory shedding and systemic dissemination. Single-nucleus RNA sequencing (snRNA-seq) delineates a pan-epithelial infection landscape, revealing a transcriptional reprogramming that drives pro-inflammatory signaling while simultaneously suppressing homeostatic tissue repair. Mechanistically, CHIKV engages the Matrix Remodeling Associated 8 (MXRA8) receptor for entry and exploits tunneling nanotubes (TNTs) for covert spread. In AG129 mice, intranasal inoculation triggers necrotizing respiratory cytopathology, breaching the mucosal barrier to seed systemic infection. This reveals a pathogenic dichotomy where airway necrosis contrasts with the characteristic inflammatory storm in distal musculoskeletal targets. Collectively, these findings establish an MXRA8-mediated arbo-respiratory axis, identifying the respiratory mucosa as a previously overlooked reservoir that critically enhances systemic pathogenesis and transmission efficiency.