A Peripheral Neuron-to-Microglia Signaling Axis Connecting Transient Viral Infection to Persistent Neuroinflammatory States

Abstract Acute viral infections can cause lasting symptoms in anatomically distant, uninfected tissues, a phenomenon that challenges traditional notions of viral pathogenesis. A leading example is long COVID, a condition in which neurological and other clinical symptoms can materialize long after viral clearance¹. In investigating the mechanisms underlying this phenomenon, we found that despite evading direct infection, olfactory sensory neurons (OSNs) demonstrate a progressive slow decline following SARS-CoV-2 infection, triggering a prolonged neuroinflammatory response that persists for weeks to months post viral resolution. Using both small animal models and human clinical samples, we demonstrate that the virus selectively infects sustentacular cells in the olfactory epithelium (OE), leading to structural disruption and secondary OSN loss. Axonal debris from degenerating OSNs accumulates in the olfactory bulb (OB), where it triggers sustained activation of resident microglia cells and persistent inflammatory signaling. These immune responses are spatially restricted to OB regions innervated by the damaged neurons and are marked by transcriptional programs involved in phagocytosis, synaptic remodeling, and debris clearance. Together, these findings delineate a conserved neuron-to-glia injury axis in which peripheral neuronal damage initiates a protracted cascade that, despite the absence of direct central nervous system infection, culminates in delayed and persistent neuroinflammation. This mechanism offers a unifying framework for how transient respiratory infections can lead to persistent neurological sequelae, including those seen in long COVID.