Work

CVA16 infection causes neurological injury by engaging TLR2/MYD88/TNF-α/CXCL1 signalling pathway in hSCARB2 knock-in mice

Year: 2025

Type: article

Abstract: Coxsackievirus A16 (CVA16), a major pathogen responsible for hand-foot-and-mouth disease (HFMD) in children, has frequently replaced Enterovirus A71 as the predominant causative agent in China and other Asia-Pacific regions. The lack effective drugs and vaccines against this virus exacerbates the concerns on its outbreaks. Clinical reports and laboratory studies indicate that CVA16 infection may lead to neurological injury, but the precise mechanisms remain elusive. In this study, we meticulously established a CVA16 murine disease model using 3-week-old hSCARB2 knock-in mice through intracranial inoculation. Within 4-7 days post-infection, the infected mice exhibited severe neurological symptoms featured as limb paralysis, hind limb weakness and ataxia. Furthermore, high viral loads were detected in the brain, spleen, skeletal muscle tissues, indicating a systemic infection. A robust cytokine response was observed, characterized with the elevation of TNF-α, IL-12 (p40), IL-10 and MIP-1β. Histological and immunofluorescence staining revealed extensive inflammation, marked by the concentrated infiltration of astrocytes cells, as well as severe neurological injury, which included hypertrophic and extended pseudopodia microglia, increased astrocytes with long and stretched protuberances, markedly decreased neuronal cell bodies and nerve fibers in brain. No visible pathological changes were observed in spinal cord tissues. RNA sequencing and immunofluorescence staining of brain tissue verification assays indicated that the neurological injury may engage in TLR2/MYD88/TNF-α/CXCL1 signal pathway. Over all, this work addressed the gap in the availability of CVA16 disease rodent model for vaccine development and provided novel insights into the mechanisms underlying neurological injury caused by enteroviruses and other neurotropic viruses. • Using hSCARB2 knock-in mice, we established a CVA16 murine disease model, which is highly susceptible to CVA16 infection. Severe neurological injury manifested as microglial hypertrophy with extended pseudopodia, astrocytes with disrupted connections to blood vessels and neurons and markedly reduced neurons. This study demonstrates, for the first time, the potential involvement of the TLR2/MYD88/TNF-α/CXCL1 signaling pathway in this neurological injury.

Source: Antiviral Research

DOI: 10.1016/j.antiviral.2025.106133