Acute IFN-γ responses predict and mediate chronic pain caused by arthritogenic alphavirus infection

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes 17.7 million musculoskeletal cases annually, of which 848,000 progress to debilitating chronic disease. We combined an intra-articular CHIKV infection model in mice, genetic and pharmacological IFN-γ manipulation, and a prospective patient cohort to investigate chronic pain mechanisms. We found that CHIKV infection induced prolonged mechanical hypersensitivity, joint inflammation, cartilage catabolism, and sensory neuron stress despite the absence of detectable viral dissemination to dorsal root ganglia. CHIKV-infected joints exhibited elevated levels of IFN-γ associated with infiltrating T cells. Administration of recombinant IFN-γ into joints recapitulated pain hypersensitivity and neuronal stress, whereas genetic deletion of IFN-γ or pharmacological blockade of its receptor abrogated pain development without affecting viral load. We identified that ~50% (12/24) of CHIKV-infected mice developed persistent pain and exhibited elevated systemic IFN-γ levels during both the acute and chronic phase. Chronic CHIKV pain was associated with peripheral nerve injury and central sensitization features, including reduced nerve conduction velocity, marked ultrastructural myelin disruption, sensory-neuron caspase-3 activation, and increased dorsal horn neuronal pERK and GFAP. Consistently, patients who developed chronic arthralgia had higher acute-phase IFN-γ than those who recovered. Finally, approximately 40% of Mayaro virus-infected mice (04/10) developed persistent pain, extending this phenotype to another arthritogenic alphavirus. Collectively, these findings establish IFN-γ as a neuroimmune mediator between antiviral responses and neural dysfunction, supporting its potential as a biomarker and therapeutic target for chronic diseases caused by arthritogenic alphaviruses.