Acute IFN-gamma responses drive sensory neuron injury and chronic pain after chikungunya virus infection

Abstract

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes acute and chronic musculoskeletal disease characterized by often debilitating pain; however, the mechanisms associated with the pain remain understudied. Here, we used an experimental mouse model and patients to investigate the role of interferon-{gamma} (IFN-{gamma}) in the pain during chronic inflammation after CHIKV infection. Our data show that CHIKV induces sustained joint inflammation, cartilage catabolism, and sensory neuron injury signatures, including Atf3 upregulation, but lacks detectable viral dissemination to dorsal root ganglia. We found that IFN-{gamma} expression was higher in CHIKV-infected joints, and direct IFN-{gamma} administration recapitulates mechanical hypersensitivity and neuronal stress independently of joint degeneration. Genetic or pharmacological disruption of IFN-{gamma} signalling prevented CHIKV-induced pain and neuronal stress without altering viral burden, demonstrating that IFN-{gamma} is required for both sensory dysfunction and joint pathology. By stratifying CHIKV-infected mice based on long-term nociceptive profiles, we show that persistent-pain subgroup characterized by elevated acute-phase systemic IFN-{gamma} and chronic peripheral neuropathic features. These findings were confirmed in human patients, where acute-phase IFN-{gamma} levels distinguished those who developed chronic arthralgia from those who recovered. Overall, our findings demonstrate that persistent post-CHIKV pain is driven by an IFN-{gamma}-mediated neuroimmune mechanism.