Mosquito salivary sialokinin reduces monocyte activation and chikungunya virus-induced inflammation via neurokinin receptors.

Global warming is expanding mosquito habitats and increasing mosquito-borne diseases. In tropical and sub-tropical regions, chikungunya virus (CHIKV) transmitted by Aedes mosquitoes has become a major concern due to the debilitating chronic joint disease it causes. Mosquito saliva contains bioactive factors that enhance viral infection, with sialokinin identified as a key contributor to vascular leakage and viral spread in mice. Here, we demonstrate that sialokinin binds to neurokinin receptors and restricts the activation of human myeloid cells. Mechanistically, sialokinin facilitates early viral dissemination, as evidenced by increased viral load in the contralateral footpad at 1 day post-infection, and significantly reduces circulating CD169+ monocytes while suppressing IFN-γ-producing T-cell-driven inflammation, as reflected by reduced joint footpad swelling in female CHIKV-infected mice. Clinically, patients with severe CHIKV disease exhibited higher levels of IgG antibodies against sialokinin, which correlated with higher viral loads and systemic inflammatory markers. Our findings highlight the multifaceted role of sialokinin in facilitating early viral dissemination and modulating host immunity during CHIKV infection. Given the growing threat of mosquito-borne diseases in a warming, disease-burdened world, targeting mosquito salivary factors like sialokinin could offer a novel therapeutic strategy to mitigate viral-induced inflammation and improve clinical outcomes.