Neuropilin-1 functions as a proviral and immunoregulatory host factor during Chikungunya virus infection

Neuropilin-1 (NRP1) is a transmembrane glycoprotein involved in angiogenesis, neurodevelopment, inflammation, cancer driven immune suppression, and immune homeostasis. However, its contribution to virus-induced immune responses is not explored. Chikungunya virus (CHIKV) is a re-emerging arthritogenic alphavirus that causes severe arthralgia, and myalgia, accompanied by heightened inflammatory cytokine responses. The host factors that drive these inflammatory responses, however, remain poorly defined. Here, in this current study, the role of NRP1 in CHIKV infection was investigated using in vitro, and in vivo model systems. Using genetic manipulation, pharmacological, and antibody blockade-mediated approaches in murine and human cellular infection models, it was demonstrated that NRP1 promotes CHIKV infection while restraining the production of proinflammatory cytokines. Furthermore, NRP1 inhibition selectively increased JNK phosphorylation. Hence, inhibiting JNK reduced the elevated cytokine production caused by NRP1 blockade. Moreover, NRP1 interacted with CHIKV-E1 and is involved in multiple phases of CHIKV infection. In addition, it was demonstrated that NRP1 inhibition using EG00229 trifluoroacetate can reduce viral infection in several CHIKV-susceptible cells, human peripheral blood macrophages, and in the in vivo mice model of infection. Together, these findings indicate that NRP1 is an important host factor and a probable therapeutic target during CHIKV infection. IMPORTANCEChikungunya virus (CHIKV) causes acute febrile illness that can progress to debilitating chronic musculoskeletal and occasional neurological complications. The absence of a globally available effective vaccine and the lack of specific antivirals underscore CHIKV as a major burden, especially in endemic tropical regions. There is a growing need to understand host factors that shape CHIKV-driven immune response. The importance of our study lies in understanding the immunoregulatory role of the host receptor Neuropilin-1 (NRP1) during CHIKV infection. We identify NRP1 as a novel host factor of CHIKV infection that also acts as a rheostat to restrict the inflammatory viral immune response. Moreover, we report anti-viral potential of the NRP1 antagonist EG00229 trifluoroacetate in multiple cell lines, primary cells, and mice model. Our findings indicate NRP1 as a probable therapeutic target in CHIKV pathogenesis.