Resposta inflamatória como determinante para a manutenção de hipernocicepção induzida por chikungunya vírus

Abstract

Chikungunya virus (CHIKV), an arbovirus of the Togaviridae family, is the etiologic agent of Chikungunya fever (CF). CF is a disease with persistent joint pain as its main characteristic in humans. The mechanisms and mediators involved in the genesis and persistence of pain during this disease are still poorly understood. The aim of the present study was to explore mechanisms potentially involved in the genesis and maintenance of persistent pain caused by CHIKV infection using a murine model that mimics many aspects of the disease in humans. Following infection, joint hypernociception was observed extending up to 21 days, and was associated with plantar pad edema in the early post-infection times. Immunophenotyping of the plantar pad of infected animals revealed an increase in neutrophils on the first day post- infection that was replaced by macrophages on the seventh day. Also, the presence of viral RNA, but not viable virus, was observed in the dorsal root ganglion (DRG) on the first day post-infection. However, intrathecal injection of CHIKV was not able to potentiate hypernociception, and treatment with the antiviral sofosbuvir, either intrathecally or systemically, only partially and similarly reduced acute pain (3dpi), but not late pain (7dpi onward) induced by infection. Increased numbers of leukocytes in the DRG, including inflammatory monocytes, were associated with elevated levels of inflammatory cytokines including CCL2, TNF, and CXCL1, as well as the enzyme COX- 2, at early and late post-infection times. Administration of celecoxib, a COX-2 inhibitor, was able to decrease pain and plantar edema, without inducing, in turn, significant changes in viral titers in the various tissues evaluated. CCR2-/- or CCR2 antagonist treated animals showed a decrease in hypernociception indicating an important role in pain initiation and maintenance. Overall, this work explores some mechanisms that could be associated with persistent pain observed in CHIKV infection, with data that may add to the existing literature in order to contribute to the understanding of the pathogenesis associated with CHIKV and consequently propose new therapeutic opportunities for the treatment of pain in this important human disease.