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Daniele da Glória de Souzahttp://lattes.cnpq.br/5063576712856234Vivian Vasconcelos CostaThiago Mattar CunhaAdriana Cristina Soares de SouzaJordana Grazziela Alves Coelho dos ReisGustavo Batista de Menezeshttp://lattes.cnpq.br/5013332937219484Carla Daiane Ferreira de Sousa2023-10-18T16:23:29Z2023-10-18T16:23:29Z2023-02-16http://hdl.handle.net/1843/59607O vírus Chikungunya (CHIKV), um arbovírus da família Togaviridae, é o agente etiológico da febre Chikungunya (FC), uma doença cuja principal característica em humanos é a dor persistente nas articulações. Os mecanismos e mediadores envolvidos na gênese e persistência da dor durante a doença causada pelo vírus ainda são pouco conhecidos. O objetivo do presente estudo foi explorar mecanismos potencialmente envolvidos na gênese e manutenção da dor persistente causada pela infecção pelo CHIKV utilizando um modelo murino que mimetiza muitos aspectos da doença em humanos. Após infecção, foi observado hipernocicepção articular que se estendeu por até 21 dias, associado a edema do coxim plantar nos tempos iniciais pós infecção. A imunofenotipagem do coxim plantar dos animais infectados revelou aumento de neutrófilos no primeiro dia pós-infecção que foi substituído por macrófagos no sétimo dia. Ainda, presença de RNA viral, mas não de vírus viável, foi observada no gânglio da raiz dorsal (DRG) no primeiro dia pós-infecção. No entanto, a injeção intratecal do CHIKV não foi capaz de potencializar a hipernocicepção, e o tratamento com o antiviral sofosbuvir, seja por via intratecal ou sistêmica, reduziu apenas parcialmente, e de maneira similar, a dor aguda (3dpi), mas não a dor tardia (7dpi em diante) induzida pela infecção. Aumentado número de leucócitos no DRG, incluindo monócitos inflamatórios, foi associado aos elevados níveis de citocinas inflamatórias incluindo CCL2, TNF e CXCL1, bem como da enzima COX-2, em tempos iniciais e tardios pós-infecção. A administração de celecoxibe, um inibidor de COX-2, foi capaz de diminuir a dor e o edema plantar, sem induzir por sua vez, alterações significativas nos títulos virais nos diversos tecidos avaliados. Animais CCR2-/- ou tratados com antagonista de CCR2, apresentaram diminuição na hipernocicepção indicando um papel importante no início e manutenção da dor. De forma geral este trabalho explora alguns mecanismos que poderiam estar associados a dor persistente observada na infecção pelo CHIKV, com dados que podem acrescentar a literatura existente de forma a contribuir para o entendimento da patogênese associada ao CHIKV e consequentemente propor novas oportunidades terapêuticas para o tratamento da dor nessa importante doença humana.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.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorporUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em MicrobiologiaUFMGBrasilICB - INSTITUTO DE CIÊNCIAS BIOLOGICASMicrobiologiaVírus ChikungunyaArbovirusInflamaçãoDorChikungunya virusArbovirusInflamaçãoDorResposta inflamatória como determinante para a manutenção de hipernocicepção induzida por chikungunya vírusinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALCarlaDFS_Tese.pdfCarlaDFS_Tese.pdfapplication/pdf2859596https://repositorio.ufmg.br/bitstream/1843/59607/1/CarlaDFS_Tese.pdf766305bbfd7b3240159d9f2f7b90f701MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-82118https://repositorio.ufmg.br/bitstream/1843/59607/2/license.txtcda590c95a0b51b4d15f60c9642ca272MD521843/596072023-10-18 13:23:29.611oai:repositorio.ufmg.br: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ório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-10-18T16:23:29Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
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