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Daniele da Glória de Souzahttp://lattes.cnpq.br/5063576712856234Vivian Vasconcelos CostaFlávio Almeida AmaralRenato Santana AguiarThiago Mattar CunhaMarcelo Torres BozzaJordana Grazziela Alves Coelho dos Reishttp://lattes.cnpq.br/9857851793964078Thaiane Pinto Moreira2023-02-27T15:55:23Z2023-02-27T15:55:23Z2022-06-08http://hdl.handle.net/1843/50451A infecção pelo chikungunya virus tem como principal característica a poliartralgia inflamatória crônica sendo associada a uma elevada taxa de morbidade da população acometida. Até o momento, os mediadores e mecanismos associados ao desenvolvimento da artralgia crônica nestes pacientes são desconhecidos e as medidas de tratamento disponíveis são paliativas e inespecíficas. Neste trabalho, usando um modelo experimental , estudamos alguns mecanismos e mediadores envolvidos na gênese e manutenção da hipernocicepção induzida pelo CHIKV. Camundongos C57BL/6 selvagens (WT) foram infectados com106 PFU de CHIKV por via intraplantar e diversas análises foram realizadas em tempos pré-estabelecidos. Os resultados demonstraram que a infecção pelo CHIKV induziu hipernocicepção mecânica prolongada e sensibilidade térmica nos animais. Foi observado um intenso dano tecidual e aumento dos níveis de mediadores inflamatórios no coxim plantar, como TNF e IL-6. Um aumento na expressão de CXCL-1, CCR5 e COX-2 no 1º dia pós-infecção e de TNF no 7º e 14º dias no gânglio da raiz dorsal (DRG) também foi observado. Em seguida, o tratamento com fármacos de diferentes classes terapêuticas com potencial analgésico foi realizado. Os tratamentos com morfina e pregabalina (ação central) reverteram o fenótipo hipernociceptivo dos camundongos nas fases aguda e tardia da infecção. Por outro lado, os tratamentos com dexametasona ou naproxeno (ação antiinflamatória) foram eficazes apenas no controle da hipernocicepção aguda induzida pela CHIKV. Por fim, avaliamos o papel da citocina TNF na indução e manutenção da hipernocicepção após a infecção pelo CHIKV, utilizando animais TNFRp55-/- ou através da inibição farmacológica dessa molécula (etanercept). Os nossos dados demonstraram que a ausência de TNF melhorou os parâmetros de doença nos animais avaliados, uma vez que apresentaram menor hipernocicepção, menor dano tecidual na pata, menor produção de mediadores pró-inflamatórios e aumento de IL-10, uma citocina com atividade anti-inflamatória, o que abre perspectivas para um potencial alvo terapêutico. Assim, nossos dados sugerem que a gênese da hipernocicepção induzida pelo CHIKV é dependente da inflamação aguda local, mas a sua manutenção parece estar associada a um estado inflamatório no DRG dos animais, mais especificamente a um aumento na expressão de TNF nesse tecido em tempos mais tardios.The main characteristic of chikungunya virus infection is chronic inflammatory polyarthralgia, which is associated with a high morbidity rate in the affected population. To date, the mediators and mechanisms associated with the development of chronic arthralgia in these patients are unknown and the available treatment measures are palliative and nonspecific. Here, using an experimental model, we studied some mechanisms and mediators involved in the genesis and maintenance of CHIKV-induced hypernociception. C57BL/6 wild type (WT) mice were infected with 106 PFU of CHIKV intraplantarly and several analyzes performed at pre-established times. The results showed that CHIKV infection induced prolonged mechanical hypernociception and thermal sensitivity. Intense tissue damage and increased levels of inflammatory mediators in the footpad, such as TNF and IL-6, were observed. An increase in the expression of CXCL-1, CCR5 and COX-2 on the 1st day post-infection and of TNF on the 7th and 14th days in the dorsal root ganglion (DRG) was also observed. Then, treatment with drugs of different therapeutic classes with analgesic potential was performed. Treatments with morphine and pregabalin (central action) reversed the hypernociceptive phenotype of mice in the acute and late phases of infection. On the other hand, treatments with dexamethasone or naproxen (anti-inflammatory action) were effective only in controlling CHIKV-induced acute hypernociception. Finally, we evaluated the role of the cytokine TNF in the induction and maintenance of hypernociception after CHIKV infection, using TNFRp55- / - mice or through the pharmacological inhibition of this molecule (etanercept). Our data showed that the absence of TNF improved disease parameters in the evaluated animals, since they showed less hypernociception, less tissue damage in the paw, less production of pro-inflammatory mediators and an increase in IL-10, a cytokine with anti-inflammatory activity, which opens perspectives for a potential therapeutic target. Thus, our data suggest that the genesis of CHIKVinduced hypernociception is dependent on local acute inflammation, but its maintenance seems to be associated with an inflammatory state in the DRG, more specifically with an increase in TNF expression in this tissue at later times.CNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorINCT – Instituto nacional de ciência e tecnologia (Antigo Instituto do Milênio)porUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em MicrobiologiaUFMGBrasilICB - DEPARTAMENTO DE MICROBIOLOGIAMicrobiologiaVírus ChikungunyaInfecçõesNociceptividadeCamundongosDorInfecçãoInflamaçãoVirusChikungunya virusArtralgiaMecanismos e mediadores envolvidos na gênese e manutenção da hipernocicepção induzida pelo Chikungunya virusinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALTese de doutorado_Microbiologia_Thaiane Pinto Moreira.pdfTese de doutorado_Microbiologia_Thaiane Pinto Moreira.pdfapplication/pdf2244602https://repositorio.ufmg.br/bitstream/1843/50451/3/Tese%20de%20doutorado_Microbiologia_Thaiane%20Pinto%20Moreira.pdfaa79a4c3b616a23c77e198656b682934MD53LICENSElicense.txtlicense.txttext/plain; charset=utf-82118https://repositorio.ufmg.br/bitstream/1843/50451/4/license.txtcda590c95a0b51b4d15f60c9642ca272MD541843/504512023-02-27 12:55:23.722oai:repositorio.ufmg.br:1843/50451TElDRU7Dh0EgREUgRElTVFJJQlVJw4fDg08gTsODTy1FWENMVVNJVkEgRE8gUkVQT1NJVMOTUklPIElOU1RJVFVDSU9OQUwgREEgVUZNRwoKQ29tIGEgYXByZXNlbnRhw6fDo28gZGVzdGEgbGljZW7Dp2EsIHZvY8OqIChvIGF1dG9yIChlcykgb3UgbyB0aXR1bGFyIGRvcyBkaXJlaXRvcyBkZSBhdXRvcikgY29uY2VkZSBhbyBSZXBvc2l0w7NyaW8gSW5zdGl0dWNpb25hbCBkYSBVRk1HIChSSS1VRk1HKSBvIGRpcmVpdG8gbsOjbyBleGNsdXNpdm8gZSBpcnJldm9nw6F2ZWwgZGUgcmVwcm9kdXppciBlL291IGRpc3RyaWJ1aXIgYSBzdWEgcHVibGljYcOnw6NvIChpbmNsdWluZG8gbyByZXN1bW8pIHBvciB0b2RvIG8gbXVuZG8gbm8gZm9ybWF0byBpbXByZXNzbyBlIGVsZXRyw7RuaWNvIGUgZW0gcXVhbHF1ZXIgbWVpbywgaW5jbHVpbmRvIG9zIGZvcm1hdG9zIMOhdWRpbyBvdSB2w61kZW8uCgpWb2PDqiBkZWNsYXJhIHF1ZSBjb25oZWNlIGEgcG9sw610aWNhIGRlIGNvcHlyaWdodCBkYSBlZGl0b3JhIGRvIHNldSBkb2N1bWVudG8gZSBxdWUgY29uaGVjZSBlIGFjZWl0YSBhcyBEaXJldHJpemVzIGRvIFJJLVVGTUcuCgpWb2PDqiBjb25jb3JkYSBxdWUgbyBSZXBvc2l0w7NyaW8gSW5zdGl0dWNpb25hbCBkYSBVRk1HIHBvZGUsIHNlbSBhbHRlcmFyIG8gY29udGXDumRvLCB0cmFuc3BvciBhIHN1YSBwdWJsaWNhw6fDo28gcGFyYSBxdWFscXVlciBtZWlvIG91IGZvcm1hdG8gcGFyYSBmaW5zIGRlIHByZXNlcnZhw6fDo28uCgpWb2PDqiB0YW1iw6ltIGNvbmNvcmRhIHF1ZSBvIFJlcG9zaXTDs3JpbyBJbnN0aXR1Y2lvbmFsIGRhIFVGTUcgcG9kZSBtYW50ZXIgbWFpcyBkZSB1bWEgY8OzcGlhIGRlIHN1YSBwdWJsaWNhw6fDo28gcGFyYSBmaW5zIGRlIHNlZ3VyYW7Dp2EsIGJhY2stdXAgZSBwcmVzZXJ2YcOnw6NvLgoKVm9jw6ogZGVjbGFyYSBxdWUgYSBzdWEgcHVibGljYcOnw6NvIMOpIG9yaWdpbmFsIGUgcXVlIHZvY8OqIHRlbSBvIHBvZGVyIGRlIGNvbmNlZGVyIG9zIGRpcmVpdG9zIGNvbnRpZG9zIG5lc3RhIGxpY2Vuw6dhLiBWb2PDqiB0YW1iw6ltIGRlY2xhcmEgcXVlIG8gZGVww7NzaXRvIGRlIHN1YSBwdWJsaWNhw6fDo28gbsOjbywgcXVlIHNlamEgZGUgc2V1IGNvbmhlY2ltZW50bywgaW5mcmluZ2UgZGlyZWl0b3MgYXV0b3JhaXMgZGUgbmluZ3XDqW0uCgpDYXNvIGEgc3VhIHB1YmxpY2HDp8OjbyBjb250ZW5oYSBtYXRlcmlhbCBxdWUgdm9jw6ogbsOjbyBwb3NzdWkgYSB0aXR1bGFyaWRhZGUgZG9zIGRpcmVpdG9zIGF1dG9yYWlzLCB2b2PDqiBkZWNsYXJhIHF1ZSBvYnRldmUgYSBwZXJtaXNzw6NvIGlycmVzdHJpdGEgZG8gZGV0ZW50b3IgZG9zIGRpcmVpdG9zIGF1dG9yYWlzIHBhcmEgY29uY2VkZXIgYW8gUmVwb3NpdMOzcmlvIEluc3RpdHVjaW9uYWwgZGEgVUZNRyBvcyBkaXJlaXRvcyBhcHJlc2VudGFkb3MgbmVzdGEgbGljZW7Dp2EsIGUgcXVlIGVzc2UgbWF0ZXJpYWwgZGUgcHJvcHJpZWRhZGUgZGUgdGVyY2Vpcm9zIGVzdMOhIGNsYXJhbWVudGUgaWRlbnRpZmljYWRvIGUgcmVjb25oZWNpZG8gbm8gdGV4dG8gb3Ugbm8gY29udGXDumRvIGRhIHB1YmxpY2HDp8OjbyBvcmEgZGVwb3NpdGFkYS4KCkNBU08gQSBQVUJMSUNBw4fDg08gT1JBIERFUE9TSVRBREEgVEVOSEEgU0lETyBSRVNVTFRBRE8gREUgVU0gUEFUUk9Dw41OSU8gT1UgQVBPSU8gREUgVU1BIEFHw4pOQ0lBIERFIEZPTUVOVE8gT1UgT1VUUk8gT1JHQU5JU01PLCBWT0PDiiBERUNMQVJBIFFVRSBSRVNQRUlUT1UgVE9ET1MgRSBRVUFJU1FVRVIgRElSRUlUT1MgREUgUkVWSVPDg08gQ09NTyBUQU1Cw4lNIEFTIERFTUFJUyBPQlJJR0HDh8OVRVMgRVhJR0lEQVMgUE9SIENPTlRSQVRPIE9VIEFDT1JETy4KCk8gUmVwb3NpdMOzcmlvIEluc3RpdHVjaW9uYWwgZGEgVUZNRyBzZSBjb21wcm9tZXRlIGEgaWRlbnRpZmljYXIgY2xhcmFtZW50ZSBvIHNldSBub21lKHMpIG91IG8ocykgbm9tZXMocykgZG8ocykgZGV0ZW50b3IoZXMpIGRvcyBkaXJlaXRvcyBhdXRvcmFpcyBkYSBwdWJsaWNhw6fDo28sIGUgbsOjbyBmYXLDoSBxdWFscXVlciBhbHRlcmHDp8OjbywgYWzDqW0gZGFxdWVsYXMgY29uY2VkaWRhcyBwb3IgZXN0YSBsaWNlbsOnYS4KRepositório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-02-27T15:55:23Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
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