AUTHOR=Geddes Victor Emmanuel Viana , Brustolini Otávio José Bernardes , Cavalcante Liliane Tavares de Faria , Moreira Filipe Romero Rebello , de Castro Fernando Luz , Guimarães Ana Paula de Campos , Gerber Alexandra Lehmkuhl , Figueiredo Camila Menezes , Diniz Luan Pereira , Neto Eurico de Arruda , Tanuri Amilcar , Souza Renan Pedra , Assunção-Miranda Iranaia , Alves-Leon Soniza Vieira , Romão Luciana Ferreira , de Souza Jorge Paes Barreto Marcondes , de Vasconcelos Ana Tereza Ribeiro , de Aguiar Renato Santana TITLE=Common Dysregulation of Innate Immunity Pathways in Human Primary Astrocytes Infected With Chikungunya, Mayaro, Oropouche, and Zika Viruses JOURNAL=Frontiers in Cellular and Infection Microbiology VOLUME=11 YEAR=2021 URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2021.641261 DOI=10.3389/fcimb.2021.641261 ISSN=2235-2988 ABSTRACT=

Arboviruses pose a major threat throughout the world and represent a great burden in tropical countries of South America. Although generally associated with moderate febrile illness, in more severe cases they can lead to neurological outcomes, such as encephalitis, Guillain-Barré syndrome, and Congenital Syndromes. In this context astrocytes play a central role in production of inflammatory cytokines, regulation of extracellular matrix, and control of glutamate driven neurotoxicity in the central nervous system. Here, we presented a comprehensive genome-wide transcriptome analysis of human primary astrocytes infected with Chikungunya, Mayaro, Oropouche, or Zika viruses. Analyses of differentially expressed genes (DEGs), pathway enrichment, and interactomes have shown that Alphaviruses up-regulated genes related to elastic fiber formation and N-glycosylation of glycoproteins, with down-regulation of cell cycle and DNA stability and chromosome maintenance genes. In contrast, Oropouche virus up-regulated cell cycle and DNA maintenance and condensation pathways while down-regulated extracellular matrix, collagen metabolism, glutamate and ion transporters pathways. Zika virus infection only up-regulated eukaryotic translation machinery while down-regulated interferon pathways. Reactome and integration analysis revealed a common signature in down-regulation of innate immune response, antiviral response, and inflammatory cytokines associated to interferon pathway for all arboviruses tested. Validation of interferon stimulated genes by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) corroborated our transcriptome findings. Altogether, our results showed a co-evolution in the mechanisms involved in the escape of arboviruses to antiviral immune response mediated by the interferon (IFN) pathway.