Common Dysregulation of Innate Immunity Pathways in Human Primary Astrocytes Infected With Chikungunya, Mayaro, Oropouche, and Zika Viruses

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.

Co-expression analysis suggests lncRNA-mRNA interactions enhance antiviral immune response during acute Chikungunya fever in whole blood of pediatric patients

“…Previous reports revealed that numerous viral infections modify the host transcriptome, including both coding and non-coding transcripts [5][6][7][8]; moreover, lncRNAs induced by infection may influence viral pathogenesis and replication (as reviewed by Fortes and Morris (2016) [25]). Although intense research is being done on CHIKV infection and pathogenesis, the mechanisms mediating host-virus interactions are still elusive.…”

“…Understanding the dynamics of host-pathogen interaction can help the search for potential therapeutic targets. Several reports evidence that viral infections significantly alter host transcriptome, including CHIKV [5][6][7]. These changes may be related to transcriptional and posttranscriptional control mechanisms mediated by long non-coding RNAs (lncRNAs) in several ways [8,9].…”

A Review of Omics Studies on Arboviruses: Alphavirus, Orthobunyavirus and Phlebovirus

“…Cell cycle arrest might account for the increased availability of capped mRNAs to act as donors for translation, the cap-snatching mechanism [ 163 , 164 ]. The down-regulation of interferon response and genes with antiviral activities was also observed (RSAD2—Viperin; OASL and OAS1—2′5′-Oligoadenylate Synthethase, MX1/2—MX Dynamin-like GTPase 1; IFIT2—Interferon-induced Protein with Tetratricopeptide Repeats 2), and evidence of the down-modulation of ion channels, transmembrane solute carriers and synapse regulation pathways was also identified, revealing manifestations of OROV neuropathology [ 165 ].…”

Editorial: Host-Pathogen Interaction in the Central Nervous System

“…Arbovirus-caused meningitis is also frequently associated with severe neurological outcomes. The comprehensive genome-wide transcriptome analysis of human primary astrocytes infected with Chikungunya, Mayaro, Oropouche, and Zika viruses described by Viana Geddes et al, has revealed a common pattern in downregulation of the host innate immune response, antiviral response, and expression levels of inflammatory cytokines associated with interferon stimulation for all the arboviruses tested (Viana Geddes et al, 2021). These findings point towards a co-evolution that all these arboviruses have engaged in developing mechanisms to escape the antiviral response induced by interferon (IFN) (Viana Geddes et al, 2021).…”