How Alphaviruses Modulate Host Gene Expression: A Systematic-Narrative Synthesis of Host-Virus Response, Key Genes, and Potential Therapeutic Targets

Abstract

Alphaviruses are positive-sense single-stranded RNA viruses belonging to the family Togaviridae; they are also part of the non-taxonomic group of arboviruses and constitute a group of arboviruses of major which are of great clinical and epidemiological relevance worldwide. These viruses can be broadly classified into encephalitic and arthritogenic alphaviruses. Important examples include Chikungunya virus (CHIKV), Mayaro virus (MAYV), Venezuelan equine encephalitis virus (VEEV), Ross River virus (RRV), Sindbis virus (SINV), and Semliki Forest virus (SFV), among others. Despite their substantial impact on global public health, characterized by the risk of new outbreaks, high transmission rates, and frequently debilitating or potentially fatal clinical manifestations, effective and specific therapeutic options, including antivirals and vaccines, remain limited for most alphavirus infections. This represents an important public health vulnerability, particularly in tropical and subtropical regions. To address this concerning scenario, a comprehensive understanding of the complex interactions between alphaviruses and their hosts is essential for identifying determinants of viral pathogenicity and, consequently, factors associated with disease severity. In this context, transcriptomic and gene expression profiling approaches have become valuable tools for investigating host responses to viral infection. These approaches provide high-resolution information on changes in host gene expression during Alphavirus infection, contributing to the elucidation of molecular mechanisms underlying disease pathogenesis. They can also provide important insights into the identification of biomarkers and molecular signatures, the upregulation or downregulation of specific genes, and the modulation of inflammatory, oxidative, immune, and other biological pathways. Accordingly, this review provides a comprehensive systematic-narrative synthesis of studies investigating alphavirus–host interactions through gene expression profiling. Studies assessing host gene expression in response to alphavirus infection using approaches such as RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), microarrays, RT-qPCR, and other relevant gene expression technologies will be considered across different host species, tissues, experimental models, and infection conditions. Particular emphasis will be placed on studies investigating how alphaviruses modulate key pathogenic pathways, immune responses, inflammation, tissue-specific damage, and other biological processes associated with infection. By integrating evidence from host gene expression profiles, this review aims to highlight the major transcriptional alterations and biological pathways associated with alphavirus pathogenesis. Such integration may provide insights into virus–host interactions and support the identification of candidate molecular targets for therapeutic development, early diagnostic tools, and effective preventive strategies. Therefore, the general objective of this study is to integrate the available evidence on the modulation of host gene expression during alphavirus infection, seeking to elucidate virus–host interactions, molecular mechanisms associated with pathogenesis, and potential key factors involved in these processes. The specific objectives are to: Describe the state of the art regarding alphavirus infections, providing a clinical and epidemiological context for these viruses; Characterize host transcriptional responses to alphavirus infection, identifying similarities and differences in the molecular mechanisms activated or suppressed across different alphaviruses and host systems; Describe molecular mechanisms associated with alphavirus pathogenesis and other biological processes through the integration of differentially expressed genes (DEGs) and enriched biological pathways; Map relevant genes and biological pathways associated with different stages and processes of alphavirus infection, across different experimental systems, including in vitro, in vivo, and publicly available transcriptomic datasets; Identify key genes and molecular factors involved in alphavirus–host interactions and explore their potential as therapeutic targets; Identify knowledge gaps, recurrent patterns, and sources of heterogeneity in the existing literature on alphavirus-associated host gene expression. Through this integrative approach, the review is expected to generate sufficient evidence to support hypotheses and future investigations into therapeutic interventions, including the manipulation, editing, or silencing of specific host genes whose modulation or inhibition may impair viral replication while preserving host-cell or host-organism viability. Keywords: alphaviruses; host-virus response; transcriptomics; molecular mechanisms; differential gene expression; viral pathogenesis