Systems immunology of transcriptional responses to viral infection identifies conserved antiviral pathways across macaques and humans

Emerging and re-emerging viruses pose a significant threat to global health. RNA viruses, in particular, are responsible for a large percentage of emerging infectious diseases. While human infection studies are ideal, ethical and practical limitations often necessitate the use of non-human primate (NHP) models, especially macaques, to understand pathogenesis, vaccine development, and therapeutic interventions. Previous research identified conserved host responses in human infections across multiple viruses, but questions remain regarding the generalizability of these responses to diverse viruses and the comparability of macaque and human immune responses. This study aims to address these gaps by leveraging transcriptomic profiles from both macaque and human infection studies to determine the utility of macaque models in understanding and predicting human responses to emerging viruses.

The introduction references several studies highlighting the significant threat of emerging RNA viruses and the importance of NHP models in viral research. It also mentions previous work by the authors that identified a conserved human host response across multiple viruses, termed the meta-virus signature (MVS). This prior work serves as a foundation for the current study, which seeks to validate the MVS in macaques and to further characterize the conserved and unique features of antiviral responses across various viruses and species.

The study used a comprehensive approach involving data collection, curation, and preprocessing of existing datasets. They searched public repositories for blood transcriptomic datasets from macaques infected with acute RNA viruses. A total of 21 datasets comprising 743 samples from 198 macaques infected with 13 viruses across five families were included. Data processing involved independent processing of each dataset, grouping time points into six categories (T0-T5), and verification of comparability across macaque species. The MVS, a previously identified conserved human host response signature, was applied to the macaque data. They also utilized single-cell RNA sequencing (scRNA-seq) data from Ebola virus-infected macaques to investigate the cellular sources of the MVS response. For comparison, human challenge studies with influenza, rhinovirus, and respiratory syncytial virus were also analyzed. Differentially expressed genes (DEGs) were identified for each viral family, and gene signatures were generated to distinguish infection from baseline using meta-analysis methods. The generalizability of these signatures was assessed across diverse human viral infections. Single-cell RNA-seq data from human COVID-19 and dengue virus infections were used to further investigate T cell responses. Statistical analyses included Wilcoxon rank-sum tests, ROC curve analysis, mixed-effects models, and gene set overrepresentation enrichment analysis.

The study's key findings demonstrate a high degree of conservation in antiviral transcriptional responses between macaques and humans. The MVS, initially identified in humans, was shown to accurately distinguish infected from uninfected macaques across all viruses studied. The MVS response was found to be primarily driven by myeloid cells in both species, similar to findings in human COVID-19. The kinetics of the MVS response, however, differed depending on the viral family. An unbiased transcriptomic analysis revealed conserved antiviral responses across macaque viral infections that robustly translated to human viral infections. A novel virus-conserved gene signature, the Viral Response Signature (VRS), was identified in macaques and was shown to be highly effective in distinguishing viral infection from healthy controls in diverse human populations, including those with chronic viral infections. The study also identified differences in T cell responses across viral infections, particularly between Flaviviridae (e.g., dengue) and other viral infections. In dengue, there was an upregulation of effector and cytotoxic CD8 T cell genes, contrasting with downregulation in severe COVID-19.

The findings strongly support the use of macaques as reliable models for studying human antiviral responses. The conserved nature of the MVS and VRS across diverse viruses and species highlights the existence of evolutionarily conserved antiviral pathways. The differences in the temporal dynamics of the antiviral response by viral family may be attributed to factors such as differences in host sensing, virus replication dynamics, virus-specific immune evasion mechanisms, infection route, and tissue tropism. The VRS, while having limited overlap with the MVS at the gene level, showed strong correlation and captured similar biological pathways, suggesting complementary insights into the antiviral response. The differences in T cell responses suggest that the type of infecting virus significantly impacts the nature of the adaptive immune response. This has implications for vaccine development and understanding the pathogenesis of various viral diseases.

This comprehensive analysis of host responses to a wide range of viruses, using both human and macaque cohorts, identified highly generalizable antiviral responses conserved in both acute and chronic viral diseases. The study validated the macaque model as a reliable tool for studying human antiviral responses and highlighted differences in response kinetics and T cell responses depending on the infecting virus. Future research should focus on further elucidating the underlying mechanisms driving these differences and translating these findings into improved diagnostic and therapeutic strategies.

Several limitations were noted. The study used existing datasets, which presented variations in the genes measured and the methodologies used. Analysis was limited to blood samples, neglecting potential differences in tissue-level responses. The representation of certain viral families was limited, potentially affecting the generalizability of the findings to all viruses within those families. Ideally, a direct comparison of scRNA-seq data from the same virus in both humans and macaques would strengthen the conclusions.