Species-Specific Transcriptomic Changes During Respiratory Syncytial Virus Infection May Advance Treatment Development

A new study shows generalizable information on the impact of host genetics on host-virus interactions and identifies new therapeutic targets for the treatment and prevention of respiratory syncytial virus infection (RSV). The study, published in Scientific Reports, used cotton rats to examine differential gene expression and showed host species-specific differences after infection with RSV.

Although cotton rats are frequently used to study respiratory viral pathogens, specifically RSV, prior research that involves gene expression analysis in these animals have been severely limited without a reference genome or published transcriptome.

RSV is the leading cause of lower respiratory tract infection (LRTI) in children under 2 years of age, in immunocompromised individuals, and the elderly. Further, there is currently no approved RSV vaccine despite ongoing research efforts and only 1 preventative monoclonal antibody (palivizumab), with use limited to high-risk children due to price.

The authors of the current study sought to generate a comprehensive transcriptome from multiple tissues of 2 species of cotton rats, S. fulviventer and S. hispidus, which are commonly used as animal models. The investigators compared the gene expression changes and immune responses to RSV infection between 2 species.

The transcriptomes were put together from the lung, spleen, kidney, heart, and intestines for each species with contigs, or transcriptions, of N50 > 1600. The annotation of contigs generated approximately 120,000 gene annotations for each species. Following this, the transcriptions were then used to assess immune response to RSV infection.

The researchers analyzed 238 unique genes that are significantly differentially expressed, including genes involved in RSV infection, such as Mx2, viperin, keratin 6A, and CXCL10, as well as genes that have not been previously described in RSV research, such as LG3BP, ABEC1, CREB1.

The comprehensive transcriptomes used as new resources for the researchers can now be used for future gene expression analysis studies in the cotton rat model and provides gene sequences for mechanistic characterization of molecular pathways. The results provided generalizable insights into the effect of host genetics on host-virus interactions and provides potential new host therapeutic targets for RSV treatment and prevention, the study authors wrote.

They noted that the identification of gene sequences allows for better understanding of cotton rat genetics and generation of molecular tools, such as qRT-PCR primers and probes that target genes of interest, recombinant protein, antibodies, and more assays.

The investigators said that therapeutics need more robust pre-clinical models for RSV, for which they hope the use of transcriptome references and gene associations with RSV will accelerate biomedical interventions against the pathogen.

Study limitations included previously published data showing that different RSV strains and isolates have differential induction of interferon activated genes in cotton rats. This study had more of a focus on RSV A/Long, and transcriptomic comparison of RSV variants should be considered for future studies, according to the study authors.

Additionally, multiple genes that were identified had not been previously implicated in RSV infection, such as LG3BP, SYWC, ABEC1, IIGP1, and CREB1. The study authors noted that the association of these genes with RSV infection is very limited in the absence of actual experimental data.

“Differential gene expression analysis revealed host species specific differences upon RSV infection,” the study authors wrote. “As the development of RSV therapeutics calls for a well-developed, robust pre-clinical models for RSV, we hope our transcriptome references and gene associations with RSV can accelerate biomedical interventions against this pathogen of significant public health importance.”

REFERENCE

Strickland, B.A., Rajagopala, S.V., Kamali, A. et al. Species-specific transcriptomic changes upon respiratory syncytial virus infection in cotton rats. Sci Rep 12, 16579 (2022). https://doi.org/10.1038/s41598-022-19810-4.