Host response to influenza, rhinovirus and SARS-CoV-2 infection

Abstract

Influenza virus and rhinovirus are two of the most commonly found respiratory viruses among patients hospitalized for respiratory tract infections. Previous studies have shown that infections caused by these two viruses manifest with different clinical presentations, inflammatory response and immune response. Furthermore, host lipids have been recognized to play a crucial role in viral pathogenesis. Yet a systematic transcriptomic and lipidomics analysis comparing the host response to influenza and rhinovirus infection is lacking. In this study, the transcriptomic and lipidomic profiles in influenza virus and rhinovirus infected bronchial epithelial cell line was compared. Comparative transcriptomics study, using RNA-Seq to measure gene expression, revealed rhinovirus infection induced a weaker immune response, with fewer differentially expressed genes, when compared to influenza A or B virus infection in the human lung epithelial Calu-3 cell line. Amongst all three viruses, interferon lambda 1 (IFNL1) and C-X-C motif chemokine ligand 10 (CXCL10) genes were highly expressed. Several other type I and III interferon-related genes were also highly expressed for all three viruses. Notably, intercellular adhesion molecule 5 (ICAM5), a receptor for enterovirus D68, was highly expressed in rhinovirus-infected cells and bound strongly with rhinovirus. Pathway analysis through gene set enrichment analysis (GSEA) showed that pathways associated with interferon response, innate immunity, and regulation of inflammatory response were highly affected by all three viruses. Network analysis also showed that steroid-related pathways were enriched. Comparative lipidomic study, performed using liquid chromatography–mass spectrometry (LC-MS) to detect lipids, revealed downregulation of most lipid features in influenza A virus and rhinovirus infected Calu-3 cells when compared to mock-infected. Notably, sphingomyelin features were highly downregulated, which was also confirmed by pathway analysis showing sphingolipid metabolism as the most perturbed pathway. Functional study for sphingomyelin revealed that bacterial sphingomyelinase was able to suppress the replication of influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but promote the replication of rhinovirus. In response to the emergence of COVID-19 pandemic in late 2019, the host response to SARS-CoV-2 was also studied. Previous studies showed that coronavirus Nsp1 is an interferon antagonist which affect mRNA translation and degradation, but not transcription. It was found that SARS-CoV-2 Nsp1 was able to suppress RIG-I-induced mRNA levels of IFNB1, IFNL1 and CXCL10, but enhanced the Sendai virus-induced mRNA levels of these cytokines/chemokines. The studies in this thesis have advanced the understanding of viral infections at both transcriptional and lipidome level, and will have implication on the development of treatment strategies. Furthermore, SARS-CoV-2 Nsp1 study has highlighted the importance of using live virus immune induction alongside targeted induction to show biological relevance in future studies. Careful consideration should be taken when treating patients with viral infection as treating one virus may promote replication of another virus.