Fig. 1: Host genes with identified genetic variants associated with altered inflammatory phenotype post-infection with the respiratory viruses.

Response to respiratory viruses requires initiation of an immune response. After viral infection of the lung epithelia, pathogen associated molecular patterns (PAMPs) are detected by host pattern recognition receptors (PRRs), such as TLRs and cytoplasmic sensors like RIG-I. This recognition starts a series of signalling cascades within the host cell, involving activation of TFs such as IRF5, IRF7 and AP-1, resulting in the production of pro-inflammatory cytokines such as IL-6, TNF and IL-1B, and type I IFNs. Cytokines produced by innate immune cells early post-infection drive several processes such as recruitment of circulating leucocytes, which, in turn, can enhance local cytokine production at the site of infection and enhance tissue damage; and activate dendritic cells to move to the lymph nodes and activate T cells by presentation of viral antigen on MHC molecules. Other innate immune cells such as macrophages and DCs also sense PAMPs through PRRs, again activating TFs and driving cytokine and IFN production. Acting through their receptors, type I IFNs establish an antiviral state in surrounding non-haematopoietic cells and recruited haematopoietic cells, where activation of TFs downstream of type I IFN receptors such as IRF9 results in the transcription of interferon stimulated genes (ISGs). The products of these ISGs play multifaceted roles: some can directly restrict processes such as viral replication and egress from the host cell, but some ISGs such as IFITM3 may also influence cytokine production in haematopoietic cells such as DCs. The cytokines produced early in infection also regulate the differentiation of T cells, with the balance between different T-cell subsets demonstrated to alter disease progression. Genes involved in these key processes, where specific genetic variants have been identified as associated with altering host inflammatory responses to IAV, RSV or SARS-CoVs, are shown. These genetic variants are further described in Table 1. Created with BioRender.com.