Researchers from the Center for Research on Influenza Pathogenesis and Transmission (CRIPT) used an integrative systems biology approach to identify antiviral gene targets and potential compounds for future pan-respiratory virus host-directed therapies (HDTs) against influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Lead author Kelsey Haas, Ph.D. published this work in Nature Communications, in conjunction with researchers from the labs of CRIPT principal investigator Aldolfo Garcia-Sastre, Ph.D., Randy Albrecht, Ph.D., and Megan Shaw, Ph.D. IAV is a recurring respiratory virus with a lack of antiviral therapies due to antigenic drift (small changes to flu viruses), antigenic shift (major changes to flu viruses), and zoonotic transmission (when a disease that infects non-human animals spreads to people), creating distinct strains of the virus that are novel to the human population. These distinct strains result in altered transmissibility, pathogenicity, and pandemic potential, which leads to vaccines of limited and variable effectiveness. An increased prevalence of drug resistance mutations has limited the effectiveness of vaccines, as well. These factors highlight the continued need for developing new therapies against IAV strains.
When viruses infect a host, they use their own viral proteins and the host’s protein factors to replicate and complete their infection cycle. HDTs have emerged as an alternative therapeutic approach, as these therapies target host factors vital to virus replication rather than targeting viral-encoded factors directly. HDTs also side-step drug resistance and have the potential for pan-viral efficacy – many viruses utilize the same host pathways for replication, including IAV and SARS-CoV-2, which co-circulate. Proteomics approaches, such as virus-host protein-protein interactions (PPIs) and virus-induced changes in host signaling pathways, can highlight key linchpins necessary for viral replication and propagation. However, proteomic approaches alone do not give the full picture of physiological targets of IAV. As such, the authors utilize a cross-disciplined and integrative approach for generating comprehensive models of viral induced host-reprogramming.
An integrative systems biology approach was employed to identify human proteins essential for replication across three strains of IAV (pH1N1, H3N2, and H5N1) and SARS-CoV-2. The researchers used affinity purification mass-spectrometry to identify 332 IAV-human PPIs representing primary and secondary infection targets. They followed this analysis with global proteomic profiling of multiple IAV-infected cell types (primary bronchial epithelial, lung epithelial, and myeloid cell lines) to get an untargeted view of proteins present during infections. Whole exome sequencing (all gene protein-coding regions), functional genetics testing (genes specifically impacted by diet, nutrition, and exercise), and pharmacological screenings were also conducted in an IAV-infected patient cohort.
The authors created a unified approach that integrated cellular proteomic data with patient genomic data, which formed a comprehensive and multidimensional network model of IAV infection. Essential druggable host targets were identified that may serve as potential treatment strategies for IAV infections. In combining the proteomic and whole exome sequencing results, several potential molecular regulators of host response and determinants of disease outcome were pinpointed. Additionally, functional genetic screening revealed 54 human genes that mapped back to 44 PPI factors, three of which also regulate infection by SARS-CoV-2 as pro-viral or antiviral factors. In screening potentially therapeutic compounds that target IAV-interacting and IAV-modulated proteins, seven compounds exhibited pan-IAV activity. Five additional compounds were found to inhibit multiple strains of IAV and SARS-CoV-2.
The findings from Haas et al. (2023) reiterate the strength of integrative systems biology approaches for multi-dimensional data profiling of IAV. By utilizing multiple techniques, the authors identified a deeper level of human gene targets and compounds to target IAV and SARS-CoV-2. This is an important starting point to develop a potential host-directed therapy, not only pan-IAV, but optimistically pan-respiratory viral HDT. The highly collaborative approach employed in this study could lead to additional pan-viral therapies and mechanisms beyond those found for IAV and SARS-CoV-2.