Meta-analysis of functional genomics studies reveals conserved cellular pathways required by viruses of pandemic concern
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The COVID-19 pandemic illustrated the need to develop medical countermeasures against emerging infectious diseases. As viruses rely on cellular machinery for replication, host-directed antivirals (HDAs) may complement conventional antiviral strategies in a manner that offers broad-spectrum efficacy, including against novel viruses, and a potentially higher barrier to viral escape. Despite their potential, HDAs are under-represented as therapeutics, partly due to a lack of consensus on druggable host targets. To address this, we have performed a meta-analysis of 62 functional genomics studies involving viral families of pandemic concern, including Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, Phenuiviridae, Picronaviridae, Poxviridae and Togaviridae. Using a robust rank aggregation and protein-protein interaction network approach, host factors and cellular processes required by multiple virus families were identified, including the V-type ATPase complex, glycosaminoglycan synthesis, Golgi trafficking and endoplasmic reticulum membrane protein insertion. These pathways include those with known relevance to infection by some viruses while providing novel insights into the lifecycles of others. Therapeutic targeting of these top ranked host factors is also discussed, with several already possessing small molecule inhibitors, highlighting their therapeutic potential. Antivirals are an essential component of medical countermeasures against viral disease and fulfil a complementary role to vaccines. Importantly, they may provide the only therapeutic option for pathogens lacking effective vaccines or for individuals unable to be vaccinated. This analysis furthers our understanding of the virus-host interface and nominates cellular targets for the future development of HDAs as medical countermeasures for pandemic resilience.
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The manuscript presents a meta analysis across several viral families to identify conserved host factors that could represent targets for host-directed antivirals. This work is presented in a clear manner, with well formed arguments. While this would be a valuable contribution to the field, minor amendment of the manuscript is required before publication. Please respond to each of the reviewers comments.
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Comments to Author
The manuscript presents a comprehensive meta analysis of 62 published genome wide loss of function screens across viruses of pandemic concern. Using robust rank aggregation (RRA) and protein-protein interaction network (PPIN) methodologies, the authors identify conserved host factors and pathways ( V ATPase, HS GAG synthesis, GPI/GAG precursor metabolism, Golgi trafficking, and EMC mediated ER membrane insertion) that are presented as potential targets for the development of host targeting antivirals. The identified host-pathway clusters are biologically plausible and supported by prior literature. The targets are not validated using experimental models, but are discussed in detail in the text. The authors write they hope their meta-analysis could aid other researchers in providing high confidence …
Comments to Author
The manuscript presents a comprehensive meta analysis of 62 published genome wide loss of function screens across viruses of pandemic concern. Using robust rank aggregation (RRA) and protein-protein interaction network (PPIN) methodologies, the authors identify conserved host factors and pathways ( V ATPase, HS GAG synthesis, GPI/GAG precursor metabolism, Golgi trafficking, and EMC mediated ER membrane insertion) that are presented as potential targets for the development of host targeting antivirals. The identified host-pathway clusters are biologically plausible and supported by prior literature. The targets are not validated using experimental models, but are discussed in detail in the text. The authors write they hope their meta-analysis could aid other researchers in providing high confidence targets that can be further explored for potential host directed antiviral drug development. The manuscript is well written and data are presented in a visually clear way. The overview figures (4&5) are prepared with care and enhance the overall clarity of the manuscript. Overall, the manuscript is well structured and addresses a relevant topic in pandemic preparedness and antiviral development. Minor comments: - The large Table 1 is comprehensive but could potentially be moved to supplementary material due to length. (Also typo Orthromyxoviridae - Orthomyxoviridae ) - In the introduction the authors could discuss prior meta-analyses and state what gap their study fills.
Please confirm that no generative AI tools or large language models have been used to generate this peer review report or to assist with any part of the peer review process.
I confirm no generative AI tools were used in preparation of this review.
Please rate the manuscript for methodological rigour
Very good
Please rate the quality of the presentation and structure of the manuscript
Very good
To what extent are the conclusions supported by the data?
Strongly support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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Comments to Author
Summary This manuscript presents a systematic review of genome-wide screening studies across 10 viral families of potential pandemic concern to identify conserved host factors that could serve as targets for broad-spectrum, host-directed antiviral development. The authors have compiled data from 62 studies, performed network analysis to identify 6 main gene clusters, and mapped potential therapeutic compounds to these clusters. While this represents a useful cataloging effort aligned with the journal's mission to disseminate data resources, some enhancements could strengthen the manuscript's utility and impact. Comments 1. Validation of therapeutic predictions: The identification of drugs targeting the 6 gene clusters is presented without any supporting evidence for antiviral activity. Even limited …
Comments to Author
Summary This manuscript presents a systematic review of genome-wide screening studies across 10 viral families of potential pandemic concern to identify conserved host factors that could serve as targets for broad-spectrum, host-directed antiviral development. The authors have compiled data from 62 studies, performed network analysis to identify 6 main gene clusters, and mapped potential therapeutic compounds to these clusters. While this represents a useful cataloging effort aligned with the journal's mission to disseminate data resources, some enhancements could strengthen the manuscript's utility and impact. Comments 1. Validation of therapeutic predictions: The identification of drugs targeting the 6 gene clusters is presented without any supporting evidence for antiviral activity. Even limited validation, for example, testing one cluster of compounds against a single virus, would substantially strengthen the manuscript's potential for identifying novel antivirals. 2. Extend inclusion criteria for top-ranked clusters: The authors made the decision to focus on genome-wide knockdown/knockout screens for their analysis. However, this study could be enhanced by conducting targeted literature review of the top-identified clusters to incorporate any genetic screens (targeted knockdown/knockout or overexpression studies) that were excluded from the initial assessment. Additionally, to further build on the meta-analysis approach, inclusion of drug screening studies that identify compounds overlapping with the therapeutic targets suggested in Table 2 would further enhance the data compiled in this work. Conclusion Overall, this manuscript provides a systematic resource that aligns well with Access Microbiology's mission to disseminate compiled datasets and support open science. With the suggested literature-based additions, specifically, analysis of top clusters within initially excluded studies (both genetic and chemical screens) and ideally some level of novel in vitro validation data, this work would serve as a more robust resource for the antiviral research community.
Please confirm that no generative AI tools or large language models have been used to generate this peer review report or to assist with any part of the peer review process.
I confirm no generative AI tools were used in preparation of this review.
Please rate the manuscript for methodological rigour
Good
Please rate the quality of the presentation and structure of the manuscript
Very good
To what extent are the conclusions supported by the data?
Strongly support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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