Genome-scale meta-analysis of host responses to Staphylococcus aureus identifies pathways for host-directed therapeutic targeting

Clark D Russell; Seraphima Goeldner-Thompson; Emilie Smith; Jonathan E Millar; Bo Wang; Nicholas Parkinson; Sara Clohisey Hendry; Maaike Swets; J Ross Fitzgerald; J Kenneth Baillie; David H Dockrell

doi:10.1093/infdis/jiaf290

Genome-scale meta-analysis of host responses to Staphylococcus aureus identifies pathways for host-directed therapeutic targeting

J Infect Dis. 2025 May 31:jiaf290. doi: 10.1093/infdis/jiaf290. Online ahead of print.

Authors

Clark D Russell^{1

2}, Seraphima Goeldner-Thompson¹, Emilie Smith¹, Jonathan E Millar^{2

3}, Bo Wang^{2

3}, Nicholas Parkinson³, Sara Clohisey Hendry^{2

3}, Maaike Swets^{3

4}, J Ross Fitzgerald³, J Kenneth Baillie^{1

2

3}, David H Dockrell¹

Affiliations

¹ University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Edinburgh, UK.
² Baillie-Gifford Pandemic Science Hub, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
³ Roslin Institute, University of Edinburgh, Edinburgh, UK.
⁴ Department of Infectious Diseases, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.

PMID: 40447280
DOI: 10.1093/infdis/jiaf290

Abstract

Background: Staphylococcus aureus infections are frequently complicated by metastatic foci, recurrence, and death. Antimicrobial resistance and intracellular bacterial persistence limit the effectiveness of conventional antimicrobials. Host-directed therapies could improve outcomes, but the interpretive complexity of pathogen-host interactions impedes identification of critical responses suitable for therapeutic targeting. To address this, we performed a meta-analysis of genome-scale studies aiming to prioritise host responses to S. aureus.

Methods: Lists of genes associated with host responses to S. aureus were retrieved from systematically identified genome-scale studies, then integrated using the meta-analysis by information content (MAIC) algorithm. This generated a single aggregated gene list, ranked based on the cumulative evidence supporting each gene.

Results: MAIC prioritised 3867 host genes. Myeloid cell immune responses were enriched with specific hubs including TLR2, IL-17, IFNγ, and IL-1β. Non-canonical effector pathways were also enriched: autophagy (specific factors including mTOR and LAMP2), apoptosis (including BAD and BID), ferroptosis and iron metabolism (TFRC ranked 8/3876), and proteasomal antimicrobial responses (including PSME3 and the novel antimicrobial peptide PPP1CB). Prioritised genes were associated with GWAS traits related to platelet count. In a cohort of patients with S. aureus bacteraemia, platelet count was differentially associated with clinical outcomes. Targets with immediate therapeutic relevance included S. aureus/fibrin/platelet microthrombus formation (VWF, GP11b), S. aureus-induced platelet loss (ASGR2), autophagy (mTOR), BID-mediated apoptosis, and intracellular bacterial killing (IFNγ).

Conclusions: This in silico analysis identifies cytokine hubs associated with the response to S. aureus infection and prioritises additional host responses including apoptosis, autophagy, iron metabolism, and thrombosis as therapeutic targets.

Keywords: Staphylococcus aureus; apoptosis; autophagy; ferroptosis; host-directed therapy; innate immunity; iron; phagocyte; platelet; proteasome.