Genome-Scale Meta-analysis of Host Responses to Staphylococcus aureus Identifies Pathways for Host-Directed Therapeutic Targeting.

1. J Infect Dis. 2025 Aug 14;232(2):e290-e300. doi: 10.1093/infdis/jiaf290. Genome-Scale Meta-analysis of Host Responses to Staphylococcus aureus Identifies Pathways for Host-Directed Therapeutic Targeting. Russell CD(1)(2), Goeldner-Thompson S(1), Smith E(1), Millar JE(2)(3), Wang B(2)(3), Parkinson N(3), Clohisey Hendry S(2)(3), Swets M(3)(4), Fitzgerald JR(3), Baillie JK(1)(2)(3), Dockrell DH(1). Author information: (1)University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Edinburgh, United Kingdom. (2)Baillie-Gifford Pandemic Science Hub, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom. (3)Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom. (4)Department of Infectious Diseases, Leiden University Medical Center, Leiden University, Leiden, The Netherlands. 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 prioritize 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 prioritized 3867 host genes. Myeloid cell immune responses were enriched with specific hubs including TLR2, IL-17, IFN-γ, and IL-1β. Noncanonical 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). Prioritized genes were associated with genome-wide association study traits related to platelet count. In a cohort of patients with S aureus bacteremia, 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 (IFN-γ). CONCLUSIONS: This in silico analysis identifies cytokine hubs associated with the response to S aureus infection and prioritizes additional host responses including apoptosis, autophagy, iron metabolism, and thrombosis as therapeutic targets. © The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America. DOI: 10.1093/infdis/jiaf290 PMCID: PMC12349957 PMID: 40447280 [Indexed for MEDLINE] Conflict of interest statement: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.