Immune-adaptive pathogen variation reveals targetable mediators of gram-positive bacterial killing in macrophages.
| Title: | Immune-adaptive pathogen variation reveals targetable mediators of gram-positive bacterial killing in macrophages. |
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| Authors: | Russell CD; University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Edinburgh EH16 4UU, UK.; Baillie-Gifford Pandemic Science Hub, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh EH16 4UU, UK.; Marshall J; University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Edinburgh EH16 4UU, UK.; McHugh BJ; University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Edinburgh EH16 4UU, UK.; Michno BJ; Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Kraków 31-007, Poland.; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Kraków 31-007, Poland.; Cholewa-Waclaw J; High Content Screening Facility, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh EH16 4UU, UK.; Yebra G; Roslin Institute, The University of Edinburgh, Midlothian EH25 9RG, UK.; Chepsat J; University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Edinburgh EH16 4UU, UK.; Jones GR; School of Infection and Immunity, University of Glasgow, Glasgow G12 8TA, UK.; McHugh MP; Department of Clinical Microbiology, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK.; School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK.; Lynskey NN; Roslin Institute, The University of Edinburgh, Midlothian EH25 9RG, UK.; Renshaw SA; Florey Institute, Bateson Centre and Division of Clinical Medicine, School of Medicine and Population Health, Sheffield S10 2RX, UK.; Prajsnar TK; Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Kraków 31-007, Poland.; Baillie JK; University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Edinburgh EH16 4UU, UK.; Baillie-Gifford Pandemic Science Hub, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh EH16 4UU, UK.; Roslin Institute, The University of Edinburgh, Midlothian EH25 9RG, UK.; Fitzgerald JR; Roslin Institute, The University of Edinburgh, Midlothian EH25 9RG, UK.; Dockrell DH; University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Edinburgh EH16 4UU, UK. |
| Source: | Science advances [Sci Adv] 2026 Feb 27; Vol. 12 (9), pp. eaea0375. Date of Electronic Publication: 2026 Feb 27. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]- |
| MeSH Terms: | Macrophages*/immunology ; Macrophages*/microbiology ; Macrophages*/metabolism ; Macrophages*/drug effects ; Streptococcus pneumoniae*/immunology ; Streptococcus pneumoniae*/drug effects ; Streptococcus pneumoniae*/pathogenicity ; Streptococcus pneumoniae*/genetics ; Host-Pathogen Interactions*/immunology ; Gram-Positive Bacteria*/immunology ; Adaptive Immunity*; Receptors, Purinergic P2X7/metabolism ; Receptors, Purinergic P2X7/genetics ; Pneumococcal Infections/immunology ; Pneumococcal Infections/microbiology ; Anti-Bacterial Agents/pharmacology ; Enterococcus faecium/immunology ; Enterococcus faecium/drug effects ; Humans ; Animals ; Mice |
| Abstract: | Host-directed therapies for bacterial infections can provide an adjunct or alternative to conventional antimicrobials, mitigating the impact of antimicrobial resistance. However, therapeutically targetable mediators of innate immune bacterial killing remain elusive. We hypothesized that immune-adaptive pathogen evolution could provide an informative perspective on this problem. We examined the interaction of a genetically diverging hypervirulent Streptococcus pneumoniae (pneumococcus) serotype with macrophages, identifying closely phylogenetically related isolates with differential susceptibility to intracellular killing. We reasoned that macrophage genes relatively suppressed during pathogen escape from killing were likely to encode mediators normally promoting bacterial killing. This led to the validation of ACOD1 and its product itaconate, NAMPT, and P2RX7 as host defense factors against pneumococci and related gram-positive pathogens. Last, we repurposed the antihistamine clemastine to augment phagolysosomal bacterial killing, via P2RX7, as a candidate host-directed therapy against pneumococci and vancomycin-resistant Enterococcus faecium. Overall, we show that pathogen-centric host screening can aid identification of microbicidal responses as targets for host-directed therapies. |
| Substance Nomenclature: | 0 (Receptors, Purinergic P2X7); 0 (Anti-Bacterial Agents) |
| Entry Date(s): | Date Created: 20260227 Date Completed: 20260306 Latest Revision: 20260306 |
| Update Code: | 20260306 |
| PubMed Central ID: | PMC12947864 |
| DOI: | 10.1126/sciadv.aea0375 |
| PMID: | 41758934 |
| Database: | MEDLINE |
Journal Article