Immune-adaptive pathogen variation reveals targetable mediators of gram-positive bacterial killing in macrophages

Clark D Russell; Jennifer Marshall; Brian J.  McHugh; Bartosz J. Michno; Justyna Cholewa-Waclaw; Jelimo Chepsat; Gareth-Rhys Jones; Martin P McHugh; Nicola Lynskey; Gonzalo Yebra; Stephen A. Renshaw; Tomasz K  Prajsnar; J. Kenneth Baillie; J. Ross Fitzgerald; David H. Dockrell

doi:10.1126/sciadv.aea0375

Immune-adaptive pathogen variation reveals targetable mediators of gram-positive bacterial killing in macrophages

Clark D Russell, Jennifer Marshall, Brian J. McHugh, Bartosz J. Michno, Justyna Cholewa-Waclaw, Jelimo Chepsat, Gareth-Rhys Jones, Martin P McHugh, Nicola Lynskey, Gonzalo Yebra, Stephen A. Renshaw, Tomasz K Prajsnar, J. Kenneth Baillie, J. Ross Fitzgerald, David H. Dockrell

Research output: Contribution to journal › Article › peer-review

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 hypothesised that immune-adaptive pathogen evolution could provide an informative perspective on this problem. We examined the interaction of a genetically diverging hyper-virulent 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 defence factors against pneumococci and related gram-positive pathogens. Finally, we re-purposed the anti-histamine 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.

Original language	English
Article number	eaea0375
Journal	Science Advances
Volume	12
Issue number	9
DOIs	https://doi.org/10.1126/sciadv.aea0375
Publication status	Published - 27 Feb 2026

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accepted_Clark RussellAccepted author manuscript, 382 KB
sciadv.aea0375Final published version, 733 KBLicence: Creative Commons: Attribution (CC-BY)

The roles of a universally conserved DNA-and RNA-binding domain in controlling MRSA virulence and antibiotic resistance
Dockrell, D. (Co-investigator)
Medical Research Council
1/04/24 → 31/03/29
Project: Research
Mitochondrial dysfunction in macrophages and impaired bacterial clearance in chronic obstructive pulmonary disease (COPD)
Dockrell, D. (Principal Investigator), McHugh, B. (Co-investigator), Walmsley, S. (Co-investigator) & Whyte, M. (Co-investigator)
Medical Research Council
1/06/22 → 31/05/27
Project: Research

IRR High Content Screening
Cholewa-Waclaw, J. (Manager) & Johnston, S. (Other)
School of Regeneration and Repair
Facility/equipment: Facility

Cite this

Russell, C. D., Marshall, J., McHugh, B. J., Michno, B. J., Cholewa-Waclaw, J., Chepsat, J., Jones, G.-R., McHugh, M. P., Lynskey, N., Yebra, G., Renshaw, S. A., Prajsnar, T. K., Baillie, J. K., Fitzgerald, J. R., & Dockrell, D. H. (2026). Immune-adaptive pathogen variation reveals targetable mediators of gram-positive bacterial killing in macrophages. Science Advances, 12(9), Article eaea0375. https://doi.org/10.1126/sciadv.aea0375

@article{5e315bed79e2455c87fc52fd2bf77ed3,

title = "Immune-adaptive pathogen variation reveals targetable mediators of gram-positive bacterial killing in macrophages",

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 hypothesised that immune-adaptive pathogen evolution could provide an informative perspective on this problem. We examined the interaction of a genetically diverging hyper-virulent 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 defence factors against pneumococci and related gram-positive pathogens. Finally, we re-purposed the anti-histamine 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.",

author = "Russell, \{Clark D\} and Jennifer Marshall and McHugh, \{Brian J.\} and Michno, \{Bartosz J.\} and Justyna Cholewa-Waclaw and Jelimo Chepsat and Gareth-Rhys Jones and McHugh, \{Martin P\} and Nicola Lynskey and Gonzalo Yebra and Renshaw, \{Stephen A.\} and Prajsnar, \{Tomasz K\} and Baillie, \{J. Kenneth\} and Fitzgerald, \{J. Ross\} and Dockrell, \{David H.\}",

note = "Conceptualization: CDR, JKB, JRF, DHD. Methodology: CDR, JM, GY, GRJ, SAR, TKP, JKB, DHD. Investigation: CDR, JM, BJM (McHugh), BJM (Michno), JCW, GY, JC, TKP Formal analysis: CDR, JCW, DHD. Resources: GRJ, MPM, NNL, JM, BJM (McHugh), JCW, JKB, DHD. Funding acquisition: CDR, JRF, DHD. Project administration: CDR, DHD. Supervision: CDR, JKB, JRF, DHD. Data curation: CDR, JCW. Visualization: CDR. Writing – original draft: CDR, DHD. Validation: JCW, DHD. Software: JKB. Writing – review \& editing: CDR, JM, BJM (McHugh), BJM (Michno), JCW, GRJ, MPM, SAR, TKP, JKB, JRF, DHD.",

year = "2026",

month = feb,

day = "27",

doi = "10.1126/sciadv.aea0375",

language = "English",

volume = "12",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

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Russell, CD, Marshall, J, McHugh, BJ, Michno, BJ, Cholewa-Waclaw, J, Chepsat, J, Jones, G-R, McHugh, MP, Lynskey, N, Yebra, G, Renshaw, SA, Prajsnar, TK, Baillie, JK , Fitzgerald, JR & Dockrell, DH 2026, 'Immune-adaptive pathogen variation reveals targetable mediators of gram-positive bacterial killing in macrophages', Science Advances, vol. 12, no. 9, eaea0375. https://doi.org/10.1126/sciadv.aea0375

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T1 - Immune-adaptive pathogen variation reveals targetable mediators of gram-positive bacterial killing in macrophages

AU - Russell, Clark D

AU - Marshall, Jennifer

AU - McHugh, Brian J.

AU - Michno, Bartosz J.

AU - Cholewa-Waclaw, Justyna

AU - Chepsat, Jelimo

AU - Jones, Gareth-Rhys

AU - McHugh, Martin P

AU - Lynskey, Nicola

AU - Yebra, Gonzalo

AU - Renshaw, Stephen A.

AU - Prajsnar, Tomasz K

AU - Baillie, J. Kenneth

AU - Fitzgerald, J. Ross

AU - Dockrell, David H.

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PY - 2026/2/27

Y1 - 2026/2/27

N2 - 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 hypothesised that immune-adaptive pathogen evolution could provide an informative perspective on this problem. We examined the interaction of a genetically diverging hyper-virulent 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 defence factors against pneumococci and related gram-positive pathogens. Finally, we re-purposed the anti-histamine 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.

AB - 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 hypothesised that immune-adaptive pathogen evolution could provide an informative perspective on this problem. We examined the interaction of a genetically diverging hyper-virulent 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 defence factors against pneumococci and related gram-positive pathogens. Finally, we re-purposed the anti-histamine 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.

U2 - 10.1126/sciadv.aea0375

DO - 10.1126/sciadv.aea0375

M3 - Article

SN - 2375-2548

VL - 12

JO - Science Advances

JF - Science Advances

IS - 9

M1 - eaea0375

ER -

Immune-adaptive pathogen variation reveals targetable mediators of gram-positive bacterial killing in macrophages

Abstract

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Projects

The roles of a universally conserved DNA-and RNA-binding domain in controlling MRSA virulence and antibiotic resistance

Mitochondrial dysfunction in macrophages and impaired bacterial clearance in chronic obstructive pulmonary disease (COPD)

Equipment

IRR High Content Screening

Cite this