2021 Carreno EBioMedicine.pdf (2.89 MB)
Splenic macrophages as the source of bacteraemia during pneumococcal pneumonia
journal contributionposted on 2022-07-01, 11:03 authored by D Carreno, JJ Wanford, Z Jasiunaite, RG Hames, WY Chung, AR Dennison, K Straatman, L Martinez-Pomares, M Pareek, CJ Orihuela, MI Restrepo, WS Lim, PW Andrew, ER Moxon, MR Oggioni
Background: Severe community-acquired pneumococcal pneumonia is commonly associated with bacteraemia. Although it is assumed that the bacteraemia solely derives from pneumococci entering the blood from the lungs it is unknown if other organs are important in the pathogenesis of bacteraemia. Using three models, we tested the relevance of the spleen in pneumonia-associated bacteraemia. Methods: We used human spleens perfused ex vivo to explore permissiveness to bacterial replication, a non-human primate model to check for splenic involvement during pneumonia and a mouse pneumonia-bacteraemia model to demonstrate that splenic involvement correlates with invasive disease. Findings: Here we present evidence that the spleen is the reservoir of bacteraemia during pneumonia. We found that in the human spleen infected with pneumococci, clusters with increasing number of bacteria were detectable within macrophages. These clusters also were detected in non-human primates. When intranasally infected mice were treated with a non-therapeutic dose of azithromycin, which had no effect on pneumonia but concentrated inside splenic macrophages, bacteria were absent from the spleen and blood and importantly mice had no signs of disease. Interpretation: We conclude that the bacterial load in the spleen, and not lung, correlates with the occurrence of bacteraemia. This supports the hypothesis that the spleen, and not the lungs, is the major source of bacteria during systemic infection associated with pneumococcal pneumonia; a finding that provides a mechanistic basis for using combination therapies including macrolides in the treatment of severe community-acquired pneumococcal pneumonia. Funding: Oxford University, Wolfson Foundation, MRC, NIH, NIHR, and MRC and BBSRC studentships supported the work.
Authors thank Zaf Zafirelis from HbO2 Therapeutics (Souderton, PA, USA) for donating Hemopure®, Kevin West for help with the H&E stains, Sarah Glenn (Leicester Preclinical Research Facility) for support with the mouse experiments and the University of Leicester Advanced Imaging Facility (RRID:SCR_020967) for use of microscope equipment. The work was in part supported by a collaboration agreement with the University of Oxford and grants from the MRC MR/M003078/1 and BBSRC BB/S507052/1 to MRO. ZJ is funded by BBSRC BB/S507052/1. JJW is supported by the MRC IMPACT DTP. Non-human primate experiments directed by CJO who is supported by NIH AI114800 and AI148368. This investigation used resources that were supported by the Southwest National Primate Research Center grant P51 OD011133 from the Office of Research Infrastructure Programs, NIH. MP is supported by the National Institute for Health Research (NIHR Post-Doctoral Fellowship, Dr Manish Pareek, PDF-2015-08-102).
CitationCarreno, David, et al. "Splenic macrophages as the source of bacteraemia during pneumococcal pneumonia." EBioMedicine 72 (2021): 103601.
Author affiliationDepartment of Genetics and Genome Biology
- VoR (Version of Record)
Science & TechnologyLife Sciences & BiomedicineMedicine, General & InternalMedicine, Research & ExperimentalGeneral & Internal MedicineResearch & Experimental MedicineBacteraemiasepsishuman organpathogenesispneumoniatherapyCOMMUNITY-ACQUIRED PNEUMONIASTREPTOCOCCUS-PNEUMONIAECD169(+) MACROPHAGESTHORACIC SOCIETYSPLEENAZITHROMYCINGUIDELINEMORTALITYINFECTIONDISEASE