2020 Mitsi AJRCCM.pdf (2.01 MB)
Nasal Pneumococcal Density Is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens
journal contributionposted on 2020-07-03, 16:44 authored by Elena Mitsi, Beatriz Carniel, Jesus Reine, Jamie Rylance, Seher Zaidi, Alessandra Soares-Schanoski, Victoria Connor, Andrea M Collins, Andreas Schlitzer, Elissavet Nikolaou, Carla Solorzano, Sherin Pojar, Helen Hill, Angela D Hyder-Wright, Kondwani C Jambo, Marco R Oggioni, Megan De Ste Croix, Stephen B Gordon, Simon P Jochems, Daniela M Ferreira
Rationale: Pneumococcal pneumonia remains a global health problem. Colonization of the nasopharynx with Streptococcus pneumoniae (Spn), although a prerequisite of infection, is the main source of exposure and immunological boosting in children and adults. However, our knowledge of how nasal colonization impacts on the lung cells, especially on the predominant alveolar macrophage (AM) population, is limited. Objectives: Using a controlled human infection model to achieve nasal colonization with 6B serotype, we investigated the effect of Spn colonization on lung cells. Methods: We collected BAL from healthy pneumococcalchallenged participants aged 18-49 years. Confocal microscopy and molecular and classical microbiology were used to investigate microaspiration and pneumococcal presence in the lower airways. AM opsonophagocytic capacity was assessed by functional assays in vitro, whereas flow cytometry and transcriptomic analysis were used to assess further changes on the lung cellular populations. Measurements and Main Results: AMs from Spn-colonized individuals exhibited increased opsonophagocytosis to pneumococcus (11.4% median increase) for approximately 3 months after experimental pneumococcal colonization. AMs also had increased responses against other bacterial pathogens. Pneumococcal DNA detected in the BAL samples of Spncolonized individuals were positively correlated with nasal pneumococcal density (r = 0.71; P = 0.029). Similarly, AMheightened opsonophagocytic capacity was correlated with nasopharyngeal pneumococcal density (r = 0.61, P = 0.025). Conclusions: Our findings demonstrate that nasal colonization with pneumococcus and microaspiration prime AMs, leading to brisker responsiveness to both pneumococcus and unrelated bacterial pathogens. The relative abundance of AMs in the alveolar spaces, alongside their potential for nonspecific protection, render them an attractive target for novel vaccines.
Supported by the Bill and Melinda Gates Foundation (OPP1117728) (awarded to D.M.F.) and Medical Research Council Grants MR/M011569/1 and MR/M003078/1 (awarded to S.B.G. and M.R.O., respectively). Flow cytometric acquisition was performed on a BD LSRII and cell sorting was performed on a BD fluorescence-activated cell sorter ARIAIII funded by WelIcome Trust Multi-User Equipment Grant 104936/Z/14/Z.
CitationAmerican Journal of Respiratory and Critical Care Medicine, 2020 Feb 1;201(3):335-347. doi: 10.1164/rccm.201903-0607OC.
Author affiliationDepartment of Genetics
- AM (Accepted Manuscript)
Published inAmerican Journal of Respiratory and Critical Care Medicine
Pagination335 - 347
PublisherAmerican Thoracic Society
Spatial coverageUnited States
Science & TechnologyLife Sciences & BiomedicineCritical Care MedicineRespiratory SystemGeneral & Internal MedicineStreptococcus pneumoniae nasopharyngeal colonizationmicroaspirationalveolar macrophagesinterferon-gammaCD4(+) T cellsSTREPTOCOCCUS-PNEUMONIAENASOPHARYNGEAL CARRIAGEINTERFERON-GAMMAMEMORYCOLONIZATIONPROTECTIONRESPONSESDYNAMICSIMMUNITYDEFENSE