Nasal Pneumococcal Density is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens.

Elena Mitsi; Beatriz Carniel; Jesus Reine Gutierrez; Jamie Rylance; Seher Zaidi; Alessandra Soares-Schanoski; Victoria Connor; Andrea Collins; Andreas Schlitzer; Elissavet Nikolaou; Carla Solorzano; Sherin Pojar; Helen Hill; Angela D. Hyder-Wright; Kondwani Jambo; Marco R. Oggioni; Megan De Ste Croix; Stephen Gordon; Simon P. Jochems; Daniela Ferreira

doi:10.1164/rccm.201903-0607oc

Nasal Pneumococcal Density is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens.

Elena Mitsi, Beatriz Carniel, Jesus Reine Gutierrez, Jamie Rylance, Seher Zaidi, Alessandra Soares-Schanoski, Victoria Connor, Andrea Collins, Andreas Schlitzer, Elissavet Nikolaou, Carla Solorzano, Sherin Pojar, Helen Hill, Angela D. Hyder-Wright, Kondwani Jambo, Marco R. Oggioni, Megan De Ste Croix, Stephen Gordon, Simon P. Jochems, Daniela Ferreira

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

29 Citations (Scopus)

Abstract

RATIONALE

Pneumococcal pneumonia remains a global health problem. Colonization of the nasopharynx with S.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 bronchoalveolar lavages from healthy pneumococcal challenged participants aged 18-49 years. Confocal microscopy, 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

AM from Spn-colonized exhibited increased opsonophagocytosis to pneumococcus (11.4% median increase) for four months after clearance of experimental pneumococcal colonization. AM had also increased responses against other bacterial pathogens. Pneumococcal DNA detected in the BAL samples of Spn-colonized were positively correlated with nasal pneumococcal density (r=0.71, p=0.029). Similarly, AM heightened 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 AM, leading to brisker responsiveness to both pneumococcus and unrelated bacterial pathogens. The relative abundance of AM in the alveolar spaces, alongside with their potential for non-specific protection, render them an attractive target for novel vaccines. Clinical trial registration available at http://www.isrctn.com, ID: ISRCTN16993271.

Original language	English
Pages (from-to)	335-347
Number of pages	13
Journal	American Journal of Respiratory and Critical Care Medicine
Volume	201
Issue number	3
Early online date	18 Oct 2019
DOIs	https://doi.org/10.1164/rccm.201903-0607oc
Publication status	Published - 1 Feb 2020

Keywords

Alveolar macrophages
CD4 T cells
Interferon-g
Microaspiration
Streptococcus pneumoniae nasopharyngeal colonization

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1164/rccm.201903-0607oc

RccmAccepted author manuscript, 7.98 MB

The human lung immune responses to nasopharyngeal pneumococcal colonisation in healthy adults
Mitsi, E. (Author), Ferreira, D. (Supervisor), Jochems, S. (Supervisor) & Jambo, K. (Supervisor), 2019
Student thesis: Doctoral thesis

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Mitsi, E., Carniel, B., Reine Gutierrez, J., Rylance, J., Zaidi, S., Soares-Schanoski, A., Connor, V., Collins, A., Schlitzer, A., Nikolaou, E., Solorzano, C., Pojar, S., Hill, H., Hyder-Wright, A. D., Jambo, K., Oggioni, M. R., De Ste Croix, M., Gordon, S., Jochems, S. P., & Ferreira, D. (2020). Nasal Pneumococcal Density is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens. American Journal of Respiratory and Critical Care Medicine, 201(3), 335-347. https://doi.org/10.1164/rccm.201903-0607oc

@article{20bc4b98d1a441e2b0c544b66f3b32fe,

title = "Nasal Pneumococcal Density is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens.",

abstract = "RATIONALEPneumococcal pneumonia remains a global health problem. Colonization of the nasopharynx with S.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.OBJECTIVESUsing a Controlled Human Infection Model to achieve nasal colonization with 6B serotype, we investigated the effect of Spn colonization on lung cells.METHODSWe collected bronchoalveolar lavages from healthy pneumococcal challenged participants aged 18-49 years. Confocal microscopy, 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 RESULTSAM from Spn-colonized exhibited increased opsonophagocytosis to pneumococcus (11.4\% median increase) for four months after clearance of experimental pneumococcal colonization. AM had also increased responses against other bacterial pathogens. Pneumococcal DNA detected in the BAL samples of Spn-colonized were positively correlated with nasal pneumococcal density (r=0.71, p=0.029). Similarly, AM heightened opsonophagocytic capacity was correlated with nasopharyngeal pneumococcal density (r=0.61, p=0.025).CONCLUSIONSOur findings demonstrate that nasal colonization with pneumococcus and microaspiration prime AM, leading to brisker responsiveness to both pneumococcus and unrelated bacterial pathogens. The relative abundance of AM in the alveolar spaces, alongside with their potential for non-specific protection, render them an attractive target for novel vaccines. Clinical trial registration available at http://www.isrctn.com, ID: ISRCTN16993271.",

keywords = "Alveolar macrophages, CD4 T cells, Interferon-g, Microaspiration, Streptococcus pneumoniae nasopharyngeal colonization",

author = "Elena Mitsi and Beatriz Carniel and \{Reine Gutierrez\}, Jesus and Jamie Rylance and Seher Zaidi and Alessandra Soares-Schanoski and Victoria Connor and Andrea Collins and Andreas Schlitzer and Elissavet Nikolaou and Carla Solorzano and Sherin Pojar and Helen Hill and Hyder-Wright, \{Angela D.\} and Kondwani Jambo and Oggioni, \{Marco R.\} and \{De Ste Croix\}, Megan and Stephen Gordon and Jochems, \{Simon P.\} and Daniela Ferreira",

year = "2020",

month = feb,

day = "1",

doi = "10.1164/rccm.201903-0607oc",

language = "English",

volume = "201",

pages = "335--347",

journal = "American Journal of Respiratory and Critical Care Medicine",

issn = "1073-449X",

publisher = "American Thoracic Society",

number = "3",

}

Mitsi, E, Carniel, B, Reine Gutierrez, J, Rylance, J, Zaidi, S, Soares-Schanoski, A, Connor, V, Collins, A, Schlitzer, A, Nikolaou, E, Solorzano, C, Pojar, S, Hill, H, Hyder-Wright, AD, Jambo, K, Oggioni, MR, De Ste Croix, M, Gordon, S, Jochems, SP & Ferreira, D 2020, 'Nasal Pneumococcal Density is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens.', American Journal of Respiratory and Critical Care Medicine, vol. 201, no. 3, pp. 335-347. https://doi.org/10.1164/rccm.201903-0607oc

Nasal Pneumococcal Density is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens. / Mitsi, Elena; Carniel, Beatriz; Reine Gutierrez, Jesus et al.
In: American Journal of Respiratory and Critical Care Medicine, Vol. 201, No. 3, 01.02.2020, p. 335-347.

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

TY - JOUR

T1 - Nasal Pneumococcal Density is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens.

AU - Mitsi, Elena

AU - Carniel, Beatriz

AU - Reine Gutierrez, Jesus

AU - Rylance, Jamie

AU - Zaidi, Seher

AU - Soares-Schanoski, Alessandra

AU - Connor, Victoria

AU - Collins, Andrea

AU - Schlitzer, Andreas

AU - Nikolaou, Elissavet

AU - Solorzano, Carla

AU - Pojar, Sherin

AU - Hill, Helen

AU - Hyder-Wright, Angela D.

AU - Jambo, Kondwani

AU - Oggioni, Marco R.

AU - De Ste Croix, Megan

AU - Gordon, Stephen

AU - Jochems, Simon P.

AU - Ferreira, Daniela

PY - 2020/2/1

Y1 - 2020/2/1

N2 - RATIONALEPneumococcal pneumonia remains a global health problem. Colonization of the nasopharynx with S.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.OBJECTIVESUsing a Controlled Human Infection Model to achieve nasal colonization with 6B serotype, we investigated the effect of Spn colonization on lung cells.METHODSWe collected bronchoalveolar lavages from healthy pneumococcal challenged participants aged 18-49 years. Confocal microscopy, 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 RESULTSAM from Spn-colonized exhibited increased opsonophagocytosis to pneumococcus (11.4% median increase) for four months after clearance of experimental pneumococcal colonization. AM had also increased responses against other bacterial pathogens. Pneumococcal DNA detected in the BAL samples of Spn-colonized were positively correlated with nasal pneumococcal density (r=0.71, p=0.029). Similarly, AM heightened opsonophagocytic capacity was correlated with nasopharyngeal pneumococcal density (r=0.61, p=0.025).CONCLUSIONSOur findings demonstrate that nasal colonization with pneumococcus and microaspiration prime AM, leading to brisker responsiveness to both pneumococcus and unrelated bacterial pathogens. The relative abundance of AM in the alveolar spaces, alongside with their potential for non-specific protection, render them an attractive target for novel vaccines. Clinical trial registration available at http://www.isrctn.com, ID: ISRCTN16993271.

AB - RATIONALEPneumococcal pneumonia remains a global health problem. Colonization of the nasopharynx with S.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.OBJECTIVESUsing a Controlled Human Infection Model to achieve nasal colonization with 6B serotype, we investigated the effect of Spn colonization on lung cells.METHODSWe collected bronchoalveolar lavages from healthy pneumococcal challenged participants aged 18-49 years. Confocal microscopy, 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 RESULTSAM from Spn-colonized exhibited increased opsonophagocytosis to pneumococcus (11.4% median increase) for four months after clearance of experimental pneumococcal colonization. AM had also increased responses against other bacterial pathogens. Pneumococcal DNA detected in the BAL samples of Spn-colonized were positively correlated with nasal pneumococcal density (r=0.71, p=0.029). Similarly, AM heightened opsonophagocytic capacity was correlated with nasopharyngeal pneumococcal density (r=0.61, p=0.025).CONCLUSIONSOur findings demonstrate that nasal colonization with pneumococcus and microaspiration prime AM, leading to brisker responsiveness to both pneumococcus and unrelated bacterial pathogens. The relative abundance of AM in the alveolar spaces, alongside with their potential for non-specific protection, render them an attractive target for novel vaccines. Clinical trial registration available at http://www.isrctn.com, ID: ISRCTN16993271.

KW - Alveolar macrophages

KW - CD4 T cells

KW - Interferon-g

KW - Microaspiration

KW - Streptococcus pneumoniae nasopharyngeal colonization

U2 - 10.1164/rccm.201903-0607oc

DO - 10.1164/rccm.201903-0607oc

M3 - Article

SN - 1073-449X

VL - 201

SP - 335

EP - 347

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

IS - 3

ER -

Nasal Pneumococcal Density is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens.

Abstract

Keywords

UN SDGs

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Student theses

The human lung immune responses to nasopharyngeal pneumococcal colonisation in healthy adults

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