Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation

Adi Biram; Jingjing Liu; Hadas Hezroni-Bravyi; Natalia Davidzohn; Dominik Schmiedel; Eman Khatib-Massalha; Montaser Haddad; Charlotte Amalie Grenov; Sacha Lebon; Tomer Meir Salame; Nili Dezorella; Dotan Hoffman; Paula Abou Karam; Moshe Biton; Tsvee Lapidot; Mats Bemark; Roi Avraham; Steffen Jung; Ziv Shulman

doi:10.1016/j.immuni.2022.01.013

Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation

Adi Biram, Jingjing Liu, Hadas Hezroni-Bravyi, Natalia Davidzohn, Dominik Schmiedel, Eman Khatib-Massalha, Montaser Haddad, Charlotte Amalie Grenov, Sacha Lebon, Tomer Meir Salame, Nili Dezorella, Dotan Hoffman, Paula Abou Karam, Moshe Biton, Tsvee Lapidot, Mats Bemark, Roi Avraham, Steffen Jung, Ziv Shulman^*

^*Corresponding author for this work

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

29 Citations (Scopus)

Abstract

Consecutive exposures to different pathogens are highly prevalent and often alter the host immune response. However, it remains unknown how a secondary bacterial infection affects an ongoing adaptive immune response elicited against primary invading pathogens. We demonstrated that recruitment of Sca-1+ monocytes into lymphoid organs during Salmonella Typhimurium (STm) infection disrupted pre-existing germinal center (GC) reactions. GC responses induced by influenza, plasmodium, or commensals deteriorated following STm infection. GC disruption was independent of the direct bacterial interactions with B cells and instead was induced through recruitment of CCR2-dependent Sca-1+ monocytes into the lymphoid organs. GC collapse was associated with impaired cellular respiration and was dependent on TNFα and IFNγ, the latter of which was essential for Sca-1+ monocyte differentiation. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon severe bacterial infection is induced at the expense of antibody-mediated immunity.

Original language	English
Pages (from-to)	442-458.e8
Number of pages	26
Journal	Immunity
Volume	55
Issue number	3
Early online date	22 Feb 2022
DOIs	https://doi.org/10.1016/j.immuni.2022.01.013
Publication status	Published - 8 Mar 2022

Funding

We thank Dr. Elena Ainbinder and Dr. Yael Fried from the Stem Cells and Advanced Cell Technologies unit of the Weizmann Institute Life Science Core Facility for assistance with metabolism assays. Z.S. is supported by the European Research Council (ERC) grant no. 677713, Israel Science Foundation (ISF) grant no. 1090/18, and the Morris Kahn Institute for Human Immunology. We thank the Azrieli Foundation; Ben B. and Joyce E. Eisenberg Foundation; Wolfson Family Charitable Trust and Wolfson Foundation; and Elie Hirschfeld, Dr. Sarah Schlesinger, and Miel de Botton for their support. Z.S. is a member of the European Molecular Biology Organization (EMBO) Young Investigator Program. A.B. conceived the study, designed and conducted the experiments, performed data analysis, and wrote the manuscript; J.L. N. Davidzohn. D.S. A.G. and S.L. helped in conducting some experiments. T.M.S. helped in conducting CyTOF experiments. E.K.-M. M.H. M. Biton and T.L. advised and helped in the design of some experiments; N. Dezorella. performed TEM imaging. P.A.K. provided resources in malaria infection experiments. D.H. and R.A. provided bacterial strains. H.H. performed RNA sequencing analysis. M. Bemark and S.J. advised throughout the study. Z.S. conceived and supervised the study, designed experiments, and wrote the manuscript. The authors declare no competing interests. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We thank Dr. Elena Ainbinder and Dr. Yael Fried from the Stem Cells and Advanced Cell Technologies unit of the Weizmann Institute Life Science Core Facility for assistance with metabolism assays. Z.S. is supported by the European Research Council (ERC) grant no. 677713 , Israel Science Foundation (ISF) grant no. 1090/18 , and the Morris Kahn Institute for Human Immunology . We thank the Azrieli Foundation; Ben B. and Joyce E. Eisenberg Foundation; Wolfson Family Charitable Trust and Wolfson Foundation; and Elie Hirschfeld, Dr. Sarah Schlesinger, and Miel de Botton for their support. Z.S. is a member of the European Molecular Biology Organization (EMBO) Young Investigator Program.

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2022.01.013

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Biram, A., Liu, J., Hezroni-Bravyi, H., Davidzohn, N., Schmiedel, D., Khatib-Massalha, E., Haddad, M., Grenov, C. A., Lebon, S., Salame, T. M., Dezorella, N., Hoffman, D., Abou Karam, P., Biton, M., Lapidot, T., Bemark, M., Avraham, R., Jung, S., & Shulman, Z. (2022). Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation. Immunity, 55(3), 442-458.e8. https://doi.org/10.1016/j.immuni.2022.01.013

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abstract = "Consecutive exposures to different pathogens are highly prevalent and often alter the host immune response. However, it remains unknown how a secondary bacterial infection affects an ongoing adaptive immune response elicited against primary invading pathogens. We demonstrated that recruitment of Sca-1+ monocytes into lymphoid organs during Salmonella Typhimurium (STm) infection disrupted pre-existing germinal center (GC) reactions. GC responses induced by influenza, plasmodium, or commensals deteriorated following STm infection. GC disruption was independent of the direct bacterial interactions with B cells and instead was induced through recruitment of CCR2-dependent Sca-1+ monocytes into the lymphoid organs. GC collapse was associated with impaired cellular respiration and was dependent on TNFα and IFNγ, the latter of which was essential for Sca-1+ monocyte differentiation. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon severe bacterial infection is induced at the expense of antibody-mediated immunity. ",

author = "Adi Biram and Jingjing Liu and Hadas Hezroni-Bravyi and Natalia Davidzohn and Dominik Schmiedel and Eman Khatib-Massalha and Montaser Haddad and Grenov, \{Charlotte Amalie\} and Sacha Lebon and Salame, \{Tomer Meir\} and Nili Dezorella and Dotan Hoffman and \{Abou Karam\}, Paula and Moshe Biton and Tsvee Lapidot and Mats Bemark and Roi Avraham and Steffen Jung and Ziv Shulman",

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Biram, A, Liu, J, Hezroni-Bravyi, H, Davidzohn, N, Schmiedel, D, Khatib-Massalha, E, Haddad, M, Grenov, CA, Lebon, S, Salame, TM , Dezorella, N, Hoffman, D, Abou Karam, P , Biton, M , Lapidot, T, Bemark, M, Avraham, R , Jung, S & Shulman, Z 2022, 'Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation', Immunity, vol. 55, no. 3, pp. 442-458.e8. https://doi.org/10.1016/j.immuni.2022.01.013

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T1 - Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation

AU - Biram, Adi

AU - Liu, Jingjing

AU - Hezroni-Bravyi, Hadas

AU - Davidzohn, Natalia

AU - Schmiedel, Dominik

AU - Khatib-Massalha, Eman

AU - Haddad, Montaser

AU - Grenov, Charlotte Amalie

AU - Lebon, Sacha

AU - Salame, Tomer Meir

AU - Dezorella, Nili

AU - Hoffman, Dotan

AU - Abou Karam, Paula

AU - Biton, Moshe

AU - Lapidot, Tsvee

AU - Bemark, Mats

AU - Avraham, Roi

AU - Jung, Steffen

AU - Shulman, Ziv

PY - 2022/3/8

Y1 - 2022/3/8

N2 - Consecutive exposures to different pathogens are highly prevalent and often alter the host immune response. However, it remains unknown how a secondary bacterial infection affects an ongoing adaptive immune response elicited against primary invading pathogens. We demonstrated that recruitment of Sca-1+ monocytes into lymphoid organs during Salmonella Typhimurium (STm) infection disrupted pre-existing germinal center (GC) reactions. GC responses induced by influenza, plasmodium, or commensals deteriorated following STm infection. GC disruption was independent of the direct bacterial interactions with B cells and instead was induced through recruitment of CCR2-dependent Sca-1+ monocytes into the lymphoid organs. GC collapse was associated with impaired cellular respiration and was dependent on TNFα and IFNγ, the latter of which was essential for Sca-1+ monocyte differentiation. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon severe bacterial infection is induced at the expense of antibody-mediated immunity.

AB - Consecutive exposures to different pathogens are highly prevalent and often alter the host immune response. However, it remains unknown how a secondary bacterial infection affects an ongoing adaptive immune response elicited against primary invading pathogens. We demonstrated that recruitment of Sca-1+ monocytes into lymphoid organs during Salmonella Typhimurium (STm) infection disrupted pre-existing germinal center (GC) reactions. GC responses induced by influenza, plasmodium, or commensals deteriorated following STm infection. GC disruption was independent of the direct bacterial interactions with B cells and instead was induced through recruitment of CCR2-dependent Sca-1+ monocytes into the lymphoid organs. GC collapse was associated with impaired cellular respiration and was dependent on TNFα and IFNγ, the latter of which was essential for Sca-1+ monocyte differentiation. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon severe bacterial infection is induced at the expense of antibody-mediated immunity.

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DO - 10.1016/j.immuni.2022.01.013

M3 - Article

SN - 1074-7613

VL - 55

SP - 442-458.e8

JO - Immunity

JF - Immunity

IS - 3

ER -

Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation

Abstract

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