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PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner

Author

Listed:
  • Anne-Katrien Stark

    (Babraham Institute
    University of Cambridge)

  • Anita Chandra

    (Babraham Institute
    University of Cambridge
    University of Cambridge
    Cambridge University Hospitals NHS Trust)

  • Krishnendu Chakraborty

    (Babraham Institute
    University of Cambridge)

  • Rafeah Alam

    (Babraham Institute)

  • Valentina Carbonaro

    (Babraham Institute)

  • Jonathan Clark

    (Babraham Institute)

  • Srividya Sriskantharajah

    (GlaxoSmithKline)

  • Glyn Bradley

    (GlaxoSmithKline)

  • Alex G. Richter

    (Queen Elizabeth Hospital
    University of Birmingham)

  • Edward Banham-Hall

    (Babraham Institute
    University of Cambridge
    Cambridge University Hospitals NHS Trust)

  • Menna R. Clatworthy

    (University of Cambridge Department of Medicine, MRC Laboratory of Molecular Biology)

  • Sergey Nejentsev

    (University of Cambridge)

  • J. Nicole Hamblin

    (GlaxoSmithKline)

  • Edith M. Hessel

    (GlaxoSmithKline)

  • Alison M. Condliffe

    (University of Sheffield)

  • Klaus Okkenhaug

    (Babraham Institute
    University of Cambridge)

Abstract

Streptococcus pneumoniae is a major cause of pneumonia and a leading cause of death world-wide. Antibody-mediated immune responses can confer protection against repeated exposure to S. pneumoniae, yet vaccines offer only partial protection. Patients with Activated PI3Kδ Syndrome (APDS) are highly susceptible to S. pneumoniae. We generated a conditional knock-in mouse model of this disease and identify a CD19+B220− B cell subset that is induced by PI3Kδ signaling, resides in the lungs, and is correlated with increased susceptibility to S. pneumoniae during early phases of infection via an antibody-independent mechanism. We show that an inhaled PI3Kδ inhibitor improves survival rates following S. pneumoniae infection in wild-type mice and in mice with activated PI3Kδ. These results suggest that a subset of B cells in the lung can promote the severity of S. pneumoniae infection, representing a potential therapeutic target.

Suggested Citation

  • Anne-Katrien Stark & Anita Chandra & Krishnendu Chakraborty & Rafeah Alam & Valentina Carbonaro & Jonathan Clark & Srividya Sriskantharajah & Glyn Bradley & Alex G. Richter & Edward Banham-Hall & Menn, 2018. "PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05674-8
    DOI: 10.1038/s41467-018-05674-8
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    Cited by:

    1. Ondrej Suchanek & John R. Ferdinand & Zewen K. Tuong & Sathi Wijeyesinghe & Anita Chandra & Ann-Katrin Clauder & Larissa N. Almeida & Simon Clare & Katherine Harcourt & Christopher J. Ward & Rachael B, 2023. "Tissue-resident B cells orchestrate macrophage polarisation and function," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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