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

Anne-Katrien Stark, Anita Chandra, Krishnendu Chakraborty, Rafeah Alam, Valentina Carbonaro, Jonathan Clark, Srividya Sriskantharajah, Glyn Bradley, Alex G. Richter, Edward Banham-Hall, Menna R. Clatworthy, Sergey Nejentsev, J. Nicole Hamblin, Edith M. Hessel, Alison M. Condliffe and Klaus Okkenhaug ()
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Anne-Katrien Stark: Babraham Institute
Anita Chandra: Babraham Institute
Krishnendu Chakraborty: Babraham Institute
Rafeah Alam: Babraham Institute
Valentina Carbonaro: Babraham Institute
Jonathan Clark: Babraham Institute
Srividya Sriskantharajah: GlaxoSmithKline
Glyn Bradley: GlaxoSmithKline
Alex G. Richter: Queen Elizabeth Hospital
Edward Banham-Hall: Babraham Institute
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

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05674-8

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