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

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2018

Nat Commun. 2018 Aug 9;9(1):3174. doi: 10.1038/s41467-018-05674-8.

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

AK Stark;A Chandra;K Chakraborty;R Alam;V Carbonaro;S Sriskantharajah;G Bradley;AG Richter;E Banham-Hall;MR Clatworthy;S Nejentsev;JN Hamblin;EM Hessel;AM Condliffe;K Okkenhaug

Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, CB21 3AT, UK. Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK. Department of Medicine, University of Cambridge, Cambridge, CB2 OQQ, UK. Cambridge University Hospitals NHS Trust, Hills Road, Cambridge, CB2 0QQ, UK. Biological Chemistry Laboratory, Babraham Institute, Cambridge, CB21 3AT, UK. Refractory Respiratory Inflammation Discovery Performance Unit, Respiratory Therapy Area, GlaxoSmithKline, Stevenage, SG1 2NY, UK. Computational Biology and Statistics, Target Sciences, GlaxoSmithKline, Stevenage, SG1 2NY, UK. Department of Immunology, Queen Elizabeth Hospital, Birmingham, B15 2TH, UK. Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TT, UK. Molecular Immunity Unit, MRC Laboratory of Molecular Biology, University of Cambridge Department of Medicine, MRC Laboratory of Molecular Biology, Cambridge, CB2 OQQ, UK. Department of Infection, Immunity and Cardiovascular Diseases, University of Sheffield, Sheffield, S10 2RX, UK. Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, CB21 3AT, UK. Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK.

Service type: Knock-in mice

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.

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