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

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Stark, Anne-Katrien  ORCID logo  https://orcid.org/0000-0001-6241-3909
Chandra, Anita 
Chakraborty, Krishnendu 
Alam, Rafeah 
Carbonaro, Valentina 

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.

Animals, Antigens, CD19, B-Lymphocytes, Class I Phosphatidylinositol 3-Kinases, Enzyme Activation, Female, Gene Knock-In Techniques, Genotype, Humans, Interleukin-10, Lung, Male, Mice, Mice, Inbred C57BL, Neutrophils, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Pneumococcal Infections, Signal Transduction, Species Specificity, Streptococcus pneumoniae
Journal Title
Nat Commun
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Springer Science and Business Media LLC
Wellcome Trust (103413/Z/13/Z)
Wellcome Trust (206618/Z/17/Z)
Medical Research Council (MR/M012328/1)
Wellcome Trust (095198/Z/10/Z)
Medical Research Council (MR/N024907/1)
Arthritis Research UK (21777)
Wellcome, MRC, BBSRC