PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner.
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Authors
Chandra, Anita
Chakraborty, Krishnendu
Alam, Rafeah
Carbonaro, Valentina
Clark, Jonathan
Sriskantharajah, Srividya
Bradley, Glyn
Richter, Alex G
Banham-Hall, Edward
Clatworthy, Menna R
Nejentsev, Sergey
Hamblin, J Nicole
Hessel, Edith M
Condliffe, Alison M
Publication Date
2018-08-09Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Volume
9
Issue
1
Pages
3174
Language
eng
Type
Article
Physical Medium
Electronic
Metadata
Show full item recordCitation
Stark, A., Chandra, A., Chakraborty, K., Alam, R., Carbonaro, V., Clark, J., Sriskantharajah, S., et al. (2018). PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner.. Nat Commun, 9 (1), 3174. https://doi.org/10.1038/s41467-018-05674-8
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.
Keywords
Lung, B-Lymphocytes, Neutrophils, Animals, Mice, Inbred C57BL, Humans, Mice, Streptococcus pneumoniae, Pneumococcal Infections, Antigens, CD19, Interleukin-10, Signal Transduction, Species Specificity, Enzyme Activation, Genotype, Female, Male, Gene Knock-In Techniques, Phosphatidylinositol 3-Kinases, Class I Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors
Sponsorship
Wellcome, MRC, BBSRC
Funder references
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)
Identifiers
External DOI: https://doi.org/10.1038/s41467-018-05674-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/283518
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