Platelet p110β mediates platelet-leukocyte interaction and curtails bacterial dissemination in pneumococcal pneumonia

Phosphatidylinositol 3-kinase catalytic subunit p110β is involved in tumorigenesis and hemostasis. However, it remains unclear if p110β also regulates platelet-mediated immune responses, which could have important consequences for immune modulation during anti-cancer treatment with p110β inhibitors. Thus, we investigate how platelet p110β affects inflammation and infection. Using a mouse model of Streptococcus pneumoniae-induced pneumonia, we find that both platelet-specific p110β deficiency and pharmacologic inhibition of p110β with TGX-221 exacerbate disease pathogenesis by preventing platelet-monocyte and neutrophil interactions, diminishing their infiltration and enhancing bacterial dissemination. Platelet p110β mediates neutrophil phagocytosis of S. pneumoniae in vitro and curtails bacteremia in vivo. Genetic deficiency or inhibition of platelet p110β also impairs macrophage recruitment in an independent model of sterile peritonitis. Our results demonstrate that platelet p110β dysfunction exacerbates pulmonary infection by impeding leukocyte functions. Thereby, our findings provide important insights into the immunomodulatory potential of PI3K inhibitors in bacterial infection. [Display omitted] •Platelet-leukocyte interplay is pivotal for host response in pneumococcal infection•Platelet PI3K isoform p110β fosters leukocyte recruitment and effector function•Targeting platelet p110β aggravates bacterial dissemination and disease severity•Clinically trialed p110β inhibitors may impair platelet-mediated immune response Platelets are increasingly recognized as essential mediators of host defense in infectious diseases. Schrottmaier et al. identify platelet PI3K catalytic isoform p110β to foster platelet interaction with neutrophils and monocytes in streptococcal infection, promoting their recruitment and effector functions to prevent bacterial dissemination and prolong survival.