Research ArticleHost-Pathogen Interactions

The adhesion GPCR BAI1 mediates macrophage ROS production and microbicidal activity against Gram-negative bacteria

Sci. Signal.  02 Feb 2016:
Vol. 9, Issue 413, pp. ra14
DOI: 10.1126/scisignal.aac6250

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Bacteria come to a sticky end

Pattern recognition receptors (PRRs) detect microbial products and stimulate the innate immune response to infections. BAI1 is a G protein–coupled receptor of the adhesion GPCR family and is also a PRR that binds to lipopolysaccharide on the surface of Gram-negative bacteria to facilitate their internalization by macrophages. Billings et al. found that BAI1 triggered the killing of the internalized bacteria by stimulating the production of reactive oxygen species. When engaged by bacteria, BAI1 activated Rac1 to stimulate the activity of the NADPH oxidase complex Nox2 in macrophages. Mice deficient in BAI1 were inefficient at clearing Gram-negative bacteria and were likely to die from the infection. Together, these data suggest that BAI1 connects bacterial internalization with their killing.

Abstract

The detection of microbes and initiation of an innate immune response occur through pattern recognition receptors (PRRs), which are critical for the production of inflammatory cytokines and activation of the cellular microbicidal machinery. In particular, the production of reactive oxygen species (ROS) by the NADPH oxidase complex is a critical component of the macrophage bactericidal machinery. We previously characterized brain-specific angiogenesis inhibitor 1 (BAI1), a member of the adhesion family of G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs), as a PRR that mediates the selective phagocytic uptake of Gram-negative bacteria by macrophages. We showed that BAI1 promoted phagosomal ROS production through activation of the Rho family guanosine triphosphatase (GTPase) Rac1, thereby stimulating NADPH oxidase activity. Primary BAI1-deficient macrophages exhibited attenuated Rac GTPase activity and reduced ROS production in response to several Gram-negative bacteria, resulting in impaired microbicidal activity. Furthermore, in a peritoneal infection model, BAI1-deficient mice exhibited increased susceptibility to death by bacterial challenge because of impaired bacterial clearance. Together, these findings suggest that BAI1 mediates the clearance of Gram-negative bacteria by stimulating both phagocytosis and NADPH oxidase activation, thereby coupling bacterial detection to the cellular microbicidal machinery.

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