Lipoteichoic acid anchor triggers Mincle to drive protective immunity against invasive group A Streptococcus infection

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-11, Vol.115 (45), p.E10662-E10671
• Main Authors: Imai, Takashi, Matsumura, Takayuki, Mayer-Lambertz, Sabine, Wells, Christine A., Ishikawa, Eri, Butcher, Suzanne K., Barnett, Timothy C., Walker, Mark J., Imamura, Akihiro, Ishida, Hideharu, Ikebe, Tadayoshi, Miyamoto, Tomofumi, Ato, Manabu, Ohga, Shouichi, Lepenies, Bernd, van Sorge, Nina M., Yamasaki, Sho
• Format: Article
• Language: English
• Subjects: Anchors; Animals; Antiinfectives and antibacterials; Bacteremia; Bacteria; Bacterial infections; Biological Sciences; CARD Signaling Adaptor Proteins - genetics; Caspase; Cytokines; Gene expression; HEK293 Cells; Humans; Immune system; Immunity; Immunity (Disease); Inflammation; Innate immunity; Lectins, C-Type - metabolism; Lethality; Lipopolysaccharides - metabolism; Lipoteichoic acid; Macrophages; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Monocytes - metabolism; Myeloid cells; Nitric oxide; Nitric-oxide synthase; PNAS Plus; Proteins; Reactive oxygen species; Receptors; Streptococcal Infections - immunology; Streptococcal Infections - microbiology; Streptococcus; Streptococcus infections; Streptococcus pyogenes - pathogenicity; Teichoic Acids - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1809100115

Group A Streptococcus (GAS) is a Gram-positive bacterial pathogen that causes a range of diseases, including fatal invasive infections. However, the mechanisms by which the innate immune system recognizes GAS are not well understood. We herein report that the C-type lectin receptor macrophage inducible C-type lectin (Mincle) recognizes GAS and initiates antibacterial immunity. Gene expression analysis of myeloid cells upon GAS stimulation revealed the contribution of the caspase recruitment domain-containing protein 9 (CARD9) pathway to the antibacterial responses. Among receptors signaling through CARD9, Mincle induced the production of inflammatory cytokines, inducible nitric oxide synthase, and reactive oxygen species upon recognition of the anchor of lipoteichoic acid, monoglucosyldiacylglycerol (MGDG), produced by GAS. Upon GAS infection, Mincle-deficient mice exhibited impaired production of proinflammatory cytokines, severe bacteremia, and rapid lethality. GAS also possesses another Mincle ligand, diglucosyldiacylglycerol; however, this glycolipid interfered with MGDG-induced activation. These results indicate that Mincle plays a central role in protective immunity against acute GAS infection.