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

Takashi Imai, Takayuki Matsumura, Sabine Mayer-Lambertz, Christine A. Wells, Eri Ishikawa, Suzanne K. Butcher, Timothy C. Barnett, Mark J. Walker, Akihiro Imamura, Hideharu Ishida, Tadayoshi Ikebe, Tomofumi Miyamoto, Manabu Ato, Shouichi Ohga, Bernd Lepenies, Nina M. Van Sorge, Sho Yamasaki

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Abstract

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.

Original languageEnglish
Pages (from-to)E10662-E10671
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number45
DOIs
Publication statusPublished - Nov 6 2018

All Science Journal Classification (ASJC) codes

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    Imai, T., Matsumura, T., Mayer-Lambertz, S., Wells, C. A., Ishikawa, E., Butcher, S. K., Barnett, T. C., Walker, M. J., Imamura, A., Ishida, H., Ikebe, T., Miyamoto, T., Ato, M., Ohga, S., Lepenies, B., Van Sorge, N. M., & Yamasaki, S. (2018). Lipoteichoic acid anchor triggers Mincle to drive protective immunity against invasive group A Streptococcus infection. Proceedings of the National Academy of Sciences of the United States of America, 115(45), E10662-E10671. https://doi.org/10.1073/pnas.1809100115