TY - JOUR
T1 - Lipoteichoic acid anchor triggers Mincle to drive protective immunity against invasive group A Streptococcus infection
AU - Imai, Takashi
AU - Matsumura, Takayuki
AU - Mayer-Lambertz, Sabine
AU - Wells, Christine A
AU - Ishikawa, Eri
AU - Butcher, Suzanne K
AU - Barnett, Timothy C
AU - Walker, Mark J
AU - Imamura, Akihiro
AU - Ishida, Hideharu
AU - Ikebe, Tadayoshi
AU - Miyamoto, Tomofumi
AU - Ato, Manabu
AU - Ohga, Shouichi
AU - Lepenies, Bernd
AU - van Sorge, Nina M
AU - Yamasaki, Sho
PY - 2018/11/6
Y1 - 2018/11/6
N2 - 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.
AB - 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.
KW - Animals
KW - CARD Signaling Adaptor Proteins/genetics
KW - HEK293 Cells
KW - Humans
KW - Lectins, C-Type/metabolism
KW - Lipopolysaccharides/metabolism
KW - Membrane Proteins/metabolism
KW - Mice
KW - Mice, Inbred C57BL
KW - Monocytes/metabolism
KW - Streptococcal Infections/immunology
KW - Streptococcus pyogenes/pathogenicity
KW - Teichoic Acids/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85056076405&partnerID=8YFLogxK
U2 - 10.1073/pnas.1809100115
DO - 10.1073/pnas.1809100115
M3 - Article
C2 - 30352847
SN - 0027-8424
VL - 115
SP - E10662-E10671
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -