Lipoteichoic acid anchor triggers Mincle to drive protective immunity against invasive group AStreptococcusinfection

Abstract

Group AStreptococcus(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.

Innate immunity in allergy

“…Both are organized in the gene cluster in the human and mouse genomes . Mincle, a member of the Dectin‐2 family, recognizes various glycolipids (Figure ), such as trehalose‐6,6′‐dimycolate (TDM) in the cell wall of Mycobacterium tuberculosis , glucosyl diacylglycerol (Glc‐DAG) of Streptococcus pneumoniae , monoglucosyldiacylglycerol (MGDG) produced by Group A Streptococcus , and others derived from self and nonself …”

Immunization With a Secreted Esterase Protects Mice Against Multiple Serotypes (M1, M3, and M28) of Group A Streptococcus

“…IFN-γ is responsible for a variety of immune functions, including the M1 polarization of macrophages (Lemire et al, 2017;Westman et al, 2018;Matsumura et al, 2019). Classically activated macrophages participate in key proinflammatory responses and enhance antigen presentation and pathogen clearance (Imai et al, 2018;Valderrama and Nizet, 2018;Hafner et al, 2019). IL-1β is a neutrophil recruitment factor produced by macrophages and DCs upon exposure to GAS (Valderrama et al, 2017;Flaherty et al, 2018;Liu et al, 2019).…”

C-Type Lectin Receptors in Host Defense Against Bacterial Pathogens

“…Mannose, α1-3 and α1-4 fucosylated glycans, GlcNAc (Suzuki et al, 1996;van Vliet et al, 2005) H. pylori (Bergman et al, 2004), Y. pseudotuberculosis (Zhang et al, 2006b), Y. pestis (Zhang et al, 2008), E. coli K12 (Zhang et al, 2006b), N. meningitidis (Steeghs et al, 2006), N. gonorrhoeae (Zhang et al, 2006a), Salmonella enterica serovar Typhimurium (Zhang et al, 2006b) Mincle (CLEC4E) Activated macrophages, some subpopulations of B cells (Matsumoto et al, 1999;Kawata et al, 2012) ITAM motif in associated FcRγ chain (Matsumoto et al, 1999;Yamasaki et al, 2008) Broad range of self and non-self glycolipids (Lu et al, 2018) K. pneumoniae (Sharma et al, 2014), H. pylori (Devi et al, 2015), S. pyogenes (Imai et al, 2018), S. pneumoniae (Imai et al, 2018) Dectin-2 (CLEC6A) Macrophages, DCs, LCs, monocytes (Ariizumi et al, 2000;Taylor et al, 2005) ITAM motif in associated FcRγ chain (Sato et al, 2006) α-mannans (Fernandes et al, 1999;Sato et al, 2006;Saijo et al, 2010) Hafnia alvei (Wittmann et al, 2016), E. coli O9a (Wittmann et al, 2016) DC, dendritic cell; LC, Langerhans cell, ITAM, intracellular tyrosine-based activation motif; GlcNAc, N-acetylglucosamine; GalNAc, N-acetylgalactosamine.…”

“…Mincle induces cellular activation through coupling with the Fc receptor common γ chain (FcRγ), which contains an intracellular ITAM signaling motif (Matsumoto et al, 1999 ; Yamasaki et al, 2008 ). Mincle interacts with glycolipid antigens from S. pyogenes , specifically the lipophilic components monoglucosyldiacylglycerol (MGDG) and diglycosyldiacylglycerol (DGDG) (Imai et al, 2018 ), which constitute membrane anchors for lipoteichoic acid (LTA) in the bacterial cell envelope. Intriguingly, MGDG activates DCs via Mincle, resulting in antigen-induced IL-17 production from CD4+ T cells, whereas DGDG prevents MGDG-induced cellular activation through the same receptor (Imai et al, 2018 ).…”