Sequential Sensing by TLR2 and Mincle Directs Immature Myeloid Cells to Protect against Invasive Group A Streptococcal Infection in Mice

摘要

Severe invasive group A Streptococcus (GAS)infection evades anti-bacterial immunity by attenuatingthe cellular components of innate immuneresponses. However, this loss of protection iscompensated for by interferon (IFN)-g-producingimmature myeloid cells (gIMCs), which are selectivelyrecruited upon severe invasive GAS infection in mice.Here, we demonstrate that gIMCs provide this IFN-gmediatedprotection by sequentially sensing GASthrough two distinct pattern recognition receptors.In a mouse model, GAS is initially recognized byToll-like receptor 2 (TLR2), which promptly inducesinterleukin (IL)-6 production in gIMCs. gIMC-derivedIL-6 promotes the upregulation of a recently identifiedGAS-sensing receptor, macrophage-inducible C-typelectin (Mincle), in an autocrine or paracrine manner.Notably, blockade of gIMC-derived IL-6 abrogatesMincle expression, downstream IFN-g production,and gIMC-mediated protection against severe invasiveGAS infection. Thus, gIMCs regulate host protectiveimmunity against severe invasive GAS infectionvia a TLR2–IL-6–Mincle axis.