Streptococcus suis serotype 2 is an important porcine bacterial pathogen and emerging zoonotic agent. Infections induce an exacerbated inflammation that can result in sudden death (septic shock) and meningitis. Though neutrophilic leukocytosis characterizes S. suis infection, the mediators involved are poorly understood. Among them, granulocyte-colony stimulating factor (G-CSF), a pro-inflammatory cytokine, triggers proliferation of neutrophil progenitors and neutrophil mobilization. However, the systemic production of G-CSF induced during S. suis infection, the cell types involved, and the underlying mechanisms remain unknown. In a S. suis serotype 2 mouse model of systemic infection, plasma levels of G-CSF rapidly increased after infection. S. suis activation of DCs and macrophages resulted in high (> 1000 pg/mL) and comparable production levels of G-CSF, as measured by ELISA. By using mutant strains deficient in capsular polysaccharide (CPS) or lipoprotein maturation in combination with purified lipoteichoic acid (LTA) from the latter mutant strain, it was showed that G-CSF production is mainly mediated by S. suis lipoproteins. The Toll-like receptor (TLR) pathway via myeloid differentiation primary response 88 (MyD88) is required for G-CSF production by DCs and macrophages following S. suis activation, with a partial involvement of TLR2. On the other hand, TLR2-independant G-CSF production induced by S. suis requires internalization and bacterial DNA might play a role in this pathway. Finally, these signals activated nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways leading to G-CSF production. In conclusion, this study demonstrated for the first time that S. suis induces G-CSF production in vivo and DCs and macrophages are key cellular sources of this cytokine mediator, mainly via the binding of lipoproteins to TLR2. The CPS significantly reduced this activation, confirming the powerful role of this component in S. suis virulence. As such, this study contributes to better understand how DCs and macrophages produce G-CSF in response to S. suis, and potentially to other streptococci.

猪链球菌血清型 2 是一种重要的猪细菌病原体和新出现的人畜共患病原体。感染会导致炎症加剧，从而导致猝死（感染性休克）和脑膜炎。尽管嗜中性白细胞增多症是猪链球菌感染的特征，但对所涉及的介质知之甚少。其中，粒细胞集落刺激因子 (G-CSF) 是一种促炎细胞因子，可触发中性粒细胞祖细胞的增殖和中性粒细胞的动员。然而，在猪链球菌感染期间诱导的 G-CSF 全身产生、涉及的细胞类型和潜在机制仍然未知。在系统性感染的猪链球菌血清型 2 小鼠模型中，感染后 G-CSF 的血浆水平迅速增加。DCs 和巨噬细胞的猪链球菌激活导致 G-CSF 的高 (> 1000 pg/mL) 和可比较的生产水平，如通过 ELISA 测量的。通过将缺乏荚膜多糖 (CPS) 或脂蛋白成熟的突变菌株与来自后一种突变菌株的纯化脂磷壁酸 (LTA) 结合使用，表明 G-CSF 的产生主要由猪链球菌脂蛋白介导。猪链球菌激活后DC 和巨噬细胞产生 G-CSF 需要通过骨髓分化初级反应 88 (MyD88) 的 Toll 样受体 (TLR) 途径，部分参与 TLR2。另一方面，猪链球菌诱导的不依赖 TLR2 的 G-CSF 产生需要内化，细菌 DNA 可能在这一途径中发挥作用。最后，这些信号激活了核因子-κB (NF-κB) 和丝裂原活化蛋白激酶 (MAPK) 通路，导致 G-CSF 的产生。总之，这项研究首次证明猪链球菌在体内诱导 G-CSF 产生，DC 和巨噬细胞是这种细胞因子介质的关键细胞来源，主要是通过脂蛋白与 TLR2 的结合。CPS 显着降低了这种激活，证实了该成分在猪链球菌毒力中的强大作用。因此，这项研究有助于更好地了解 DC 和巨噬细胞如何产生 G-CSF 以响应猪链球菌和其他链球菌。