Pentraxin3(PTX3),一个长五聚素和一个体液模式识别分子(PRM),已经证明对烟曲霉有保护作用,空气传播的人类真菌病原体。我们探索了它与烟曲霉的相互作用模式,以及由此产生的宿主免疫反应的影响。这里,我们证明了PTX3与烟曲霉以形态类型依赖性方式相互作用:(a)它通过氨基半乳糖半乳聚糖识别发芽的分生孢子,烟曲霉表面暴露的细胞壁多糖,(b)在休眠分生孢子中,表面蛋白作为弱PTX3配体,和(c)表面活性剂蛋白D(SP-D)和补体蛋白C1q和C3b,其他体液PRM,增强PTX3与休眠分生孢子的相互作用。SP-D,C3b或C1q调理的分生孢子刺激人初级免疫细胞释放促炎细胞因子和趋化因子。然而,随后PTX3与SP-D结合,C1q或C3b调理的分生孢子显着降低了促炎细胞因子/趋化因子的产生。与未调理的对应物相比,PTX3调理的发芽分生孢子还显着降低了促炎细胞因子/趋化因子的产生,同时增加了免疫细胞释放的IL-10(抗炎细胞因子)。总的来说,我们的研究表明,PTX3直接或通过与其他体液PRM相互作用识别烟曲霉,从而抑制有害的炎症。此外,侵袭性肺曲霉病(IPA)和COVID-19相关肺曲霉病(CAPA)患者血清中PTX3水平明显升高,支持以前在IPA患者中的观察,并表明它可能是由烟曲霉引起的这些病理状况的潜在小组生物标志物。
Pentraxin 3 (PTX3), a long pentraxin and a humoral pattern recognition molecule (PRM), has been demonstrated to be protective against Aspergillus fumigatus, an airborne human fungal pathogen. We explored its mode of interaction with A. fumigatus, and the resulting implications in the host immune response. Here, we demonstrate that PTX3 interacts with A. fumigatus in a morphotype-dependent manner: (a) it recognizes germinating conidia through galactosaminogalactan, a surface exposed cell wall polysaccharide of A. fumigatus, (b) in dormant conidia, surface proteins serve as weak PTX3 ligands, and (c) surfactant protein D (SP-D) and the complement proteins C1q and C3b, the other humoral PRMs, enhance the interaction of PTX3 with dormant conidia. SP-D, C3b or C1q opsonized conidia stimulated human primary immune cells to release pro-inflammatory cytokines and chemokines. However, subsequent binding of PTX3 to SP-D, C1q or C3b opsonized conidia significantly decreased the production of pro-inflammatory cytokines/chemokines. PTX3 opsonized germinating conidia also significantly lowered the production of pro-inflammatory cytokines/chemokines while increasing IL-10 (an anti-inflammatory cytokine) released by immune cells when compared to the unopsonized counterpart. Overall, our study demonstrates that PTX3 recognizes A. fumigatus either directly or by interplaying with other humoral PRMs, thereby restraining detrimental inflammation. Moreover, PTX3 levels were significantly higher in the serum of patients with invasive pulmonary aspergillosis (IPA) and COVID-19-associated pulmonary aspergillosis (CAPA), supporting previous observations in IPA patients, and suggesting that it could be a potential panel-biomarker for these pathological conditions caused by A. fumigatus.