Increasing evidences demonstrate that microorganism and their products protect against bacterial and viral pathogens through various mechanisms including immunomodulation. Streptococcus pneumoniae endopeptidase O (PepO), a pneumococcal virulence protein, has been proven to enhance the phagocytosis of Staphylococcus aureus and Streptococcus pneumoniae by macrophages in our previous study, where we detected the down regulation of SH2 domain-containing inositol phosphatase 1 (SHIP1) and the up regulation of complement receptor 3 (CR3) in PepO-stimulated macrophages. In the present study, using SHIP1 over-expression plasmid and CR3 siRNA, we proved that the down regulation of SHIP1 and the up regulation of CR3 mediate the enhanced phagocytosis of S. aureus and S. pneumoniae by PepO-stimulated macrophages. The down regulation of SHIP1 also mediates the up regulation of CR3. To further determine whether PepO protects against respiratory pathogens, we constructed a mouse model with intranasal infection of S. aureus or S. pneumoniae and found that PepO significantly promoted their clearance. The down regulation of SHIP1 and the up regulation of CR3 also play a role in this process. This study provides a new preventive and therapeutic option for respiratory infectious diseases and lays the theoretical basis for the development of PepO as an immunomodulation agent.

越来越多的证据表明，微生物及其产物可通过多种机制（包括免疫调节）保护免受细菌和病毒病原体侵害。 肺炎链球菌 内肽酶O（PepO）是一种肺炎球菌毒力蛋白，已被证明可增强吞噬作用。 金黄色葡萄球菌 和 肺炎链球菌在之前的研究中，我们通过巨噬细胞检测到了PepO刺激的巨噬细胞中含有SH2域的肌醇磷酸酶1（SHIP1）的下调和补体受体3（CR3）的上调。在本研究中，使用SHIP1过表达质粒和CR3 siRNA，我们证明SHIP1的下调和CR3的上调介导了吞噬作用的增强。金黄色葡萄球菌 和 肺炎链球菌由PepO刺激的巨噬细胞。SHIP1的下调也介导CR3的上调。为了进一步确定PepO是否能预防呼吸道病原体，我们构建了鼻内感染的小鼠模型。金黄色葡萄球菌 要么 肺炎链球菌并发现PepO大大促进了它们的清除。SHIP1的下调和CR3的上调在此过程中也起作用。这项研究为呼吸道传染病提供了一种新的预防和治疗选择，并为开发PepO作为免疫调节剂奠定了理论基础。