Tseng, Yu-WenYu-WenTsengChang, Chun-ChiChun-ChiChangYUNG-CHI CHANG2023-12-192023-12-1920212235-2988https://scholars.lib.ntu.edu.tw/handle/123456789/637951Streptococcus pneumoniae is one of most deadly Gram-positive bacterium that causes significant mortality and morbidity worldwide. Intense inflammation and cytotoxicity is a hallmark of invasive pneumococcal disease. Pneumococcal NanA has been shown to exaggerate the production of inflammatory cytokines via unmasking of inhibitory Siglec-5 from its sialyl cis-ligands. To further investigate the mechanistic role of NanA and Siglec-5 in pneumococccal diseases, we systemically analyzed genes and signaling pathways differentially regulated in macrophages infected with wild type and NanA-deficient pneumococcus. We found that NanA-mediated desialylation impairs the Siglec-5-TLR-2 interaction and reduces the recruitment of phosphatase SHP-1 to Siglec-5. This dysregulated crosstalk between TLR-2 and inhibitory Siglec-5 exaggerated multiple inflammatory and death signaling pathways and consequently caused excessive inflammation and cytotoxicity in the infected macrophage. Collectively, our results reveal a novel virulence role of NanA in pneumococcal pathogenesis and suggest that targeting NanA activity may ameliorate the pneumococcus-mediated inflammation and cytotoxicity in severe invasive pneumococcal diseases.enNanA; Streptococcus pneumoniae; caspase; inflammasome; sialidase[SDGs]SDG3journal article10.3389/fcimb.2021.613195337778322-s2.0-85103012073https://api.elsevier.com/content/abstract/scopus_id/85103012073