Novel Virulence Role of Pneumococcal NanA in Host Inflammation and Cell Death Through the Activation of Inflammasome and the Caspase Pathway

Author:

Tseng Yu-Wen,Chang Chun-Chi,Chang Yung-Chi

Abstract

Streptococcus pneumoniaeis 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 sialylcis-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.

Funder

Ministry of Science and Technology, Taiwan

National Taiwan University

Publisher

Frontiers Media SA

Subject

Infectious Diseases,Microbiology (medical),Immunology,Microbiology

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