Pneumococcal sialidase promotes bacterial survival by fine-tuning of pneumolysin-mediated membrane disruption
Sayaka Shizukuishi,
Michinaga Ogawa,
Eisuke Kuroda,
Shigeto Hamaguchi,
Chisato Sakuma,
Soichiro Kakuta,
Isei Tanida,
Yasuo Uchiyama,
Yukihiro Akeda,
Akihide Ryo,
Makoto Ohnishi
Affiliations
Sayaka Shizukuishi
Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan; Department of Microbiology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
Michinaga Ogawa
Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan; Corresponding author
Eisuke Kuroda
Department of Transformative Infection Control Development Studies, Osaka University Graduate School of Medicine, Osaka, Japan; Division of Fostering Required Medical Human Resources, Center for Infectious Disease Education and Research (CiDER), Osaka University, Osaka, Japan
Shigeto Hamaguchi
Division of Fostering Required Medical Human Resources, Center for Infectious Disease Education and Research (CiDER), Osaka University, Osaka, Japan; Department of Transformative Analysis for Human Specimen, Osaka University Graduate School of Medicine, Osaka, Japan; Division of Infection Control and Prevention, Osaka University Hospital, Osaka, Japan
Chisato Sakuma
Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan
Soichiro Kakuta
Laboratory of Morphology and Image Analysis, Biomedical Research Core Facilities, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Cellular and Molecular Neuropathology, Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan
Isei Tanida
Department of Cellular and Molecular Neuropathology, Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan
Yasuo Uchiyama
Department of Cellular and Molecular Neuropathology, Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan
Yukihiro Akeda
Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan
Akihide Ryo
Department of Microbiology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan; Department of Virology III, National Institute of Infectious Diseases, Tokyo, Japan
Makoto Ohnishi
Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan
Summary: Pneumolysin (Ply) is an indispensable cholesterol-dependent cytolysin for pneumococcal infection. Although Ply-induced disruption of pneumococci-containing endosomal vesicles is a prerequisite for the evasion of endolysosomal bacterial clearance, its potent activity can be a double-edged sword, having a detrimental effect on bacterial survivability by inducing severe endosomal disruption, bactericidal autophagy, and scaffold epithelial cell death. Thus, Ply activity must be maintained at optimal levels. We develop a highly sensitive assay to monitor endosomal disruption using NanoBiT-Nanobody, which shows that the pneumococcal sialidase NanA can fine-tune Ply activity by trimming sialic acid from cell-membrane-bound glycans. In addition, oseltamivir, an influenza A virus sialidase inhibitor, promotes Ply-induced endosomal disruption and cytotoxicity by inhibiting NanA activity in vitro and greater tissue damage and bacterial clearance in vivo. Our findings provide a foundation for innovative therapeutic strategies for severe pneumococcal infections by exploiting the duality of Ply activity.
