TY - JOUR
T1 - Potential involvement of Streptococcus mutans possessing collagen binding protein Cnm in infective endocarditis
AU - Nomura, Ryota
AU - Otsugu, Masatoshi
AU - Hamada, Masakazu
AU - Matayoshi, Saaya
AU - Teramoto, Noboru
AU - Iwashita, Naoki
AU - Naka, Shuhei
AU - Matsumoto-Nakano, Michiyo
AU - Nakano, Kazuhiko
N1 - Funding Information:
The authors thank Prof. Howard K. Kuramitsu (State University of New York at Buffalo) for editing the manuscript. We also thank Ms. Rewa Yanagisawa, Department of Pediatric Dentistry, Osaka University Graduate School of Dentistry, for technical support with the molecular analyses. This work was supported by JSPS KAK-ENHI (Grant nos. 15K11363, 18H03010, 18K09831, and 18K17254).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Streptococcus mutans, a significant contributor to dental caries, is occasionally isolated from the blood of patients with infective endocarditis. We previously showed that S. mutans strains expressing collagen-binding protein (Cnm) are present in the oral cavity of approximately 10–20% of humans and that they can effectively invade human umbilical vein endothelial cells (HUVECs). Here, we investigated the potential molecular mechanisms of HUVEC invasion by Cnm-positive S. mutans. The ability of Cnm-positive S. mutans to invade HUVECs was significantly increased by the presence of serum, purified type IV collagen, and fibrinogen (p < 0.001). Microarray analyses of HUVECs infected by Cnm-positive or -negative S. mutans strains identified several transcripts that were differentially upregulated during invasion, including those encoding the small G protein regulatory proteins ARHGEF38 and ARHGAP9. Upregulation of these proteins occurred during invasion only in the presence of serum. Knockdown of ARHGEF38 strongly reduced HUVEC invasion by Cnm-positive S. mutans. In a rat model of infective endocarditis, cardiac endothelial cell damage was more prominent following infection with a Cnm-positive strain compared with a Cnm-negative strain. These results suggest that the type IV collagen–Cnm–ARHGEF38 pathway may play a crucial role in the pathogenesis of infective endocarditis.
AB - Streptococcus mutans, a significant contributor to dental caries, is occasionally isolated from the blood of patients with infective endocarditis. We previously showed that S. mutans strains expressing collagen-binding protein (Cnm) are present in the oral cavity of approximately 10–20% of humans and that they can effectively invade human umbilical vein endothelial cells (HUVECs). Here, we investigated the potential molecular mechanisms of HUVEC invasion by Cnm-positive S. mutans. The ability of Cnm-positive S. mutans to invade HUVECs was significantly increased by the presence of serum, purified type IV collagen, and fibrinogen (p < 0.001). Microarray analyses of HUVECs infected by Cnm-positive or -negative S. mutans strains identified several transcripts that were differentially upregulated during invasion, including those encoding the small G protein regulatory proteins ARHGEF38 and ARHGAP9. Upregulation of these proteins occurred during invasion only in the presence of serum. Knockdown of ARHGEF38 strongly reduced HUVEC invasion by Cnm-positive S. mutans. In a rat model of infective endocarditis, cardiac endothelial cell damage was more prominent following infection with a Cnm-positive strain compared with a Cnm-negative strain. These results suggest that the type IV collagen–Cnm–ARHGEF38 pathway may play a crucial role in the pathogenesis of infective endocarditis.
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U2 - 10.1038/s41598-020-75933-6
DO - 10.1038/s41598-020-75933-6
M3 - Article
C2 - 33154489
AN - SCOPUS:85095133085
SN - 2045-2322
VL - 10
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 19118
ER -