Claire Gendrin1, Nicholas J Shubin2, Erica Boldenow2, Sean Merillat2, Morgan Clauson2, Danial Power2, Kelly S Doran3, Magnus Abrink4, Gunnar Pejler5, Lakshmi Rajagopal6, Adrian M Piliponsky7. 1. Department of Pediatric Infectious Diseases, University of Washington, Seattle, Wash; Seattle Children's Research Institute, Seattle, Wash. 2. Seattle Children's Research Institute, Seattle, Wash. 3. Department of Biology and Center for Microbial Sciences, San Diego State University, San Diego, Calif; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, Calif. 4. Department of Biomedical Sciences and Veterinary Public Health, Swedish University for Agricultural Sciences, Uppsala, Sweden. 5. Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; Department of Anatomy, Physiology and Biochemistry, the Swedish University of Agricultural Sciences, Uppsala, Sweden. 6. Department of Pediatric Infectious Diseases, University of Washington, Seattle, Wash; Seattle Children's Research Institute, Seattle, Wash; Department of Global Health, University of Washington, Seattle, Wash. Electronic address: lakshmi.rajagopal@seattlechildrens.org. 7. Department of Pediatric Infectious Diseases, University of Washington, Seattle, Wash; Seattle Children's Research Institute, Seattle, Wash. Electronic address: adrian.piliponsky@seattlechildrens.org.
Abstract
BACKGROUND: Group B Streptococcus (GBS) or Streptococcus agalactiae are β-hemolytic gram-positive bacteria that colonize the lower genital tracts of women and are frequently associated with infections during pregnancy. Innate immune defenses are critical for controlling GBS dissemination and systemic infection. Mast cells are resident sentinel cells that come into contact with pathogens early during colonization and infection. OBJECTIVE: We aimed to investigate the contribution of chymase to systemic GBS infection and rates of preterm birth. METHODS: Pharmacologic and genetic approaches using mice deficient in mast cell protease (MCPT) 4, the mouse functional homologue of human chymase, were used. RESULTS: Our studies show that mast cells release a protease with chymotrypsin-like cleavage specificity in response to GBS. Additionally, increased GBS systemic infection and preterm births were observed in MCPT4-deficient mice versus MCPT4-sufficient mice. Furthermore, we observed that proteolytic cleavage of the host extracellular matrix protein fibronectin by peritoneal cell-derived mast cell lysates diminished GBS adherence. Consistent with this observation, the increase in GBS dissemination and preterm births observed in MCPT4-deficient mice was abolished when GBS was deficient in expression of the fibronectin-binding protein SfbA. CONCLUSIONS: Taken together, our results suggest that the protective effect of MCPT4 against GBS dissemination and preterm labor can be attributed in part to MCPT4-mediated proteolysis of fibronectin. Our studies reveal a novel role of mast cells in defense against bacterial infections.
BACKGROUND:Group B Streptococcus (GBS) or Streptococcus agalactiae are β-hemolytic gram-positive bacteria that colonize the lower genital tracts of women and are frequently associated with infections during pregnancy. Innate immune defenses are critical for controlling GBS dissemination and systemic infection. Mast cells are resident sentinel cells that come into contact with pathogens early during colonization and infection. OBJECTIVE: We aimed to investigate the contribution of chymase to systemic GBS infection and rates of preterm birth. METHODS: Pharmacologic and genetic approaches using mice deficient in mast cell protease (MCPT) 4, the mouse functional homologue of humanchymase, were used. RESULTS: Our studies show that mast cells release a protease with chymotrypsin-like cleavage specificity in response to GBS. Additionally, increased GBS systemic infection and preterm births were observed in MCPT4-deficientmice versus MCPT4-sufficient mice. Furthermore, we observed that proteolytic cleavage of the host extracellular matrix protein fibronectin by peritoneal cell-derived mast cell lysates diminished GBS adherence. Consistent with this observation, the increase in GBS dissemination and preterm births observed in MCPT4-deficientmice was abolished when GBS was deficient in expression of the fibronectin-binding protein SfbA. CONCLUSIONS: Taken together, our results suggest that the protective effect of MCPT4 against GBS dissemination and preterm labor can be attributed in part to MCPT4-mediated proteolysis of fibronectin. Our studies reveal a novel role of mast cells in defense against bacterial infections.
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