Abstract
Group A Streptococcus (GAS) invades epithelial cells causing persistent infection. GAS has a variety of effector proteins that modulate host systems to affect their survival in host environments. The main effector proteins of GAS are NAD-glycohydrolase (Nga) and streptolysin O (SLO). Although Nga has NADase activity and shows SLO-dependent cytotoxicity, some clinical isolates harbor NADase-inactive subtypes of Nga, and the function of NADase-inactive Nga is still unclear. In this study, we found that deletion of nga enhanced the internalization of GAS into HeLa and Ca9-22 cells. Amino acid substitution of Nga R289K/G330D (NADase-inactive) does not enhance GAS invasion, suggesting that Nga may inhibit the internalization of GAS into host cells in an NADase-independent manner. Moreover, double deletion of slo and nga showed similar invasion percentages compared with wild-type GAS, indicating the important role of SLO in the inhibition of GAS invasion by Nga. Furthermore, enhanced internalization of the nga deletion mutant was not observed in Cav1-knockout HeLa cells. Altogether, these findings demonstrate an unrecognized NADase-independent function of Nga as a negative regulator of CAV1-mediated internalization into epithelial cells.
Highlights
Group A Streptococcus (GAS) or Streptococcus pyogenes is an important human pathogen that causes a variety of infections, resulting in a range of symptoms, from mild symptoms such as pharyngitis and impetigo, to severe diseases, such as necrotizing fasciitis and severe invasive streptococcal infection (Walker et al, 2014)
Our results showed that Nga, a protein secreted from GAS, inhibited Caveolin 1 (CAV1)-mediated internalization into epithelial cells
To the best of our knowledge, this is the first report demonstrating that increased invasion of the nga mutant occurred via CAV1-mediated internalization
Summary
Group A Streptococcus (GAS) or Streptococcus pyogenes is an important human pathogen that causes a variety of infections, resulting in a range of symptoms, from mild symptoms such as pharyngitis and impetigo, to severe diseases, such as necrotizing fasciitis and severe invasive streptococcal infection (Walker et al, 2014). GAS can invade and survive in epithelial cells. The intracellular survival of GAS contributes to persistence by escaping from host immune systems and antibiotics, such as penicillin, which shows poor penetration into cells, resulting in asymptomatic infections and invasive diseases (Neeman et al, 1998; Cunningham, 2000). GAS adheres to and invades epithelial cells via endocytotic pathways, via cytoskeletal rearrangement using fibronectin-integrin signaling (Molinari et al, 2000; Rohde and Cleary, 2016). Sfb1-expressing GAS has been shown to be internalized from caveolae-like membrane structures (Rohde et al, 2003). CAV1 was shown to restrict invasion of GAS into HEp2 cells in a caveolae-independent manner (Lim et al, 2017). The mechanisms through which CAV1 regulates invasion, remain unknown
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.