Next Article in Journal
The Streptococcus pneumoniae yefM-yoeB and relBE Toxin-Antitoxin Operons Participate in Oxidative Stress and Biofilm Formation
Next Article in Special Issue
Aggregatibacter actinomycetemcomitans Leukotoxin Is Delivered to Host Cells in an LFA-1-Indepdendent Manner When Associated with Outer Membrane Vesicles
Previous Article in Journal
Dietary Deoxynivalenol (DON) May Impair the Epithelial Barrier and Modulate the Cytokine Signaling in the Intestine of Atlantic Salmon (Salmo salar)
Previous Article in Special Issue
Synergistic Effects of Influenza and Staphylococcus aureus Toxins on Inflammation Activation and Cytotoxicity in Human Monocytic Cell Lines
Article Menu
Issue 9 (September) cover image

Export Article

Open AccessArticle
Toxins 2018, 10(9), 377;

A Critical Role for HlgA in Staphylococcus aureus Pathogenesis Revealed by A Switch in the SaeRS Two-Component Regulatory System

Integrated Biotherapeutics Inc., Rockville, MD 20850, USA
Department of Microbiology and Immunology, Indiana University School of Medicine-Northwest, Gary, IN 46408, USA
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Received: 19 August 2018 / Revised: 11 September 2018 / Accepted: 11 September 2018 / Published: 18 September 2018
(This article belongs to the Special Issue Leukotoxins)
Full-Text   |   PDF [3018 KB, uploaded 18 September 2018]   |  


Cytolytic pore-forming toxins including alpha hemolysin (Hla) and bicomponent leukotoxins play an important role in the pathogenesis of Staphylococcus aureus. These toxins kill the polymorphonuclear phagocytes (PMNs), disrupt epithelial and endothelial barriers, and lyse erythrocytes to provide iron for bacterial growth. The expression of these toxins is regulated by the two-component sensing systems Sae and Agr. Here, we report that a point mutation (L18P) in SaeS, the histidine kinase sensor of the Sae system, renders the S. aureus Newman hemolytic activity fully independent of Hla and drastically increases the PMN lytic activity. Furthermore, this Hla-independent activity, unlike Hla itself, can lyse human erythrocytes. The Hla-independent activity towards human erythrocytes was also evident in USA300, however, under strict agr control. Gene knockout studies revealed that this Hla-independent Sae-regulated activity was entirely dependent on gamma hemolysin A subunit (HlgA). In contrast, hemolytic activity of Newman towards human erythrocytes from HlgAB resistant donors was completely dependent on agr. The culture supernatant from Newman S. aureus could be neutralized by antisera against two vaccine candidates based on LukS and LukF subunits of Panton-Valentine leukocidin but not by an anti-Hla neutralizing antibody. These findings display the complex involvement of Sae and Agr systems in regulating the virulence of S. aureus and have important implications for vaccine and immunotherapeutics development for S. aureus disease in humans. View Full-Text
Keywords: S. aureus; hlgA; hla; leukotoxins; Newman; SaeS; agr S. aureus; hlgA; hla; leukotoxins; Newman; SaeS; agr

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Share & Cite This Article

MDPI and ACS Style

Venkatasubramaniam, A.; Kanipakala, T.; Ganjbaksh, N.; Mehr, R.; Mukherjee, I.; Krishnan, S.; Bae, T.; Aman, M.J.; Adhikari, R.P. A Critical Role for HlgA in Staphylococcus aureus Pathogenesis Revealed by A Switch in the SaeRS Two-Component Regulatory System. Toxins 2018, 10, 377.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Toxins EISSN 2072-6651 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top