Stringent response governs the oxidative stress resistance and virulence of Francisella tularensis

Autoři: Zhuo Ma aff001;  Kayla King aff001;  Maha Alqahtani aff002;  Madeline Worden aff001;  Parthasarathy Muthuraman aff001;  Christopher L. Cioffi aff001;  Chandra Shekhar Bakshi aff002;  Meenakshi Malik aff001
Působiště autorů: Department of Basic and Clinical Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York, United States of America aff001;  Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


Francisella tularensis is a Gram-negative bacterium responsible for causing tularemia in the northern hemisphere. F. tularensis has long been developed as a biological weapon due to its ability to cause severe illness upon inhalation of as few as ten organisms and, based on its potential to be used as a bioterror agent is now classified as a Tier 1 Category A select agent by the CDC. The stringent response facilitates bacterial survival under nutritionally challenging starvation conditions. The hallmark of stringent response is the accumulation of the effector molecules ppGpp and (p)ppGpp known as stress alarmones. The relA and spoT gene products generate alarmones in several Gram-negative bacterial pathogens. RelA is a ribosome-associated ppGpp synthetase that gets activated under amino acid starvation conditions whereas, SpoT is a bifunctional enzyme with both ppGpp synthetase and ppGpp hydrolase activities. Francisella encodes a monofunctional RelA and a bifunctional SpoT enzyme. Previous studies have demonstrated that stringent response under nutritional stresses increases expression of virulence-associated genes encoded on Francisella Pathogenicity Island. This study investigated how stringent response governs the oxidative stress response of F. tularensis. We demonstrate that RelA/SpoT-mediated ppGpp production alters global gene transcriptional profile of F. tularensis in the presence of oxidative stress. The lack of stringent response in relA/spoT gene deletion mutants of F. tularensis makes bacteria more susceptible to oxidants, attenuates survival in macrophages, and virulence in mice. This work is an important step forward towards understanding the complex regulatory network underlying the oxidative stress response of F. tularensis.

Klíčová slova:

Antioxidants – Gene expression – Gene regulation – Oxidative stress – Regulator genes – Transcriptional control – Francisella tularensis – Francisella


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