Type I toxin-antitoxin systems and persister cell formation

Project 1: ‘Bacterial persistence during infection: What is the role of type I Toxin-antitoxin systems?’

The rampant emergence of widespread antibiotic resistance in bacteria is a well-known and urgent problem. A related phenomenon of high impact, is bacterial persistence. Persisters arise as a subpopulation of cells that are tolerant to antibiotic treatment, despite of being genetically identical to the majority of the population1 (Figure 1). They undergo a phenotypic switch displaying different characteristics; they enter a dormant or very slow-growing state, with reduced metabolic activities1,2. Though persisters are not resistant to antibiotic treatment, they demonstrate tolerance since most antibiotics kill growing cells. Thus, infections may become difficult to combat, since internalisation of bacteria in the host cells triggers this phenotypic change1,2. Bacterial persisters are genetically identical to the rest of the population, giving rise to both susceptible and tolerant cells1. Consequently, they recreate a bacterial population that could cause relapsing infections. This vicious cycle may potentially last for long periods of time2, leading to overuse of antibiotics and therefore to antibiotic resistance2.

In recent years, toxin-antitoxin (TA) systems have emerged as key factors that affect persister phenotypes. There are six distinct types of these gene pairs, distinguished based on the neutralisation mechanism of the toxin, and the molecular nature of the antitoxin3. The two main types of TA systems, type I and type II, have both been proposed to be involved in persistence3. In type I TA systems, which this project concerns, the antitoxin is an antisense small RNA that base-pairs to the toxin mRNA, thus repressing its translation and ultimately inhibiting toxicity3 (Figure 2). Given the role of TA systems in bacterial persistence, it is of great importance to reveal the regulatory mechanisms of this phenomenon, in order to design new therapeutic approaches.

The PhD project will focus on the effects of several type I TA systems in persister formation of Salmonella typhimurium. Different aspects will be investigated, such as; persister formation during host cell infections, which stressors lead to this phenotypic alteration, and which mechanisms control type I toxin expression.