Abstract
RHS elements are components of conserved toxin-delivery systems, wide-spread within the bacterial kingdom and some of the most positively selected genes known. However, very little is known about how Rhs toxins affect bacterial biology. Salmonella Typhimurium contains a full-length rhs gene and an adjacent orphan rhs gene, which lacks the conserved delivery part of the Rhs protein. Here we show that, in addition to the conventional delivery, Rhs toxin-antitoxin pairs encode for functional type-II toxin-antitoxin (TA) loci that regulate S. Typhimurium proliferation within macrophages. Mutant S. Typhimurium cells lacking both Rhs toxins proliferate 2-times better within macrophages, mainly because of an increased growth rate. Thus, in addition to providing strong positive selection for the rhs loci under conditions when there is little or no toxin delivery, internal expression of the toxin-antitoxin system regulates growth in the stressful environment found inside macrophages.
Highlights
How bacteria regulate their growth during infection is of fundamental interest for bacterial physiology and for development of new improved treatment regimens for bacterial infections
We show that RHS elements, previously known to function as mobilizable toxins that inhibit growth of neighboring bacteria, function as internally expressed toxin-antitoxin systems that regulate Salmonella Typhimurium growth in macrophages
Our results suggest an explanation to why rhs genes are under such strong positive selection in addition to suggesting a novel function for these toxins in regulating bacterial growth
Summary
How bacteria regulate their growth during infection is of fundamental interest for bacterial physiology and for development of new improved treatment regimens for bacterial infections. Previous studies show that toxin-antitoxin (TA) modules are important for regulating the growth of bacteria within phagocytic vacuoles in immune cells [1, 2]. TA-systems are divided into six classes (I-VI) depending on the nature of the toxin and antitoxin (protein or RNA) and the way the antitoxin mediates protection (binding, degradation or regulation of expression) (reviewed in [3]). The toxin and antitoxin of type II TA-systems are both proteins and the antitoxin protect against toxicity of the cognate toxin by binding and blocking its activity. The antitoxins of type II TA-systems are actively targeted by cellular proteases and less stable, i.e. have a shorter protein half-live than their cognate toxins [4, 5]. Type II TA-systems were later found to be abundant in bacterial genomes and have since been linked to bacterial virulence in many bacteria, including Escherichia coli [11], Mycobacterium tuberculosis [12], Staphylococcus aureus [13] and Salmonella enterica [14]
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