Abstract
Bacterial type I toxin–antitoxin (TA) systems are widespread, and consist of a stable toxic peptide whose expression is monitored by a labile RNA antitoxin. We characterized Staphylococcus aureus SprA2/SprA2AS module, which shares nucleotide similarities with the SprA1/SprA1AS TA system. We demonstrated that SprA2/SprA2AS encodes a functional type I TA system, with the cis-encoded SprA2AS antitoxin acting in trans to prevent ribosomal loading onto SprA2 RNA. We proved that both TA systems are distinct, with no cross-regulation between the antitoxins in vitro or in vivo. SprA2 expresses PepA2, a toxic peptide which internally triggers bacterial death. Conversely, although PepA2 does not affect bacteria when it is present in the extracellular medium, it is highly toxic to other host cells such as polymorphonuclear neutrophils and erythrocytes. Finally, we showed that SprA2AS expression is lowered during osmotic shock and stringent response, which indicates that the system responds to specific triggers. Therefore, the SprA2/SprA2AS module is not redundant with SprA1/SprA1AS, and its PepA2 peptide exhibits an original dual mode of action against bacteria and host cells. This suggests an altruistic behavior for S. aureus in which clones producing PepA2 in vivo shall die as they induce cytotoxicity, thereby promoting the success of the community.
Highlights
Staphylococcus aureus is a serious human bacterial pathogen that causes life-threatening nosocomial and community-acquired infections [1]
We did RACE mapping to determine the 5 and 3 boundaries, confirming that both genes overlap in their 3 regions
We used IntaRNA software [27] for in silico exploration of the two RNA sequences. This showed that, as for the sprA1/sprA1AS pair, these two RNAs could interact in trans with their 5 regions through partial pairings (Figure 1C), with SprA2AS binding SprA2 both at a putative ribosomal binding site and at its adjacent start codon, suggesting that it could act as a type I TA system
Summary
Staphylococcus aureus is a serious human bacterial pathogen that causes life-threatening nosocomial and community-acquired infections [1]. Gene expression and the adjustment of bacterial physiology to external signals are both usually dependent on regulators such as regulatory RNAs (sRNAs, called non-coding RNAs) or transcription factors [2,3]. In S. aureus, sRNAs range in size from 50 to 500 nucleotides (nt), are usually non-coding, and control the expression of RNA targets that are involved in a wide range of biological processes which include virulence, antibiotic resistance, and central metabolism regulation [4,5,6]. Most S. aureus sRNAs act by base-pairing with an RNA target to modulate translation initiation and/or RNA stability. They normally fall into two categories: cis- or trans-encoded sRNAs [4]. Among the cis-encoded sRNAs, some studies evidenced the presence of small sense–antisense clusters, some of which can belong to toxin–antitoxin (TA) modules [7,8,9,10,11,12,13]
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