Abstract
Pseudomonas aeruginosa has evolved multiple strategies to disarm and take advantage of its host. For this purpose, this opportunist pathogen has particularly developed protein secretion in the surrounding medium or injection into host cells. Among this, the type VI secretion system (T6SS) is utilized to deliver effectors into eukaryotic host as well as target bacteria. It assembles into a contractile bacteriophage tail-like structure that functions like a crossbow, injecting an arrow loaded with effectors into the target cell. The repertoire of T6SS antibacterial effectors of P. aeruginosa is remarkably broad to promote environmental adaptation and survival in various bacterial communities, and presumably in the eukaryotic host too. Here, we report the discovery of a novel pair of antibacterial effector and immunity of P. aeruginosa, Tle3 and Tli3. Tli3 neutralizes the toxicity of Tle3 in the periplasm to protect from fratricide intoxication. The characterization of the secretion mechanism of Tle3 indicates that it requires a cytoplasmic adaptor, Tla3, to be targeted and loaded onto the VgrG2b spike and thus delivered by the H2-T6SS machinery. Tla3 is different from the other adaptors discovered so far and defines a novel family among T6SS with a DUF2875. Interestingly, this led us to discover that VgrG2b that we previously characterized as an anti-eukaryotic effector possesses an antibacterial activity as well, as it is toxic towards Escherichia coli. Excitingly Tli3 can counteract VgrG2b toxicity. VgrG2b is thus a novel trans-kingdom effector targeting both bacteria and eukaryotes. VgrG2b represents an interesting target for fighting against P. aeruginosa in the environment and in the context of host infection.
Highlights
Pseudomonas aeruginosa is one of the most virulent opportunistic pathogens, being responsible for various diseases such as acute infections of lungs and burned skin that can lead to septicemia more in immunocompromized patients, or broncho-alveolar colonization in cystic fibrosis sufferers
To demonstrate the antibacterial activity of Tle3 and to identify its immunity protein, we developed a heterologous toxicity assay in E. coli on the basis that Tle3 should be toxic when produced in the periplasm of E. coli and that it should be counteracted by the co-production of its immunity protein
Through heterologous toxicity assay and bacterial competition, we show that Tle3 was toxic once delivered in the periplasm of prey bacteria and that Tli3 can neutralize the toxin in this compartment
Summary
Pseudomonas aeruginosa is one of the most virulent opportunistic pathogens, being responsible for various diseases such as acute infections of lungs and burned skin that can lead to septicemia more in immunocompromized patients, or broncho-alveolar colonization in cystic fibrosis sufferers. P. aeruginosa has developed various pathogenicity strategies among which protein secretion or protein delivery into target cells is key. This pathogen possesses five of the six secretion systems so far identified among Gram-negative bacteria, if we exclude the T9SS (type IX secretion system) restricted to one phylum, and remarkably in several copies for most of them (Bleves et al, 2010). The type VI secretion system (T6SS) was first discovered in the context of eukaryotic host infection (Mougous et al, 2006; Pukatzki et al, 2006) and later during bacterial competition (Hood et al, 2010), which seems to be its primary function (Cianfanelli et al, 2016b). Toxins are usually directed against eukaryotic cells (like AB toxins or RTX pore-forming toxins) or against rival bacteria (like bacteriocins)
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