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Quorum sensing differentially regulates Pseudomonas aeruginosa type VI secretion locus I and homologous loci II and III, which are required for pathogenesis

B. Lesic^1,2,3,,

M. Starkey^1,2,3,

¹ Department of Surgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
² Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA, USA
³ Shriners Burns Institute, Boston, MA, USA

Pseudomonas aeruginosa harbours three type VI secretion (T6S) loci. Although HSI-I has been partially studied, limited knowledge is available on the homologous loci HSI-II and HSI-III. We show that quorum sensing (QS) differentially regulates the expression of genes at all three loci. HSI-I-associated gene expression is suppressed by both the homoserine lactone transcription factor LasR and the 4-hydroxy-2-alkylquinoline (HAQ) transcriptional regulator MvfR. Conversely, both HSI-II and HSI-III loci are positively controlled by LasR and MvfR. PqsE, a key component of the MvfR regulon, is required for the expression of part of HSI-III but not HSI-II, and previously identified inhibitors of HAQ biosynthesis significantly downregulate HSI-II and -III gene expression. Animal and plant infection studies reveal that both HSI-II and -III play important roles in pathogenesis. Furthermore, analysis of a double HSI-II : : III mutant suggests that these loci functionally compensate for one another in virulence. This study illustrates the contribution of the QS systems to T6S gene regulation and reveals the importance of HSI-II and -III in mediating P. aeruginosa pathogenesis. Moreover, this work provides new insights into the design and development of selective compounds that may restrict human P. aeruginosa and possibly other clinical infections.

Correspondence
L. G. Rahme
rahme{at}molbio.mgh.harvard.edu

These authors contributed equally to this work.

Present address: Danone Research, RD 128, 91767 Palaiseau, France.

The GEO series accession number for the microarray data discussed in this paper is GSE17147.

Two supplementary figures, showing a CLUSTAL W alignment of PA14 HSI-I, -II, and -III Hcp and VgrG proteins, and the genomic context of the four hcp2 homologues in PA14 and a CLUSTAL W alignment of the VgrG proteins adjacent to the hcp2 homologues, are available with the online version of this paper.