The PmlI-PmlR Quorum-Sensing System in Burkholderia pseudomallei Plays a Key Role in Virulence and Modulates Production of the MprA Protease

Abstract

Burkholderia pseudomallei is the causative agent of melioidosis, an often fatal infection of humans and animals. The virulence of this pathogen is thought to depend on a number of secreted proteins, including the MprA metalloprotease. We observed that MprA is produced upon entry into the stationary phase, when the cell density is high, and this prompted us to study cell density-dependent regulation in B. pseudomallei. A search of the B. pseudomallei genome led to identification of a quorum-sensing system involving the LuxI-LuxR homologs PmlI-PmlR. PmlI directed the synthesis of an N-acylhomoserine lactone identified as N-decanoylhomoserine lactone. A B. pseudomallei pmlI mutant was significantly less virulent than the parental strain in a murine model of infection by the intraperitoneal, subcutaneous, and intranasal routes. Inactivation of pmlI resulted in overproduction of MprA at the onset of the stationary phase. A wild-type phenotype was restored following complementation with pmlI or addition of cell-free culture supernatant. In contrast, there was no significant difference between the virulence of a B. pseudomallei mprA mutant and the virulence of the wild-type strain. These results suggest that the PmlI-PmlR quorum-sensing system of B. pseudomallei is essential for full virulence in a mouse model and downregulates the production of MprA at a high cell density.

Piericidins, Novel Quorum-Sensing Inhibitors against Chromobacterium violaceum CV026, from Streptomyces sp. TOHO-Y209 and TOHO-O348

“…When the concentration of such an excreted metabolite reaches its threshold level, certain types of gene expression resulting in bioluminescence [1], biofilm formation [2,3], swarming motility [4], antibiotic biosynthesis [5,6] virulence factor production [7,8], etc., are triggered by the metabolite (autoinducer). Disruption of the QS system in pathogenic Burkholderia cepacia and B. pseudomallei resulted in reduced pathogenicity in murine and hamster infection [9,10], and erythromycin inhibits biofilm formation of Pseudomonas aeruginosa below the minimum inhibitory concentration (MIC) [11]. Therefore, compounds that inhibit QS have great potential for use in the treatment of bacterial infectious diseases.…”

Quorum Sensing: a Transcriptional Regulatory System Involved in the Pathogenicity of Burkholderia mallei

“…In supernatants from B. mallei, the signaling molecules C 8 -HSL and C 10 -HSL were detected ( Table 4). As with B. mallei, it was recently shown that B. pseudomallei 008 produces C 10 -HSL via the PmlI protein (36). Similar to B. mallei, with the exception of N-(3-oxotetradecanoyl)-L-homoserine lactone, B. pseudomallei DD503 synthesizes C 8 -HSL, 3-hydroxy-C 8 -HSL, C 10 -HSL, and 3-hydroxy-C 10 -HSL (34).…”

“…For human and plant pathogens, AHL-based communication systems allow a microbial community to strategically induce or repress expression of genes, specifically alleles encoding putative virulence factors, in response to environmental stimuli. Several reports have identified functional QS systems in various Burkholderia species and have shown that these bacterial communication networks both positively and negatively regulate numerous extracellular virulence factors in addition to contributing to animal pathogenicity (B. cepacia) (1,3,20,21,31,34,36).…”

“…Functional QS networks have recently been identified in Burkholderia cepacia, Burkholderia vietnamiensis, Burkholderia thailandensis, and Burkholderia pseudomallei (1,3,15,20,32,(34)(35)(36). Collectively, these Burkholderia QS networks have been shown to both positively and negatively regulate various cellular processes, including AHL and protease production, siderophore biosynthesis, biofilm formation, lipase and betahemolytic activities, swarming and twitching motilities, and substrate utilization (18,20,21,32,35,36).…”

“…Collectively, these Burkholderia QS networks have been shown to both positively and negatively regulate various cellular processes, including AHL and protease production, siderophore biosynthesis, biofilm formation, lipase and betahemolytic activities, swarming and twitching motilities, and substrate utilization (18,20,21,32,35,36). Furthermore, disruption of these cell signaling systems has been shown to reduce the pathogenicity of B. cepacia and Burkholderia pseudomallei in murine and hamster models of infection (1,31,34,36).…”