Disease relevance of phoP

• Characterization of defensin resistance phenotypes associated with mutations in the phoP virulence regulon of Salmonella typhimurium [1].
• We present here the DNA sequence of the phoP gene and show that the deduced amino acid sequence of phoP has extensive homology with the Escherichia coli transcriptional regulators PhoB and OmpR, which control the expression of loci in response to different environmental stimuli [2].
• One of these, phoP, was cotransducible by phage P22 with purB, whereas the second, phoN, was cotransducible by phage P1 with purA [3].
• Strains with phoP locus mutations are effective as live vaccines in mice, and strains with a constitutive regulatory mutation, a point mutation in PhoQ, can protect mice against typhoid fever when only very few organisms are administered [4].
• To explore the approaches and mechanisms for reversing the immune tolerance in transgenic mouse, and the pathogenicity of hepatitis G virus (HGV), the promoter of phoP-activated gene (P(pagC)) of Salmonella typhimurium was used as a transcriptionally regulating element to construct an attenuated S. typhimurium expressing HGV NS3 [5].

High impact information on phoP

• In contrast, infection of MPhi with the phoP constitutive mutant strain CS022, which does not induce apoptosis in infected MPhi, does not result in presentation of a bacteria-derived antigen by bystander DCs unless the infected MPhi are induced to undergo apoptosis by treatment with lipopolysaccharide and ATP [6].
• A Salmonella strain containing a constitutive mutation in the phoP virulence regulatory locus (PhoPc) induced significantly fewer SP [7].
• Differentially expressed genes included those that affect host cell death, suggesting that the phoP regulatory system controls bacterial genes that alter macrophage survival [8].
• Characterization of the mutants showed that one had a defective lipopolysaccharide and another mutant harbored a mutation in phoP, a locus previously shown to control expression of Salmonella virulence genes [9].
• The DNA sequence for the phoP locus indicates that it is composed of two genes present in an operon, termed phoP and phoQ [10].

Chemical compound and disease context of phoP

• Starvation- and Stationary-phase-induced resistance to the antimicrobial peptide polymyxin B in Salmonella typhimurium is RpoS (sigma(S)) independent and occurs through both phoP-dependent and -independent pathways [11].

Biological context of phoP

• These experiments indicate that phoP plays a role in Salmonella-induced human macrophage cell death [8].
• The deduced amino acid sequence of the phoP and phoQ gene products are highly similar to other members of bacterial two-component transcriptional regulators that respond to environmental stimuli [10].
• Sequences homologous to phoP were found in several Gram-negative species and in the yeast Saccharomyces cerevisiae [2].
• S. typhimurium strains with transposon insertions that create transcriptional and translational gene fusions that require phoP and phoQ for expression have been isolated and have different chromosomal locations, indicating that this system is a regulon [10].
• In addition, phoP-regulated gene expression was shown to influence processing of antigen phagocytosed independently of the bacteria [12].

Anatomical context of phoP

• The virulence defect conferred by mutations in the phoP-phoQ two-component regulatory system is not completely explained by alterations in resistance to cationic proteins and involves the control of other proteins necessary for S. typhimurium survival within macrophages [1].
• Increased levels of pmrH, phoP, and prgH transcription but not ssaB were observed in bacteria isolated from the lumen of the distal ileum [13].
• However, at this time point, the proportion of vacuoles containing phoP-mutant bacteria that were associated with each of the markers ranged from 25% to 50% [14].
• Neither of the phoP/Q mutants were growth impaired in HeLa cells, however the PhoPc mutant was impaired in invasion [15].
• Effect of constitutively expressed phoP gene on the localization of Salmonella typhimurium within Mac-1 positive phagocytes [16].

Regulatory relationships of phoP

• This response to the macrophage intracellular environment is simulated by phoP/phoQ constitutive mutations (phenotype PhoPc) that increase the expression of pag genes and repress the synthesis of approximately 20 proteins encoded by phoP-repressed genes (prg genes) (S. I. Miller and J. J. Mekalanos, J. Bacteriol. 172:2485-2490, 1990) [17].

Other interactions of phoP

• Strains with mutations in either gene of the regulatory pair (phoP [transcriptional activator] or phoQ [membrane sensor kinase]) had increased sensitivities to defensin [1].
• Strains with pagC, phoP, or phoQ mutations have decreased survival in cultured mouse macrophages [10].
• The results indicate the presence of an rpoS- and phoP-independent pathway important to starvation- and stationary-phase-induced resistance to membrane-permeabilizing antimicrobial agents [11].
• Expression of sopD2 was induced inside host cells and was dependent on functional ssrA/B and phoP/Q, two component regulatory systems [18].
• In this study, mutants of Salmonella Typhimurium and Enteritidis with deletions in phoP and rpoS, either alone or in combination with ompC, were characterised and tested for their level of attenuation and their ability to inhibit the intestinal colonisation of the isogenic parent strains in chickens [19].

Analytical, diagnostic and therapeutic context of phoP

• Host microarray analysis reveals a role for the Salmonella response regulator phoP in human macrophage cell death [8].
• We used a 22,571 human cDNA microarray to identify host pathways that are affected by the Salmonella enterica subspecies typhimurium phoP gene, a transcription factor required for virulence, by comparing the expression profiles of human monocytic tissue culture cells infected with either the wild-type bacteria or a phoPTn10 mutant strain [8].
• Digital imaging and flow cytometry were used to follow the induction of the phoP promoter of Salmonella enterica Typhimurium within live macrophages [20].
• While most strains that protected grew or persisted in vivo, a phoP::Tn10 mutant of S. typhimurium did not grow or persist; this phoP mutant did not cause immunosuppression, but gave 100% protection against challenge with wild type S. typhimurium, suggesting that such mutants have advantageous properties as live vaccines [21].
• Evaluation of a phoP/phoQ-deleted, aroA-deleted live oral Salmonella typhi vaccine strain in human volunteers [22].

References