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PhoP-PhoQ activates transcription of pmrAB, encoding a two-component regulatory system involved in Salmonella
1University of Washington, Seattle 98195, USA.
Abstract:
Antimicrobial cationic peptides are a host defense mechanism of many animal species including mammals, insects, and amphibians. Salmonella typhimurium is an enteric and intracellular pathogen that interacts with antimicrobial peptides within neutrophil and macrophage phagosomes and at intestinal mucosal surfaces. The Salmonella spp. virulence regulators, PhoP and PhoQ, activate the transcription of genes (pag) within macrophage phagosomes necessary for resistance to cationic antimicrobial peptides. One PhoP-activated gene, pagB, forms an operon with pmrAB (5' pagB-pmrA-pmrB 3'), a two-component regulatory system involved in resistance to the antimicrobial peptides polymyxin, azurocidin (CAP37), bactericidal/permeability-increasing protein (BPI or CAP57), protamine, and polylysine. Expression of pmrAB increased transcription of pagB-pmrAB by activation of a promoter 5' to pagB. pmrAB is also expressed from a second promoter, not regulated by PhoP-PhoQ or PmrA-PmrB, located within the pagB coding sequence. S. typhimurium strains with increased pag locus expression were demonstrated to be polymyxin resistant because of induction of pagB-pmrAB; however, PmrA-PmrB was not responsible for the increased sensitivity of PhoP-null mutants to NP-1 defensin. Therefore, PhoP regulates at least two separate networks of genes responsible for cationic antimicrobial peptide resistance. These data suggest that resistance to the polymyxin-CAP family is controlled by a cascade of regulatory protein expression that activates transcription upon environmental sensing.
Insights
Salmonella typhimurium uses PhoP to control resistance to host defense peptides. PhoP activates gene networks, including pagB-pmrAB, to combat antimicrobial peptides and ensure bacterial survival.
Area of Science:
- Microbiology
- Immunology
- Bacterial Pathogenesis
Background:
- Antimicrobial cationic peptides are crucial host defense molecules.
- Salmonella typhimurium, an enteric pathogen, encounters these peptides in host cells and tissues.
- Bacterial resistance mechanisms are vital for pathogen survival.
Purpose of the Study:
- To investigate the role of Salmonella typhimurium virulence regulators PhoP and PhoQ in antimicrobial peptide resistance.
- To elucidate the function of the pagB-pmrAB operon in Salmonella's defense against cationic peptides.
- To understand the regulatory networks controlling Salmonella's resistance.
Main Methods:
- Analysis of gene transcription and regulation in Salmonella typhimurium.
- Investigating the function of PhoP, PhoQ, and PmrA-PmrB regulatory systems.
- Assessing bacterial resistance to various antimicrobial peptides (polymyxin, defensins, etc.).
Main Results:
- PhoP and PhoQ activate genes, including pagB-pmrAB, for resistance to cationic antimicrobial peptides.
- The pagB-pmrAB operon confers resistance to polymyxin and other peptides.
- PhoP regulates distinct gene networks, indicating complex resistance strategies.
Conclusions:
- Salmonella typhimurium employs sophisticated regulatory networks, controlled by PhoP, to resist host antimicrobial defenses.
- Resistance to polymyxin-family peptides involves a cascade of regulatory protein expression.
- PhoP plays a central role in orchestrating Salmonella's survival against diverse antimicrobial challenges.