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A novel virulence strategy for Pseudomonas aeruginosa mediated by an autotransporter with arginine-specific aminopeptidase activity
- Source :
- PLoS Pathogens, PLoS Pathogens, Vol 8, Iss 8, p e1002854 (2012)
- Publication Year :
- 2012
-
Abstract
- The opportunistic human pathogen, Pseudomonas aeruginosa, is a major cause of infections in chronic wounds, burns and the lungs of cystic fibrosis patients. The P. aeruginosa genome encodes at least three proteins exhibiting the characteristic three domain structure of autotransporters, but much remains to be understood about the functions of these three proteins and their role in pathogenicity. Autotransporters are the largest family of secreted proteins in Gram-negative bacteria, and those characterised are virulence factors. Here, we demonstrate that the PA0328 autotransporter is a cell-surface tethered, arginine-specific aminopeptidase, and have defined its active site by site directed mutagenesis. Hence, we have assigned PA0328 with the name AaaA, for arginine-specific autotransporter of P. aeruginosa. We show that AaaA provides a fitness advantage in environments where the sole source of nitrogen is peptides with an aminoterminal arginine, and that this could be important for establishing an infection, as the lack of AaaA led to attenuation in a mouse chronic wound infection which correlated with lower levels of the cytokines TNFα, IL-1α, KC and COX-2. Consequently AaaA is an important virulence factor playing a significant role in the successful establishment of P. aeruginosa infections.<br />Author Summary We present a new Pseudomonas aeruginosa virulence factor that promotes chronic skin wound infections. We propose the name AaaA for this cell-surface tethered autotransporter. This arginine-specific aminopeptidase confers a growth advantage upon P. aeruginosa, providing a fitness advantage by creating a supply of arginine in chronic wounds where oxygen availability is limited and biofilm formation is involved. To our knowledge, this is the first mechanistic evidence linking the upregulation of genes involved in arginine metabolism with pathogenicity of P. aeruginosa, and we propose potential underlying mechanisms. The superbug P. aeruginosa is the leading cause of morbidity in cystic fibrosis patients. The ineffective host immune response to bacterial colonization is likely to play a critical role in the demise of these patients, making the possibility that AaaA could interface with the innate immune system, influencing the activity of iNOS and consequently the host's defence against invading pathogens. The surface localisation of AaaA makes it accessible to inhibitors that could reduce growth of P. aeruginosa during colonisation and alter biofilm formation, potentially improving the efficacy of current antimicrobials. Indeed, structurally related aminopeptidases play a central role in several disease states (stroke, diabetes, cancer, HIV and neuropsychiatric disorders), and inhibitors alleviate symptoms.
- Subjects :
- Human pathogen
Pathogenesis
medicine.disease_cause
Aminopeptidase
Aminopeptidases
Biochemistry
Virulence factor
Mice
Microbial Physiology
Biology (General)
0303 health sciences
3. Good health
Bacterial Pathogens
Host-Pathogen Interaction
Medical Microbiology
Pseudomonas aeruginosa
Cytokines
Research Article
Proteases
QH301-705.5
Virulence Factors
Immunology
Virulence
Biology
Microbiology
03 medical and health sciences
Bacterial Proteins
Virology
Genetics
medicine
Animals
Humans
Pseudomonas Infections
Molecular Biology
Microbial Pathogens
030304 developmental biology
Microbial Metabolism
030306 microbiology
RC581-607
Disease Models, Animal
Secretory protein
Chronic Disease
Mutagenesis, Site-Directed
Wound Infection
Parasitology
Immunologic diseases. Allergy
Carrier Proteins
Peptides
Autotransporters
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens, PLoS Pathogens, Vol 8, Iss 8, p e1002854 (2012)
- Accession number :
- edsair.doi.dedup.....ee1cf5e0373364ca9aa10135f9d32d75