Abstract
Objectives
Antimicrobial resistance is a global burden highlighted by the WHO as one of the top ten global public health threats. However, antimicrobial resistance is only one strategy employed by bacterial pathogens to overcome treatment. Other mechanisms such as immune escape are currently completely neglected and under-investigated, even though their contribution is significant during an infection.
Methods
We screened for mutations in Pseudomonas aeruginosa strains isolated from cystic fibrosis patients which reduced the pathogenicity and virulence of the infecting bacteria. Whole cell proteomics allowed to infer changes in protein expression which could reduce the bacterial virulence. Infections carried out in the airway epithelium air-liquid-interface infection model system corroborated these results providing a mechanistic explanation of the reduced virulence.
Results
Mutations in the uL4 and uL22 ribosomal proteins cause high level resistance to macrolide antibiotics together with an unexpected reduction of expression of the type III secretion system, which is a system deployed by bacteria to damage the epithelial layer. Similarly, mutations in the pyruvate dehydrogenase enzyme involved in central carbon metabolism, causes metabolic specialization and reduced T3SS expression assuring prolonged infection and reduced immunogenicity in air-liquid-interface cultures.
Conclusions
Certain antibiotic resistance mutations and metabolic specialization are drivers of pathogenicity, leading to invasion into the airway epithelium, and conditional escaping from the immune system. This provides additional advantages to the infecting bacteria, reducing the eradication of both resistant and susceptible bacteria. Proper diagnosis and management of immune escaping pathogens is, therefore, of high priority since it will allow the design of more efficient treatment strategies, and lastly will contribute to meeting the challenges of antimicrobial resistance.
Antimicrobial resistance is a global burden highlighted by the WHO as one of the top ten global public health threats. However, antimicrobial resistance is only one strategy employed by bacterial pathogens to overcome treatment. Other mechanisms such as immune escape are currently completely neglected and under-investigated, even though their contribution is significant during an infection.
Methods
We screened for mutations in Pseudomonas aeruginosa strains isolated from cystic fibrosis patients which reduced the pathogenicity and virulence of the infecting bacteria. Whole cell proteomics allowed to infer changes in protein expression which could reduce the bacterial virulence. Infections carried out in the airway epithelium air-liquid-interface infection model system corroborated these results providing a mechanistic explanation of the reduced virulence.
Results
Mutations in the uL4 and uL22 ribosomal proteins cause high level resistance to macrolide antibiotics together with an unexpected reduction of expression of the type III secretion system, which is a system deployed by bacteria to damage the epithelial layer. Similarly, mutations in the pyruvate dehydrogenase enzyme involved in central carbon metabolism, causes metabolic specialization and reduced T3SS expression assuring prolonged infection and reduced immunogenicity in air-liquid-interface cultures.
Conclusions
Certain antibiotic resistance mutations and metabolic specialization are drivers of pathogenicity, leading to invasion into the airway epithelium, and conditional escaping from the immune system. This provides additional advantages to the infecting bacteria, reducing the eradication of both resistant and susceptible bacteria. Proper diagnosis and management of immune escaping pathogens is, therefore, of high priority since it will allow the design of more efficient treatment strategies, and lastly will contribute to meeting the challenges of antimicrobial resistance.
| Original language | English |
|---|---|
| Article number | S138 |
| Journal | Journal of Cystic Fibrosis |
| Volume | 22 |
| ISSN | 1569-1993 |
| DOIs | |
| Publication status | Published - 2023 |
