Clarithromycin impairs tissue-resident memory and Th17 responses to macrolide-resistant Streptococcus pneumoniae infections.
Marc LindenbergLuis AlmeidaAyesha Dhillon-LaBrooyEkkehard SiegelBirgitta Henriques-NormarkTim SparwasserPublished in: Journal of molecular medicine (Berlin, Germany) (2021)
The increasing prevalence of antimicrobial resistance in pathogens is a growing public health concern, with the potential to compromise the success of infectious disease treatments in the future. Particularly, the number of infections by macrolide antibiotics-resistant Streptococcus pneumoniae is increasing. We show here that Clarithromycin impairs both the frequencies and number of interleukin (IL)-17 producing T helper (Th) 17 cells within the lungs of mice infected with a macrolide-resistant S. pneumoniae serotype 15A strain. Subsequently, the tissue-resident memory CD4+ T cell (Trm) response to a consecutive S. pneumoniae infection was impaired. The number of lung resident IL-17+ CD69+ Trm was diminished upon Clarithromycin treatment during reinfection. Mechanistically, Clarithromycin attenuated phosphorylation of the p90-S6-kinase as part of the ERK pathway in Th17 cells. Moreover, a strong increase in the mitochondrial-mediated maximal respiratory capacity was observed, while mitochondrial protein translation and mTOR sisgnaling were unimpaired. Therefore, treatment with macrolide antibiotics may favor the spread of antimicrobial-resistant pathogens not only by applying a selection pressure but also by decreasing the natural T cell immune response. Clinical administration of macrolide antibiotics as standard therapy procedure during initial hospitalization should be reconsidered accordingly and possibly be withheld until microbial resistance is determined. KEY MESSAGES: • Macrolide-resistant S. pneumoniae infection undergoes immunomodulation by Clarithromycin • Clarithromycin treatment hinders Th17 and tissue-resident memory responses • Macrolide antibiotics impair Th17 differentiation in vitro by ERK-pathway inhibition.
Keyphrases
- helicobacter pylori
- antimicrobial resistance
- helicobacter pylori infection
- public health
- immune response
- induced apoptosis
- signaling pathway
- oxidative stress
- quality improvement
- working memory
- cell cycle arrest
- stem cells
- staphylococcus aureus
- risk assessment
- escherichia coli
- pi k akt
- adipose tissue
- type diabetes
- dendritic cells
- inflammatory response
- combination therapy
- gram negative
- minimally invasive
- microbial community
- regulatory t cells
- global health
- resistance training
- high fat diet induced