Clarithromycin impairs tissue-resident memory and Th17 responses to macrolide-resistant Streptococcus pneumoniae infections

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 center dot Macrolide-resistant S. pneumoniae infection undergoes immunomodulation by Clarithromycin center dot Clarithromycin treatment hinders Th17 and tissue-resident memory responses center dot Macrolide antibiotics impair Th17 differentiation in vitro by ERK-pathway inhibition

Automated summary

The study demonstrates that Clarithromycin affects the frequency and number of IL-17 producing T helper cells in the lungs of mice infected with macrolide-resistant Streptococcus pneumoniae, as well as impairs the tissue-resident memory T cell response. Mechanistically, Clarithromycin inhibits Th17 cell differentiation through ERK pathway inhibition.