Clarithromycin impairs tissue-resident memory and Th17 responses to macrolide-resistant Streptococcus pneumoniae
Marc Lindenberg1,2,3, Luis Almeida1,4, Ayesha Dhillon-LaBrooy1,4
1Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hanover, Germany.
Abstract:
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.
Insights
Clarithromycin treatment reduces crucial T cell responses against macrolide-resistant Streptococcus pneumoniae. This antibiotic may worsen infections by weakening the immune system, suggesting reconsidering its use until resistance is known.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- Antimicrobial resistance, particularly in Streptococcus pneumoniae, is a significant public health threat.
- Macrolide antibiotics are widely used but their impact on host immune responses against resistant strains is not fully understood.
Purpose of the Study:
- To investigate the immunomodulatory effects of Clarithromycin on T helper 17 (Th17) and tissue-resident memory T cell (Trm) responses during infection with macrolide-resistant Streptococcus pneumoniae.
- To elucidate the underlying molecular mechanisms of Clarithromycin's impact on immune cells.
Main Methods:
- Mice infected with macrolide-resistant S. pneumoniae serotype 15A were treated with Clarithromycin.
- Flow cytometry was used to analyze lung immune cell populations, specifically IL-17 producing Th17 cells and CD4+ Trm cells.
- Western blotting assessed the ERK pathway and mTOR signaling.
- Mitochondrial respiration was measured.
Main Results:
- Clarithromycin treatment decreased the frequency and number of IL-17+ Th17 cells in the lungs.
- Subsequent S. pneumoniae infection showed an impaired Trm response, with fewer IL-17+ CD69+ Trm cells in Clarithromycin-treated mice.
- Clarithromycin inhibited ERK pathway phosphorylation in Th17 cells and increased mitochondrial respiratory capacity.
Conclusions:
- Macrolide antibiotics like Clarithromycin can impair T cell-mediated immunity against resistant S. pneumoniae, potentially exacerbating infections.
- The findings suggest that Clarithromycin may hinder Th17 differentiation via ERK pathway inhibition.
- Clinical use of macrolides should be reconsidered until antimicrobial resistance patterns are established to avoid compromising host defenses.
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