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
Highlights
Pneumonia represents a major public health concern worldwide, regardless of established antibiotic and supportive treatment regimens
Since an empirical macrolide antibiotic treatment of patients infected with a macrolide antibiotic-resistant S. pneumoniae isolate is likely to occur, we investigated the effects of this treatment on the adaptive T cell response in a mouse model of pneumonia
Macrolide antibiotics like Clarithromycin and Azithromycin are known for their immunomodulatory capacities and have been used to dampen inflammatory conditions [25,26,27,28]
Summary
Pneumonia represents a major public health concern worldwide, regardless of established antibiotic and supportive treatment regimens. CD4+ tissue-resident memory T cells producing IL-17 (Trm17) were identified as important mediators of neutrophil activation, conferring protection against subsequent S. pneumoniae infections [3,4,5]. Smith et al showed that secondary protection conferred by a memory T cell response was limited to the lung lobe, which had been already infected once, and was absent in the contralateral one. J Mol Med (2021) 99:817–829 with CD4-depleting or IL-17-neutralizing antibodies impaired this protective response, showcasing the importance of Trm cells in secondary infections [4]. Parabiosis experiments revealed that tissue-resident T cells rather than migrating cells are the main players in mediating mucosal memory immunity to lung pathogens [7]. The studies mentioned above indicate that Trm cells are central in host protection to secondary lung infections. Importance is their capacity to mediate this protection in an S. pneumoniae serotypeindependent fashion as currently available vaccines only protect for a certain set of serotypes
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