Macrolides Decrease the Proinflammatory Activity of Macrolide-Resistant Streptococcus pneumoniae.

Content Provider	Europe PMC
Author	Domon, Hisanori Hirayama, Satoru Isono, Toshihito Sasagawa, Karin Takizawa, Fumio Maekawa, Tomoki Yanagihara, Katsunori Terao, Yutaka
Editor	LaRock, Christopher N.
Copyright Year	2023
Abstract	ABSTRACTOver the past 2 decades, the prevalence of macrolide-resistant Streptococcus pneumoniae (MRSP) has increased considerably, due to widespread macrolide use. Although macrolide usage has been proposed to be associated with treatment failure in patients with pneumococcal diseases, macrolides may be clinically effective for treating these diseases, regardless of the susceptibility of the causative pneumococci to macrolides. As we previously demonstrated that macrolides downregulate the transcription of various genes in MRSP, including the gene encoding the pore-forming toxin pneumolysin, we hypothesized that macrolides affect the proinflammatory activity of MRSP. Using HEK-Blue cell lines, we found that the supernatants from macrolide-treated MRSP cultures induced decreased NF-κB activation in cells expressing Toll-like receptor 2 and nucleotide-binding oligomerization domain 2 compared to the supernatants from untreated MRSP cells, suggesting that macrolides inhibit the release of these ligands from MRSP. Real-time PCR analysis revealed that macrolides significantly downregulated the transcription of various genes encoding peptidoglycan synthesis-, lipoteichoic acid synthesis-, and lipoprotein synthesis-related molecules in MRSP cells. The silkworm larva plasma assay demonstrated that the peptidoglycan concentrations in the supernatants from macrolide-treated MRSP cultures were significantly lower than those from untreated MRSP cultures. Triton X-114 phase separation revealed that lipoprotein expression decreased in macrolide-treated MRSP cells compared to the lipoprotein expression in untreated MRSP cells. Consequently, macrolides may decrease the expression of bacterial ligands of innate immune receptors, resulting in the decreased proinflammatory activity of MRSP.IMPORTANCE To date, the clinical efficacy of macrolides in pneumococcal disease is assumed to be linked to their ability to inhibit the release of pneumolysin. However, our previous study demonstrated that oral administration of macrolides to mice intratracheally infected with macrolide-resistant Streptococcus pneumoniae resulted in decreased levels of pneumolysin and proinflammatory cytokines in bronchoalveolar lavage fluid samples compared to the levels in samples from untreated infected control mice, without affecting the bacterial load in the fluid. This finding suggests that additional mechanisms by which macrolides negatively regulate proinflammatory cytokine production may be involved in their efficacy in vivo. Furthermore, in this study, we demonstrated that macrolides downregulated the transcription of various proinflammatory-component-related genes in S. pneumoniae, which provides an additional explanation for the clinical benefits of macrolides.
Page Count	17
Volume Number	11
PubMed Central reference number	PMC10269745
Issue Number	3
PubMed reference number	37191519
Journal	Microbiology Spectrum [Microbiol Spectr]
e-ISSN	21650497
DOI	10.1128/spectrum.00148-23
Language	English
Publisher	American Society for Microbiology
Publisher Date	2023-05-16
Publisher Place	N.W., Washington, DC
Access Restriction	Open
Rights License	This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Copyright © 2023 Domon et al.
Subject Keyword	inflammation lipoproteins lipoteichoic acid macrolide-resistant Streptococcus pneumoniae macrolides peptidoglycan
Content Type	Text
Resource Type	Article
Subject	Cell Biology Physiology Infectious Diseases Immunology and Microbiology Genetics Microbiology (medical) Ecology