Clarithromycin impairs tissue-resident memory and Th17 responses to macrolide-resistant Streptococcus pneumoniae infections
-
Published:2021-02-17
Issue:6
Volume:99
Page:817-829
-
ISSN:0946-2716
-
Container-title:Journal of Molecular Medicine
-
language:en
-
Short-container-title:J Mol Med
Author:
Lindenberg MarcORCID, Almeida Luis, Dhillon-LaBrooy Ayesha, Siegel Ekkehard, Henriques-Normark Birgitta, Sparwasser TimORCID
Abstract
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
Funder
Deutsches Zentrum für Infektionsforschung Joint Programming Initiative on Antimicrobial Resistance
Publisher
Springer Science and Business Media LLC
Subject
Genetics(clinical),Drug Discovery,Molecular Medicine
Reference48 articles.
1. O’Brien KL, Wolfson LJ, Watt JP et al (2009) Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 374:893–902 2. Troeger CE, Khalil IA, Blacker BF, Biehl MH, Albertson SB, Zimsen SRM, Rao PC, Abate D, Admasie A, Ahmadi A, Ahmed MLCB, Akal CG, Alahdab F, Alam N, Alene KA, Alipour V, Aljunid SM, al-Raddadi RM, Alvis-Guzman N, Amini S, Anjomshoa M, Antonio CAT, Arabloo J, Aremu O, Atalay HT, Atique S, Avokpaho EFGA, Awad S, Awasthi A, Badawi A, Balakrishnan K, Banoub JAM, Barac A, Bassat Q, Bedi N, Bennett DA, Bhattacharyya K, Bhutta ZA, Bijani A, Bills CB, Car J, Carvalho F, Castañeda-Orjuela CA, Causey K, Christopher DJ, Cohen AJ, Dandona L, Dandona R, Daryani A, Demeke FM, Djalalinia S, Dubey M, Dubljanin E, Duken EE, el Sayed Zaki M, Endries AY, Fernandes E, Fischer F, Frostad J, Fullman N, Gardner WM, Geta B, Ghadiri K, Gorini G, Goulart AC, Guo Y, Hailu GB, Haj-Mirzaian A, Haj-Mirzaian A, Hamidi S, Hassen HY, Hoang CL, Horita N, Hostiuc M, Hussain Z, Irvani SSN, James SL, Jha RP, Jonas JB, Karch A, Kasaeian A, Kassa TD, Kassebaum NJ, Kefale AT, Khader YS, Khan EA, Khan G, Khan MN, Khang YH, Khoja AT, Kimokoti RW, Kisa A, Kisa S, Kissoon N, Knibbs LD, Kochhar S, Kosen S, Koul PA, Koyanagi A, Kuate Defo B, Kumar GA, Lal DK, Leshargie CT, Lewycka S, Li S, Lodha R, Macarayan ERK, Majdan M, Mamun AA, Manguerra H, Mehta V, Melese A, Memish ZA, Mengistu DT, Meretoja TJ, Mestrovic T, Miazgowski B, Mirrakhimov EM, Moazen B, Mohammad KA, Mohammed S, Monasta L, Moore CE, Morawska L, Mosser JF, Mousavi SM, Murthy S, Mustafa G, Nazari J, Nguyen CT, Nguyen HLT, Nguyen LH, Nguyen SH, Nielsen KR, Nisar MI, Nixon MR, Ogbo FA, Okoro A, Olagunju AT, Olagunju TO, Oren E, Ortiz JR, P A M, Pakhale S, Postma MJ, Qorbani M, Quansah R, Rafiei A, Rahim F, Rahimi-Movaghar V, Rai RK, Reitsma MB, Rezai MS, Rezapour A, Rios-Blancas MJ, Ronfani L, Rothenbacher D, Rubino S, Saleem Z, Sambala EZ, Samy AM, Santric Milicevic MM, Sarmiento-Suárez R, Sartorius B, Savic M, Sawhney M, Saxena S, Sbarra A, Seyedmousavi S, Shaikh MA, Sheikh A, Shigematsu M, Smith DL, Sreeramareddy CT, Stanaway JD, Sufiyan M'B, Temsah MH, Tessema B, Tran BX, Tran KB, Tsadik AG, Ullah I, Updike RL, Vasankari TJ, Veisani Y, Wada FW, Waheed Y, Welgan K, Wiens KE, Wiysonge CS, Yimer EM, Yonemoto N, Zaidi Z, Zar HJ, Lim SS, Vos T, Mokdad AH, Murray CJL, Kyu HH, Hay SI, Reiner RC (2020) Quantifying risks and interventions that have affected the burden of lower respiratory infections among children younger than 5 years: an analysis for the Global Burden of Disease Study 2017. Lancet Infect Dis 20:60–79 3. Wilson R, Cohen JM, Jose RJ, de Vogel C, Baxendale H, Brown JS (2015) Protection against Streptococcus pneumoniae lung infection after nasopharyngeal colonization requires both humoral and cellular immune responses. Mucosal Immunol 8:627–639 4. Smith NM, Wasserman GA, Coleman FT et al (2018) Regionally compartmentalized resident memory T cells mediate naturally acquired protection against pneumococcal pneumonia. Mucosal Immunol 11:220–235 5. Lu Y, Gross J, Bogaert D et al (2008) Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathog 4:e1000159
Cited by
4 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|