{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T03:03:58Z","timestamp":1740107038481,"version":"3.37.3"},"reference-count":48,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T00:00:00Z","timestamp":1613520000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T00:00:00Z","timestamp":1613520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100009139","name":"Deutsches Zentrum f\u00fcr Infektionsforschung","doi-asserted-by":"publisher","award":["MD\/PhD stipend"],"award-info":[{"award-number":["MD\/PhD stipend"]}],"id":[{"id":"10.13039\/100009139","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013281","name":"Joint Programming Initiative on Antimicrobial Resistance","doi-asserted-by":"publisher","award":["JPIAMR2018-044 Pneumospread"],"award-info":[{"award-number":["JPIAMR2018-044 Pneumospread"]}],"id":[{"id":"10.13039\/100013281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Mol Med"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec>\n                <jats:title>Abstract<\/jats:title>\n                <jats:p>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 <jats:italic>Streptococcus pneumoniae<\/jats:italic> 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 <jats:italic>S. pneumoniae<\/jats:italic> serotype 15A strain. Subsequently, the tissue-resident memory CD4<jats:sup>+<\/jats:sup> T cell (Trm) response to a consecutive <jats:italic>S. pneumoniae<\/jats:italic> infection was impaired. The number of lung resident IL-17<jats:sup>+<\/jats:sup> CD69<jats:sup>+<\/jats:sup> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Key messages<\/jats:title>\n                <jats:p>\u2022 Macrolide-resistant <jats:italic>S. pneumoniae<\/jats:italic> infection undergoes immunomodulation by Clarithromycin<\/jats:p>\n                <jats:p>\u2022 Clarithromycin treatment hinders Th17 and tissue-resident memory responses<\/jats:p>\n                <jats:p>\u2022 Macrolide antibiotics impair Th17 differentiation in vitro by ERK-pathway inhibition<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00109-021-02039-5","type":"journal-article","created":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T02:57:39Z","timestamp":1613703459000},"page":"817-829","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Clarithromycin impairs tissue-resident memory and Th17 responses to macrolide-resistant Streptococcus pneumoniae infections"],"prefix":"10.1007","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8205-2458","authenticated-orcid":false,"given":"Marc","family":"Lindenberg","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"Almeida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayesha","family":"Dhillon-LaBrooy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekkehard","family":"Siegel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birgitta","family":"Henriques-Normark","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5645-902X","authenticated-orcid":false,"given":"Tim","family":"Sparwasser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,2,17]]},"reference":[{"key":"2039_CR1","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/S0140-6736(09)61204-6","volume":"374","author":"KL O\u2019Brien","year":"2009","unstructured":"O\u2019Brien 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\u2013902","journal-title":"Lancet"},{"key":"2039_CR2","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/S1473-3099(19)30410-4","volume":"20","author":"CE Troeger","year":"2020","unstructured":"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, Casta\u00f1eda-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-Su\u00e1rez 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\u201379","journal-title":"Lancet Infect Dis"},{"key":"2039_CR3","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/mi.2014.95","volume":"8","author":"R Wilson","year":"2015","unstructured":"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\u2013639","journal-title":"Mucosal Immunol"},{"key":"2039_CR4","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1038\/mi.2017.43","volume":"11","author":"NM Smith","year":"2018","unstructured":"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\u2013235","journal-title":"Mucosal Immunol"},{"key":"2039_CR5","doi-asserted-by":"publisher","first-page":"e1000159","DOI":"10.1371\/journal.ppat.1000159","volume":"4","author":"Y Lu","year":"2008","unstructured":"Lu Y, Gross J, Bogaert D et al (2008) Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathog 4:e1000159","journal-title":"PLoS Pathog"},{"key":"2039_CR6","doi-asserted-by":"publisher","first-page":"233","DOI":"10.4049\/jimmunol.1602051","volume":"199","author":"MM Wilk","year":"2017","unstructured":"Wilk MM, Misiak A, McManus RM et al (2017) Lung CD4 tissue-resident memory T cells mediate adaptive immunity induced by previous infection of mice with Bordetella pertussis. J Immunol 199:233\u2013243","journal-title":"J Immunol"},{"key":"2039_CR7","doi-asserted-by":"publisher","first-page":"5510","DOI":"10.4049\/jimmunol.1102243","volume":"187","author":"JR Teijaro","year":"2011","unstructured":"Teijaro JR, Turner D, Pham Q, Wherry EJ, Lefran\u00e7ois L, Farber DL (2011) Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J Immunol 187:5510\u20135514","journal-title":"J Immunol"},{"key":"2039_CR8","doi-asserted-by":"publisher","first-page":"22328","DOI":"10.1074\/jbc.M110.123299","volume":"285","author":"AJ Bankovich","year":"2010","unstructured":"Bankovich AJ, Shiow LR, Cyster JG (2010) CD69 suppresses sphingosine 1-phosophate receptor-1 (S1P1) function through interaction with membrane helix 4. J Biol Chem 285:22328\u201322337","journal-title":"J Biol Chem"},{"key":"2039_CR9","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/mi.2013.67","volume":"7","author":"DL Turner","year":"2014","unstructured":"Turner DL, Bickham KL, Thome JJ, Kim CY, D'Ovidio F, Wherry EJ, Farber DL (2014) Lung niches for the generation and maintenance of tissue-resident memory T cells. Mucosal Immunol 7:501\u2013510","journal-title":"Mucosal Immunol"},{"key":"2039_CR10","doi-asserted-by":"publisher","first-page":"E45","DOI":"10.1164\/rccm.201908-1581ST","volume":"200","author":"JP Metlay","year":"2019","unstructured":"Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, Cooley LA, Dean NC, Fine MJ, Flanders SA, Griffin MR, Metersky ML, Musher DM, Restrepo MI, Whitney CG (2019) Diagnosis and treatment of adults with community-acquired pneumonia. Am J Respir Crit Care Med 200:E45\u2013E67","journal-title":"Am J Respir Crit Care Med"},{"key":"2039_CR11","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3389\/fcimb.2016.00098","volume":"6","author":"MR Schroeder","year":"2016","unstructured":"Schroeder MR, Stephens DS (2016) Macrolide resistance in Streptococcus pneumoniae. Front Cell Infect Microbiol 6:98","journal-title":"Front Cell Infect Microbiol"},{"key":"2039_CR12","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1186\/s12879-015-0941-9","volume":"15","author":"M van der Linden","year":"2015","unstructured":"van der Linden M, Perniciaro S, Im\u00f6hl M (2015) Increase of serotypes 15A and 23B in IPD in Germany in the PCV13 vaccination era. BMC Infect Dis 15:207","journal-title":"BMC Infect Dis"},{"key":"2039_CR13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2807\/1560-7917.ES.2016.21.50.30423","volume":"21","author":"C Sheppard","year":"2016","unstructured":"Sheppard C, Fry NK, Mushtaq S, Woodford N, Reynolds R, Janes R, Pike R, Hill R, Kimuli M, Staves P, Doumith M, Harrison T, Livermore DM (2016) Rise of multidrug-resistant non-vaccine serotype 15A Streptococcus pneumoniae in the United Kingdom, 2001 to 2014. Eurosurveillance 21:1\u201310","journal-title":"Eurosurveillance"},{"doi-asserted-by":"publisher","unstructured":"Zimmermann P, Ziesenitz VC, Curtis N, Ritz N (2018) The immunomodulatory effects of macrolides\u2014a systematic review of the underlying mechanisms. Front Immunol 9. https:\/\/doi.org\/10.3389\/fimmu.2018.00302","key":"2039_CR14","DOI":"10.3389\/fimmu.2018.00302"},{"doi-asserted-by":"publisher","unstructured":"Amsden GW Anti-inflammatory effects of macrolides-an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? https:\/\/doi.org\/10.1093\/jac\/dkh519","key":"2039_CR15","DOI":"10.1093\/jac\/dkh519"},{"key":"2039_CR16","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1093\/jac\/dkn007","volume":"61","author":"BS Murphy","year":"2008","unstructured":"Murphy BS, Sundareshan V, Cory TJ, Hayes D, Anstead MI, Feola DJ (2008) Azithromycin alters macrophage phenotype. J Antimicrob Chemother 61:554\u2013560","journal-title":"J Antimicrob Chemother"},{"key":"2039_CR17","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1111\/j.1365-2249.2011.04480.x","volume":"166","author":"S Iwamoto","year":"2011","unstructured":"Iwamoto S, Kumamoto T, Azuma E, Hirayama M, Ito M, Amano K, Ido M, Komada Y (2011) The effect of azithromycin on the maturation and function of murine bone marrow-derived dendritic cells. Clin Exp Immunol 166:385\u2013392","journal-title":"Clin Exp Immunol"},{"key":"2039_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep07438","volume":"4","author":"F Ratzinger","year":"2014","unstructured":"Ratzinger F, Haslacher H, Poeppl W, Hoermann G, Kovarik JJ, Jutz S, Steinberger P, Burgmann H, Pickl WF, Schmetterer KG (2014) Azithromycin suppresses CD4 + T-cell activation by direct modulation of mTOR activity. Sci Rep 4:1\u201310","journal-title":"Sci Rep"},{"key":"2039_CR19","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/0005-2787(73)90439-5","volume":"331","author":"H De Vries","year":"1973","unstructured":"De Vries H, Arendzen AJ, Kroon AM (1973) The interference of the macrolide antibiotics with mitochondrial protein synthesis. Biochim Biophys Acta - Nucleic Acids Protein Synth 331:264\u2013275","journal-title":"Biochim Biophys Acta - Nucleic Acids Protein Synth"},{"doi-asserted-by":"crossref","unstructured":"Woodhead JL, Yang K, Oldach D, et al (2019) Analyzing the mechanisms behind macrolide antibiotic-induced liver injury using quantitative systems toxicology modeling","key":"2039_CR20","DOI":"10.1007\/s11095-019-2582-y"},{"key":"2039_CR21","doi-asserted-by":"publisher","first-page":"R911","DOI":"10.1016\/j.cub.2015.07.055","volume":"25","author":"JM Archibald","year":"2015","unstructured":"Archibald JM (2015) Endosymbiosis and eukaryotic cell evolution. Curr Biol 25:R911\u2013R921","journal-title":"Curr Biol"},{"key":"2039_CR22","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.immuni.2020.11.001","volume":"54","author":"L Almeida","year":"2020","unstructured":"Almeida L, Dhillon-LaBrooy A, Castro CN, Adossa N, Carriche GM, Guderian M, Lippens S, Dennerlein S, Hesse C, Lambrecht BN, Berod L, Schauser L, Blazar BR, Kalesse M, M\u00fcller R, Moita LF, Sparwasser T (2020) Ribosome-targeting antibiotics impair T cell effector function and ameliorate autoimmunity by blocking mitochondrial protein synthesis. Immunity. 54:68\u201383.e6","journal-title":"Immunity."},{"key":"2039_CR23","doi-asserted-by":"publisher","first-page":"3112","DOI":"10.1128\/MCB.24.8.3112-3124.2004","volume":"24","author":"M Pende","year":"2004","unstructured":"Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, Mueller M, Fumagalli S, Kozma SC, Thomas G (2004) S6K1-\/-\/S6K2-\/- mice exhibit perinatal lethality and rapamycin-sensitive 5\u2019-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 24:3112\u20133124","journal-title":"Mol Cell Biol"},{"key":"2039_CR24","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1093\/jac\/dkm084","volume":"59","author":"M Shinkai","year":"2007","unstructured":"Shinkai M, L\u00f3pez-Boado YS, Rubin BK (2007) Clarithromycin has an immunomodulatory effect on ERK-mediated inflammation induced by Pseudomonas aeruginosa flagellin. J Antimicrob Chemother 59:1096\u20131101","journal-title":"J Antimicrob Chemother"},{"key":"2039_CR25","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.1164\/ajrccm.157.6.9710075","volume":"157","author":"S Kudoh","year":"1998","unstructured":"Kudoh S, Azuma A, Yamamoto M et al (1998) Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med 157:1829\u20131832","journal-title":"Am J Respir Crit Care Med"},{"key":"2039_CR26","doi-asserted-by":"publisher","first-page":"442","DOI":"10.3122\/jabfm.2012.04.110309","volume":"25","author":"DL Hahn","year":"2012","unstructured":"Hahn DL, Grasmick M, Hetzel S, Yale S (2012) Azithromycin for bronchial asthma in adults: an effectiveness trial. J Am Board Fam Med 25:442\u2013459","journal-title":"J Am Board Fam Med"},{"key":"2039_CR27","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1136\/thx.2005.057950","volume":"61","author":"A Clement","year":"2006","unstructured":"Clement A (2006) Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial. Thorax 61:895\u2013902","journal-title":"Thorax"},{"key":"2039_CR28","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1016\/S0140-6736(12)60953-2","volume":"380","author":"C Wong","year":"2012","unstructured":"Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, Milne D, Fergusson W, Tuffery C, Sexton P, Storey L, Ashton T (2012) Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 380:660\u2013667","journal-title":"Lancet"},{"key":"2039_CR29","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1111\/j.1440-1843.2012.02166.x","volume":"17","author":"F-M Ding","year":"2012","unstructured":"Ding F-M, Zhu S-L, Shen C, Jiang Y-Q (2012) Low-dose clarithromycin therapy modulates CD4+ T-cell responses in a mouse model of chronic Pseudomonas aeruginosa lung infection. Respirology 17:727\u2013734","journal-title":"Respirology"},{"key":"2039_CR30","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1186\/1465-9921-11-90","volume":"11","author":"A Beigelman","year":"2010","unstructured":"Beigelman A, Mikols CL, Gunsten SP, Cannon CL, Brody SL, Walter MJ (2010) Azithromycin attenuates airway inflammation in a mouse model of viral bronchiolitis. Respir Res 11:90","journal-title":"Respir Res"},{"key":"2039_CR31","doi-asserted-by":"publisher","first-page":"1764","DOI":"10.3389\/fimmu.2018.01764","volume":"9","author":"L Borkner","year":"2018","unstructured":"Borkner L, Misiak A, Wilk MM, Mills KHG (2018) Azithromycin clears Bordetella pertussis infection in mice but also modulates innate and adaptive immune responses and T cell memory. Front Immunol 9:1764","journal-title":"Front Immunol"},{"key":"2039_CR32","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1128\/iai.65.1.257-260.1997","volume":"65","author":"K Takashima","year":"1997","unstructured":"Takashima K, Tateda K, Matsumoto T, Iizawa Y, Nakao M, Yamaguchi K (1997) Role of tumor necrosis factor alpha in pathogenesis of pneumococcal pneumonia in mice. Infect Immun 65:257\u2013260","journal-title":"Infect Immun"},{"key":"2039_CR33","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/S0924-8579(01)00430-7","volume":"18","author":"WL Hand","year":"2001","unstructured":"Hand WL, Hand DL (2001) Characteristics and mechanisms of azithromycin accumulation and efflux in human polymorphonuclear leukocytes. Int J Antimicrob Agents 18:419\u2013425","journal-title":"Int J Antimicrob Agents"},{"key":"2039_CR34","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1155\/2012\/584262","volume":"2012","author":"HC Steel","year":"2012","unstructured":"Steel HC, Theron AJ, Cockeran R, Anderson R, Feldman C (2012) Pathogen-and host-directed anti-inflammatory activities of macrolide antibiotics. Mediators Inflamm 2012:17\u201317","journal-title":"Mediators Inflamm"},{"key":"2039_CR35","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1128\/AAC.40.1.75","volume":"40","author":"A Wildfeuer","year":"1996","unstructured":"Wildfeuer A, Laufen H, Zimmermann T (1996) Uptake of azithromycin by various cells and its intracellular activity under in vivo conditions. Antimicrob Agents Chemother 40:75\u201379","journal-title":"Antimicrob Agents Chemother"},{"key":"2039_CR36","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1179\/joc.1997.9.1.23","volume":"9","author":"A Fietta","year":"1997","unstructured":"Fietta A, Merlini C, Gialdroni Grassi G (1997) Requirements for intracellular accumulation and release of clarithromycin and azithromycin by human phagocytes. J Chemother 9:23\u201331","journal-title":"J Chemother"},{"key":"2039_CR37","doi-asserted-by":"publisher","first-page":"2323","DOI":"10.1093\/jac\/dkr306","volume":"66","author":"C Tagliabue","year":"2011","unstructured":"Tagliabue C, Techasaensiri C, Torres JP, Katz K, Meek C, Kannan TR, Coalson JJ, Esposito S, Principi N, Leff R, Baseman JB, Hardy RD (2011) Efficacy of increasing dosages of clarithromycin for treatment of experimental Mycoplasma pneumoniae pneumonia. J Antimicrob Chemother 66:2323\u20132329","journal-title":"J Antimicrob Chemother"},{"key":"2039_CR38","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1183\/09031936.06.00116805","volume":"27","author":"Y Fukuda","year":"2006","unstructured":"Fukuda Y, Yanagihara K, Higashiyama Y, Miyazaki Y, Hirakata Y, Mukae H, Tomono K, Mizuta Y, Tsukamoto K, Kohno S (2006) Effects of macrolides on pneumolysin of macrolide-resistant Streptococcus pneumoniae. Eur Respir J 27:1020\u20131025","journal-title":"Eur Respir J"},{"key":"2039_CR39","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1183\/09031936.94.07071275","volume":"7","author":"D Honeybourne","year":"1994","unstructured":"Honeybourne D, Kees F, Andrews JM, Baldwin D, Wise R (1994) The levels of clarithromycin and its 14-hydroxy metabolite in the lung. Eur Respir J 7:1275\u20131280","journal-title":"Eur Respir J"},{"key":"2039_CR40","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1016\/j.celrep.2012.02.007","volume":"1","author":"Y Kurebayashi","year":"2012","unstructured":"Kurebayashi Y, Nagai S, Ikejiri A, Ohtani M, Ichiyama K, Baba Y, Yamada T, Egami S, Hoshii T, Hirao A, Matsuda S, Koyasu S (2012) PI3K-Akt-mTORC1-S6K1\/2 axis controls Th17 differentiation by regulating gfi1 expression and nuclear translocation of ROR\u03b3. Cell Rep 1:360\u2013373","journal-title":"Cell Rep"},{"key":"2039_CR41","doi-asserted-by":"publisher","first-page":"L75","DOI":"10.1152\/ajplung.00093.2005","volume":"290","author":"M Shinkai","year":"2006","unstructured":"Shinkai M, Foster GH, Rubin BK (2006) Macrolide antibiotics modulate ERK phosphorylation and IL-8 and GM-CSF production by human bronchial epithelial cells. Am J Physiol - Lung Cell Mol Physiol 290:L75\u2013L85","journal-title":"Am J Physiol - Lung Cell Mol Physiol"},{"key":"2039_CR42","doi-asserted-by":"publisher","first-page":"4397","DOI":"10.1007\/s00018-016-2297-8","volume":"73","author":"D Lake","year":"2016","unstructured":"Lake D, Corr\u00eaa SAL, M\u00fcller J (2016) Negative feedback regulation of the ERK1\/2 MAPK pathway. Cell Mol Life Sci 73:4397\u20134413","journal-title":"Cell Mol Life Sci"},{"doi-asserted-by":"publisher","unstructured":"Nett IR, Mulas C, Gatto L et al (2018) Negative feedback via RSK modulates Erk-dependent progression from na\u00efve pluripotency. EMBO Rep 19. https:\/\/doi.org\/10.15252\/embr.201745642","key":"2039_CR43","DOI":"10.15252\/embr.201745642"},{"key":"2039_CR44","doi-asserted-by":"publisher","first-page":"e15425","DOI":"10.1371\/journal.pone.0015425","volume":"5","author":"AJ Marko","year":"2010","unstructured":"Marko AJ, Miller RA, Kelman A, Frauwirth KA (2010) Induction of glucose metabolism in stimulated T lymphocytes is regulated by mitogen-activated protein kinase signaling. PLoS One 5:e15425","journal-title":"PLoS One"},{"key":"2039_CR45","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/s41419-017-0044-1","volume":"9","author":"MN Serasinghe","year":"2018","unstructured":"Serasinghe MN, Gelles JD, Li K, Zhao L, Abbate F, Syku M, Mohammed JN, Badal B, Rangel CA, Hoehn KL, Celebi JT, Chipuk JE (2018) Dual suppression of inner and outer mitochondrial membrane functions augments apoptotic responses to oncogenic MAPK inhibition. Cell Death Dis 9:29","journal-title":"Cell Death Dis"},{"key":"2039_CR46","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.coi.2019.05.011","volume":"59","author":"ME Snyder","year":"2019","unstructured":"Snyder ME, Farber DL (2019) Human lung tissue resident memory T cells in health and disease. Curr Opin Immunol 59:101\u2013108","journal-title":"Curr Opin Immunol"},{"key":"2039_CR47","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1038\/mi.2015.128","volume":"9","author":"M Dudek","year":"2016","unstructured":"Dudek M, Puttur F, Arnold-Schrauf C, K\u00fchl AA, Holzmann B, Henriques-Normark B, Berod L, Sparwasser T (2016) Lung epithelium and myeloid cells cooperate to clear acute pneumococcal infection. Mucosal Immunol 9:1288\u20131302","journal-title":"Mucosal Immunol"},{"key":"2039_CR48","doi-asserted-by":"publisher","first-page":"2429","DOI":"10.4049\/jimmunol.1900980","volume":"204","author":"S Moy\u00e9","year":"2020","unstructured":"Moy\u00e9 S, Bormann T, Maus R, Sparwasser T, Sandrock I, Prinz I, Warnecke G, Welte T, Gauldie J, Kolb M, Maus UA (2020) Regulatory T cells limit Pneumococcus-induced exacerbation of lung fibrosis in mice. J Immunol 204:2429\u20132438","journal-title":"J Immunol"}],"container-title":["Journal of Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00109-021-02039-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00109-021-02039-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00109-021-02039-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,29]],"date-time":"2023-01-29T09:03:36Z","timestamp":1674983016000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00109-021-02039-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,17]]},"references-count":48,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["2039"],"URL":"https:\/\/doi.org\/10.1007\/s00109-021-02039-5","relation":{},"ISSN":["0946-2716","1432-1440"],"issn-type":[{"type":"print","value":"0946-2716"},{"type":"electronic","value":"1432-1440"}],"subject":[],"published":{"date-parts":[[2021,2,17]]},"assertion":[{"value":"5 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 December 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 January 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 February 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"All animal experiments were conducted in accordance with the German animal protection law (TierSchG BGBl. I S. 1105; 25.05.1998) and were approved by the Lower Saxony Committee on the Ethics of Animal Experiments as well as the responsible state office (Lower Saxony State Office of Consumer Protection and Food Safety) under the permit number 33.19-42502-04-17\/2688.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code availability"}}]}}