{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:02:16Z","timestamp":1790013736051,"version":"4.0.1"},"reference-count":51,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T00:00:00Z","timestamp":1624579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012283","name":"Chiayi Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CMRPG6J0231-0232"],"award-info":[{"award-number":["CMRPG6J0231-0232"]}],"id":[{"id":"10.13039\/501100012283","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 109-2314-B-182A-024-MY3"],"award-info":[{"award-number":["MOST 109-2314-B-182A-024-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Periprosthetic joint infections (PJIs) caused by Staphylococcus aureus infection are difficult to treat due to antibiotic resistance. It is known that the biofilms from methicillin-resistant S. aureus (MRSA) promote expansion of myeloid-derived suppressor cells (MDSCs) to suppress T-cell proliferation and benefit bacterial infections. This study finds that GMI, a fungal immunomodulatory peptide isolated from Ganoderma microsporum, suppresses MDSC expansion to promote the proliferation of cytotoxic T cells. The enhancement is likely attributed to increased expression of IL-6 and TNF-\u03b1 and reduction in ROS expression. Similar beneficial effects of GMI on the suppression of MDSC expansion and IL-6 expression are also observed in the whole blood and reduces the accumulation of MDSCs in the infected bone region in a mouse PJI infection model. This study shows that GMI is potentially useful for treating S. aureus-induced PJIs.<\/jats:p>","DOI":"10.3390\/ijms22136854","type":"journal-article","created":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T11:07:40Z","timestamp":1624619260000},"page":"6854","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["GMI, an Immunomodulatory Peptide from Ganoderma microsporum, Restrains Periprosthetic Joint Infections via Modulating the Functions of Myeloid-Derived Suppressor Cells and Effector T Cells"],"prefix":"10.3390","volume":"22","author":[{"given":"Kuo-Ti","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Puzi 61363, Taiwan"},{"name":"College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiun-Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Puzi 61363, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5507-8396","authenticated-orcid":false,"given":"Liang-Tseng","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Puzi 61363, Taiwan"},{"name":"College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-An","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Puzi 61363, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Hsiu","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Puzi 61363, Taiwan"},{"name":"College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiang-Wen","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Basic Medical Sciences and Recurrent Diseases, Health Promotion Research Center, Department of Nursing, Chang Gung University of Science and Technology, Puzi 61363, Taiwan"},{"name":"Research Center for Industry of Human Ecology, Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan"},{"name":"Department of Rehabilitation, Chang Gung Memorial Hospital, Puzi 61363, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6492-0346","authenticated-orcid":false,"given":"Pey-Jium","family":"Chang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan"},{"name":"Department of Nephrology, Chang-Gung Memorial Hospital, Chiayi 61363, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung-Yu","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan"},{"name":"Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan"},{"name":"Department of Nursing, Chiayi Campus, Chang Gung University of Science and Technology, Chiayi 61363, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s12178-018-9501-4","article-title":"Staphylococcus aureus Evasion of Host Immunity in the Setting of Prosthetic Joint Infection: Biofilm and Beyond","volume":"11","author":"Ricciardi","year":"2018","journal-title":"Curr. Rev. Musculoskelet. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"147","DOI":"10.3109\/17453674.2014.966290","article-title":"The role of microbial biofilms in prosthetic joint infections","volume":"86","author":"Gbejuade","year":"2015","journal-title":"Acta Orthop."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.5507\/bp.2003.004","article-title":"Pathogenesis of prosthesis-related infection","volume":"147","author":"Gallo","year":"2003","journal-title":"Biomed. Pap."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S177","DOI":"10.1097\/PRS.0b013e3182001f0f","article-title":"Treating osteomyelitis: Antibiotics and surgery","volume":"127","author":"Rao","year":"2011","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1007\/s12178-018-9504-1","article-title":"Risk Factors and Treatment Options for Failure of a Two-Stage Exchange","volume":"11","author":"Fagotti","year":"2018","journal-title":"Curr. Rev. Musculoskelet. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1469-0691.2010.03244.x","article-title":"Outcome and predictors of treatment failure in early post-surgical prosthetic joint infections due to Staphylococcus aureus treated with debridement","volume":"17","author":"Vilchez","year":"2011","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.2106\/JBJS.16.01103","article-title":"Irrigation and Debridement with Component Retention for Acute Infection After Hip Arthroplasty: Improved Results with Contemporary Management","volume":"99","author":"Bryan","year":"2017","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/j.knee.2017.05.016","article-title":"Success rates, characteristics, and costs of articulating antibiotic spacers for total knee periprosthetic joint infection","volume":"24","author":"Nodzo","year":"2017","journal-title":"Knee"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"61.e1","DOI":"10.1016\/j.arth.2012.02.022","article-title":"Economic burden of periprosthetic joint infection in the United States","volume":"27","author":"Kurtz","year":"2012","journal-title":"J. Arthroplast."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1111\/j.1469-0691.2011.03758.x","article-title":"Cost analysis of debridement and retention for management of prosthetic joint infection","volume":"19","author":"Peel","year":"2013","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"186","DOI":"10.5539\/jmbr.v7n1p186","article-title":"Identification of DNA gyrase Subunit a Mutations Associated with Ciprofloxacin Resistance in Staphylococcus aureus Isolated from Nasal Infection in Kurdistan, Iran","volume":"7","author":"Darbani","year":"2017","journal-title":"J. Mol. Biol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/j.apjtm.2017.10.003","article-title":"Antimicrobial resistance and underlying mechanisms in Staphylococcus aureus isolates","volume":"10","author":"Yilmaz","year":"2017","journal-title":"Asian Pac. J. Trop. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1093\/femsre\/fux007","article-title":"Antibiotic resistance in Staphylococcus aureus: Current status and future prospects","volume":"41","author":"Foster","year":"2017","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Drago, L., De Vecchi, E., Nicola, L., and Gismondo, M.R. (2007). In vitro evaluation of antibiotics\u2019 combinations for empirical therapy of suspected methicillin resistant Staphylococcus aureus severe respiratory infections. BMC Infect. Dis., 7.","DOI":"10.1186\/1471-2334-7-111"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/S0140-6736(06)68853-3","article-title":"Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat","volume":"368","author":"Grundmann","year":"2006","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1078\/1438-4221-00192","article-title":"Molecular genetics of methicillin-resistant Staphylococcus aureus","volume":"292","author":"Hiramatsu","year":"2002","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1111\/apm.12673","article-title":"Antibiotic treatment of biofilm infections","volume":"125","author":"Ciofu","year":"2017","journal-title":"APMIS"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nrmicro2415","article-title":"The biofilm matrix","volume":"8","author":"Flemming","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1159\/000489830","article-title":"Myeloid-Derived Suppressor Cells in Infection: A General Overview","volume":"10","author":"Medina","year":"2018","journal-title":"J. Innate Immun."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Peng, K.T., Hsieh, C.C., Huang, T.Y., Chen, P.C., Shih, H.N., Lee, M.S., and Chang, P.J. (2017). Staphylococcus aureus biofilm elicits the expansion, activation and polarization of myeloid-derived suppressor cells in vivo and in vitro. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183271"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1108\/00346651111170905","article-title":"Functional foods: An empirical study on perceived health benefits in relation to pre-purchase intentions","volume":"41","author":"Labrecque","year":"2011","journal-title":"Nutr. Food Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhao, S., Gao, Q., Rong, C., Wang, S., Zhao, Z., Liu, Y., and Xu, J. (2020). Immunomodulatory Effects of Edible and Medicinal Mushrooms and Their Bioactive Immunoregulatory Products. J. Fungi, 6.","DOI":"10.3390\/jof6040269"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"365","DOI":"10.3109\/07388551.2010.543967","article-title":"Recent status and prospects of the fungal immunomodulatory protein family","volume":"31","author":"Li","year":"2011","journal-title":"Crit. Rev. Biotechnol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"132","DOI":"10.3389\/fnut.2020.00132","article-title":"Current Understanding of the Structure and Function of Fungal Immunomodulatory Proteins","volume":"7","author":"Liu","year":"2020","journal-title":"Front. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.antiviral.2014.08.006","article-title":"Alleviation of respiratory syncytial virus replication and inflammation by fungal immunomodulatory protein FIP-fve from Flammulina velutipes","volume":"110","author":"Chang","year":"2014","journal-title":"Antivir. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chen, W.Y., Chang, C.Y., Li, J.R., Wang, J.D., Wu, C.C., Kuan, Y.H., Liao, S.L., Wang, W.Y., and Chen, C.J. (2018). Anti-inflammatory and Neuroprotective Effects of Fungal Immunomodulatory Protein Involving Microglial Inhibition. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113678"},{"key":"ref_27","unstructured":"Wu, M.-y., Hsu, M.-F., Huang, C.-S., Fu, H.-Y., Wang, A., Hseu, R.-S., Huang, C.-T., and Yang, C.-S. (2007, January 2\u20133). A 2.0 \u00c5 Structure of the Fungal Immunomodulatory Protein GMI from Ganoderma microsporum. Proceedings of the 2nd Asia-Oceania Forum for Synchrotron Radiation Research, Hsinchu, Taiwan."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1111\/j.1476-5381.2012.02073.x","article-title":"Inhibition of lysosome degradation on autophagosome formation and responses to GMI, an immunomodulatory protein from Ganoderma microsporum","volume":"167","author":"Hsin","year":"2012","journal-title":"Br. J. Pharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"873","DOI":"10.4161\/auto.7.8.15698","article-title":"GMI, an immunomodulatory protein from Ganoderma microsporum, induces autophagy in non-small cell lung cancer cells","volume":"7","author":"Hsin","year":"2011","journal-title":"Autophagy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"12014","DOI":"10.1021\/jf103068w","article-title":"GMI, a Ganoderma immunomodulatory protein, down-regulates tumor necrosis factor alpha-induced expression of matrix metalloproteinase 9 via NF-\u03baB pathway in human alveolar epithelial A549 cells","volume":"58","author":"Lin","year":"2010","journal-title":"J. Agric. Food Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1016\/j.procbio.2010.06.006","article-title":"A new immunomodulatory protein from Ganoderma microsporum inhibits epidermal growth factor mediated migration and invasion in A549 lung cancer cells","volume":"45","author":"Lin","year":"2010","journal-title":"Process. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/978-1-60761-411-1_4","article-title":"Identification of ROS using oxidized DCFDA and flow-cytometry","volume":"594","author":"Eruslanov","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1476-9255-11-17","article-title":"Early effects of Staphylococcus aureus biofilm secreted products on inflammatory responses of human epithelial keratinocytes","volume":"11","author":"Tankersley","year":"2014","journal-title":"J. Inflamm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.3389\/fimmu.2018.02499","article-title":"Reactive Oxygen Species as Regulators of MDSC-Mediated Immune Suppression","volume":"9","author":"Ohl","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.clim.2008.08.018","article-title":"The effects of IL-6 on CD4 T cell responses","volume":"130","author":"Dienz","year":"2009","journal-title":"Clin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"469","DOI":"10.2147\/IJN.S191504","article-title":"Curcumin nanoparticles are a promising anti-bacterial and anti-inflammatory agent for treating periprosthetic joint infections","volume":"14","author":"Peng","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.immuni.2014.10.009","article-title":"Cutaneous innate immune sensing of Toll-like receptor 2\u20136 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells","volume":"41","author":"Skabytska","year":"2014","journal-title":"Immunity"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1189\/jlb.4VMA0315-125RR","article-title":"Interleukin-10 production by myeloid-derived suppressor cells contributes to bacterial persistence during Staphylococcus aureus orthopedic biofilm infection","volume":"98","author":"Heim","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3861","DOI":"10.4049\/jimmunol.1402689","article-title":"IL-12 promotes myeloid-derived suppressor cell recruitment and bacterial persistence during Staphylococcus aureus orthopedic implant infection","volume":"194","author":"Heim","year":"2015","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.3389\/fimmu.2017.01895","article-title":"Monocytic Myeloid-Derived Suppressor Cells in Chronic Infections","volume":"8","author":"Dorhoi","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"53","DOI":"10.2174\/1874285801711010053","article-title":"Understanding the Mechanism of Bacterial Biofilms Resistance to Antimicrobial Agents","volume":"11","author":"Singh","year":"2017","journal-title":"Open Microbiol. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"153384","DOI":"10.1016\/j.phymed.2020.153384","article-title":"Functional proteomic analysis reveals that fungal immunomodulatory protein reduced expressions of heat shock proteins correlates to apoptosis in lung cancer cells","volume":"80","author":"Lin","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1006\/cimm.1993.1182","article-title":"Ling Zhi-8: A novel T cell mitogen induces cytokine production and upregulation of ICAM-1 expression","volume":"150","author":"Kino","year":"1993","journal-title":"Cell Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/jcp.21144","article-title":"Reishi immuno-modulation protein induces interleukin-2 expression via protein kinase-dependent signaling pathways within human T cells","volume":"215","author":"Hsu","year":"2008","journal-title":"J. Cell Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4873","DOI":"10.4049\/jimmunol.1501362","article-title":"Polarization of Monocytic Myeloid-Derived Suppressor Cells by Hepatitis B Surface Antigen Is Mediated via ERK\/IL-6\/STAT3 Signaling Feedback and Restrains the Activation of T Cells in Chronic Hepatitis B Virus Infection","volume":"195","author":"Fang","year":"2015","journal-title":"J. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1093\/infdis\/jit469","article-title":"HIV type 1 gp120-induced expansion of myeloid derived suppressor cells is dependent on interleukin 6 and suppresses immunity","volume":"209","author":"Garg","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4761","DOI":"10.4049\/jimmunol.174.8.4761","article-title":"IL-6 increases primed cell expansion and survival","volume":"174","author":"Rochman","year":"2005","journal-title":"J. Immunol"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1002\/eji.200425237","article-title":"Interleukin-6 is a direct mediator of T cell migration","volume":"34","author":"Weissenbach","year":"2004","journal-title":"Eur. J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S0161-5890(02)00210-9","article-title":"The two faces of IL-6 on Th1\/Th2 differentiation","volume":"39","author":"Diehl","year":"2002","journal-title":"Mol. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e1204","DOI":"10.1002\/cti2.1204","article-title":"Increased IL-10-producing regulatory T cells are characteristic of severe cases of COVID-19","volume":"9","author":"Neumann","year":"2020","journal-title":"Clin. Transl. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.cyto.2016.08.003","article-title":"TNF activity and T cells","volume":"101","author":"Mehta","year":"2018","journal-title":"Cytokine"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6854\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:24:13Z","timestamp":1760163853000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6854"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,25]]},"references-count":51,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22136854"],"URL":"https:\/\/doi.org\/10.3390\/ijms22136854","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,25]]}}}