{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T03:01:17Z","timestamp":1774666877725,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T00:00:00Z","timestamp":1674604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund (FWF) Doctoral Program of Excellence HOROS","doi-asserted-by":"publisher","award":["HOROS W-1253"],"award-info":[{"award-number":["HOROS W-1253"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund (FWF) Doctoral Program of Excellence HOROS","doi-asserted-by":"publisher","award":["F.17608"],"award-info":[{"award-number":["F.17608"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Land Tirol","award":["HOROS W-1253"],"award-info":[{"award-number":["HOROS W-1253"]}]},{"name":"Land Tirol","award":["F.17608"],"award-info":[{"award-number":["F.17608"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>Background: Mucormycetes, a heterogeneous group of fungi, induce a life-threatening disease called mucormycosis. Immune deficiencies represent a major risk factor; hence, we wanted to illuminate the role of complement and platelets in the defense against mucormycetes. Methods: Rhizopus arrhizus (Ra), Rhizopus microsporus (Rm), Lichtheimia ramosa (Lr), Lichtheimia corymbifera (Lc), Rhizomucor pusillus (Rmp), and Mucor circinelloides (Mc) spores were opsonized with human and mouse serum, and C1q, C3c, and terminal complement complex (C5b-9) deposition was measured. Additionally, thrombocytopenic, C3-deficient, or C6-deficient mice were intravenously infected with selected isolates. Survival and immunological parameters were monitored, and fungal burden was determined and compared to that of immunocompetent and neutropenic mice. Results: In vitro experiments showed significant differences in complement deposition between mucormycetes. Mc isolates bound up to threefold more human C5b-9 than other mucormycetes. Lr, Lc, and Mc bound high levels of murine C3c, whereas human C3c deposition was reduced on Mc compared to Lr and Lc. Murine C3c deposition negatively correlated with virulence. Complement deficiencies and neutropenia, but not thrombocytopenia, were shown to be a risk factor for a lethal outcome. Conclusion: Complement deposition varies between mucormycetes. Additionally, we demonstrated that complement and neutrophilic granulocytes, but not platelets, play an important role in a murine model of disseminated mucormycosis.<\/jats:p>","DOI":"10.3390\/jof9020162","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T04:54:41Z","timestamp":1674622481000},"page":"162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Complement, but Not Platelets, Plays a Pivotal Role in the Outcome of Mucormycosis In Vivo"],"prefix":"10.3390","volume":"9","author":[{"given":"Verena","family":"Harpf","sequence":"first","affiliation":[{"name":"Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria"},{"name":"Christian Doppler Laboratory for Invasive Fungal Infections, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7574-7868","authenticated-orcid":false,"given":"G\u00fcnter","family":"Rambach","sequence":"additional","affiliation":[{"name":"Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria"},{"name":"Christian Doppler Laboratory for Invasive Fungal Infections, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia","family":"Parth","sequence":"additional","affiliation":[{"name":"Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria"},{"name":"Christian Doppler Laboratory for Invasive Fungal Infections, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Neurauter","sequence":"additional","affiliation":[{"name":"Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria"},{"name":"Christian Doppler Laboratory for Invasive Fungal Infections, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verena","family":"Fleischer","sequence":"additional","affiliation":[{"name":"Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria"},{"name":"Christian Doppler Laboratory for Invasive Fungal Infections, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9073-2886","authenticated-orcid":false,"given":"Michaela","family":"Lackner","sequence":"additional","affiliation":[{"name":"Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2946-7785","authenticated-orcid":false,"given":"Cornelia","family":"Lass-Fl\u00f6rl","sequence":"additional","affiliation":[{"name":"Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6804-442X","authenticated-orcid":false,"given":"Reinhard","family":"W\u00fcrzner","sequence":"additional","affiliation":[{"name":"Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cornelia","family":"Speth","sequence":"additional","affiliation":[{"name":"Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria"},{"name":"Christian Doppler Laboratory for Invasive Fungal Infections, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/1469-0691.12566","article-title":"Mucormycosis\u2014From the pathogens to the disease","volume":"20","author":"Binder","year":"2014","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_2","first-page":"765","article-title":"Outbreaks of Mucorales and the Species Involved","volume":"185","author":"Walther","year":"2020","journal-title":"Mycopathologia"},{"key":"ref_3","first-page":"219","article-title":"Immunopathogenesis of invasive mould infections","volume":"31","year":"2014","journal-title":"Rev. Iberoam. Micol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1111\/j.1469-0691.2010.03456.x","article-title":"Zygomycosis in Europe: Analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007","volume":"17","author":"Skiada","year":"2011","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Prakash, H., and Chakrabarti, A. (2021). Epidemiology of Mucormycosis in India. Microorganisms, 9.","DOI":"10.3390\/microorganisms9030523"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1128\/CMR.18.3.556-569.2005","article-title":"Novel perspectives on mucormycosis: Pathophysiology, presentation, and management","volume":"18","author":"Spellberg","year":"2005","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Baldin, C., and Ibrahim, A.S. (2017). Molecular mechanisms of mucormycosis-The bitter and the sweet. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006408"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"John, T.M., Jacob, C.N., and Kontoyiannis, D.P. (2021). When Uncontrolled Diabetes Mellitus and Severe COVID-19 Converge: The Perfect Storm for Mucormycosis. J. Fungi, 7.","DOI":"10.3390\/jof7040298"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/mmy\/myx101","article-title":"Challenges in the diagnosis and treatment of mucormycosis","volume":"56","author":"Skiada","year":"2018","journal-title":"Med. Mycol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"15898","DOI":"10.1038\/s41598-017-16123-9","article-title":"Intrinsic short-tailed azole resistance in mucormycetes is due to an evolutionary conserved aminoacid substitution of the lanosterol 14alpha-demethylase","volume":"7","author":"Caramalho","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.fbr.2016.11.002","article-title":"Mucor: A Janus-faced fungal genus with human health impact and industrial applications","volume":"31","author":"Nodet","year":"2017","journal-title":"Fungal. Biology. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.pharmthera.2016.11.014","article-title":"Complement: A primer for the coming therapeutic revolution","volume":"172","author":"Barnum","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"46","DOI":"10.3390\/biom2010046","article-title":"Factor h: A complement regulator in health and disease, and a mediator of cellular interactions","volume":"2","author":"Kopp","year":"2012","journal-title":"Biomolecules"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1159\/000136316","article-title":"Complement: An efficient sword of innate immunity","volume":"15","author":"Rambach","year":"2008","journal-title":"Contrib. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1161\/CIRCRESAHA.121.319821","article-title":"Platelet and Megakaryocyte Roles in Innate and Adaptive Immunity","volume":"130","author":"Koupenova","year":"2022","journal-title":"Circ. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.3389\/fimmu.2019.01590","article-title":"The Human Platelet as an Innate Immune Cell: Interactions Between Activated Platelets and the Complement System","volume":"10","author":"Eriksson","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.chom.2016.05.023","article-title":"Dual-Track Clearance of Circulating Bacteria Balances Rapid Restoration of Blood Sterility with Induction of Adaptive Immunity","volume":"20","author":"Broadley","year":"2016","journal-title":"Cell Host. Microbe."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1055\/s-0038-1676349","article-title":"Anaphylatoxin Receptor C3aR Contributes to Platelet Function, Thrombus Formation and In Vivo Haemostasis","volume":"119","author":"Sauter","year":"2019","journal-title":"Thromb. Haemost."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3352","DOI":"10.1038\/s41467-021-23499-w","article-title":"The C5a\/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets","volume":"12","author":"Nording","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2880","DOI":"10.1182\/blood.V78.11.2880.2880","article-title":"Participation of protein kinases in complement C5b-9-induced shedding of platelet plasma membrane vesicles","volume":"78","author":"Wiedmer","year":"1991","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1086\/605607","article-title":"Potential antifungal effects of human platelets against zygomycetes in vitro","volume":"200","author":"Perkhofer","year":"2009","journal-title":"J. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1093\/mmy\/myy042","article-title":"Galleria mellonella as a model system to study virulence potential of mucormycetes and evaluation of antifungal treatment","volume":"57","author":"Maurer","year":"2019","journal-title":"Med. Mycol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/j.1432-1033.1985.tb08671.x","article-title":"Strain-dependent variation in ribosomal DNA arrangement in Absidia glauca","volume":"146","author":"Wostemeyer","year":"1985","journal-title":"Eur. J. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.rinim.2015.12.001","article-title":"Ly6G-mediated depletion of neutrophils is dependent on macrophages","volume":"6","author":"Bruhn","year":"2016","journal-title":"Results Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1179\/his.2000.23.4.341","article-title":"A Combined Hematoxylin and EosinIMethnamine Silver Stain for the Histological Diagnosis of Fungi in Tissue Sections","volume":"23","author":"Lamps","year":"2013","journal-title":"J. Histotechnol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Rambach, G., Fleischer, V., Harpf, V., Lackner, M., Meinitzer, A., Maier, H., Engesser, J., Lass-Florl, C., and Speth, C. (2020). Comparative immunopathogenesis in a murine model of inhalative infection with the mucormycetes Lichtheimia corymbifera and Rhizopus arrhizus. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0234063"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1111\/1469-0691.12563","article-title":"Epidemiology of mucormycosis in Europe","volume":"20","author":"Petrikkos","year":"2014","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"278","DOI":"10.3109\/13693780903096669","article-title":"Spores of Mucor ramosissimus, Mucor plumbeus and Mucor circinelloides and their ability to activate human complement system in vitro","volume":"48","author":"Granja","year":"2010","journal-title":"Med. Mycol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e00653-19","DOI":"10.1128\/AAC.00653-19","article-title":"A Revised Species Concept for Opportunistic Mucor Species Reveals Species-Specific Antifungal Susceptibility Profiles","volume":"63","author":"Wagner","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Prakash, H., and Chakrabarti, A. (2019). Global Epidemiology of Mucormycosis. J. Fungi, 5.","DOI":"10.3390\/jof5010026"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3046","DOI":"10.3389\/fimmu.2018.03046","article-title":"Pentraxins in Complement Activation and Regulation","volume":"9","author":"Ma","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/nature01195","article-title":"Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response","volume":"420","author":"Garlanda","year":"2002","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5170","DOI":"10.1182\/blood-2009-12-258376","article-title":"Role of complement and Fc{gamma} receptors in the protective activity of the long pentraxin PTX3 against Aspergillus fumigatus","volume":"116","author":"Moalli","year":"2010","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.jconrel.2021.08.048","article-title":"Complement opsonization of nanoparticles: Differences between humans and preclinical species","volume":"338","author":"Li","year":"2021","journal-title":"J. Control Release"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1093\/infdis\/jis743","article-title":"Aspergillus fumigatus Activates Thrombocytes by Secretion of Soluble Compounds","volume":"207","author":"Speth","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1160\/TH14-01-0074","article-title":"Platelet immunology in fungal infections","volume":"112","author":"Speth","year":"2014","journal-title":"Thromb. Haemost."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1093\/infdis\/jiv191","article-title":"Identification of Aspergillus fumigatus Surface Components That Mediate Interaction of Conidia and Hyphae with Human Platelets","volume":"212","author":"Rambach","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Tischler, B.Y., Tosini, N.L., Cramer, R.A., and Hohl, T.M. (2020). Platelets are critical for survival and tissue integrity during murine pulmonary Aspergillus fumigatus infection. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008544"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1097\/MOT.0b013e3283425365","article-title":"Platelets: Versatile modifiers of innate and adaptive immune responses to transplants","volume":"16","author":"Baldwin","year":"2011","journal-title":"Curr. Opin. Organ. Transplant."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/nri2956","article-title":"Platelets and the immune continuum","volume":"11","author":"Semple","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/ni.1923","article-title":"Complement: A key system for immune surveillance and homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_42","first-page":"1","article-title":"Spores and Yeasts of Mucor Polymorphosporus and their ability to Activate Human Complement System in vitro","volume":"7","author":"Granja","year":"2016","journal-title":"Arch. Clin. Microbiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6921","DOI":"10.4049\/jimmunol.173.11.6921","article-title":"Platelet-activating factor and kinin-dependent vascular leakage as a novel functional activity of the soluble terminal complement complex","volume":"173","author":"Bossi","year":"2004","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1210\/er.2014-1099","article-title":"Role of complement and complement regulatory proteins in the complications of diabetes","volume":"36","author":"Ghosh","year":"2015","journal-title":"Endocr. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"10587","DOI":"10.1038\/ncomms10587","article-title":"Structural basis of complement membrane attack complex formation","volume":"7","author":"Serna","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"375","DOI":"10.5858\/2001-125-0375-HFOZ","article-title":"Histologic features of zygomycosis: Emphasis on perineural invasion and fungal morphology","volume":"125","author":"Frater","year":"2001","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1111\/1462-2920.12601","article-title":"Deciphering the uniqueness of Mucoromycotina cell walls by combining biochemical and phylogenomic approaches","volume":"17","author":"Melida","year":"2015","journal-title":"Environ. Microbiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1099\/00221287-30-3-401","article-title":"Fine structure of vegetative hyphae of Rhizopus","volume":"30","author":"Hawker","year":"1963","journal-title":"J. Gen. Microbiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1007\/BF00412841","article-title":"Electron microscopy of spore germination and cell wall formation in Mucor rouxii","volume":"63","author":"Nelson","year":"1968","journal-title":"Arch. Mikrobiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1128\/EC.00109-08","article-title":"Contribution of galactofuranose to the virulence of the opportunistic pathogen Aspergillus fumigatus","volume":"7","author":"Schmalhorst","year":"2008","journal-title":"Eukaryot. Cell"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Cron, R.Q., and Begrens, E.M. (2019). Cytokine Storm Syndrome, Springer International Publishing. [1st ed.].","DOI":"10.1007\/978-3-030-22094-5"}],"container-title":["Journal of Fungi"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2309-608X\/9\/2\/162\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:15:10Z","timestamp":1760120110000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2309-608X\/9\/2\/162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,25]]},"references-count":51,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["jof9020162"],"URL":"https:\/\/doi.org\/10.3390\/jof9020162","relation":{},"ISSN":["2309-608X"],"issn-type":[{"value":"2309-608X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,25]]}}}