Abstract
Purpose of Review
Mucormycosis is an opportunistic fungal infection associated with high mortality. Understanding the pathogenesis and the resultant pathology in various organs enables to improve early diagnosis and treatment options.
Recent Findings
An immunocompetent host with intact skin/mucosal barrier and innate immunity is usually resistant to the infection; however, natural disasters and trauma account for the disease in healthy hosts. Neutropenia, immunosuppression, hyperglycemia, ketoacidosis, and other factors impair host defenses and make increased serum iron available to the pathogen for its growth. The fungus has special iron assimilation mechanisms. The cell wall composition and genetic alterations allow rapid growth in host environment and evade host defenses. Expression of CotH proteins on the spores and hyphae facilitates adhesion to the receptors on endothelial cells, angioinvasion, and dissemination. Elaboration of lytic enzymes and proteases along with mycotoxins augment fungal invasion. Rhinocerebral mucormycosis is the most common clinical form. The pathology hall mark in various organs is angioinvasion resulting in hemorrhage, infarction, and suppurative inflammation.
Summary
The host defenses and how the risk factors alter and impair the host’s ability to prevent the invasion of the fungus are reviewed. The virulence factors of the fungus to rapidly grow and disseminate in the host by evading recognition, suppressing immune response, manipulate the environment to derive nutrition, and cause disease are discussed.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
•• Baldin C, Ibrahim AS. Molecular mechanisms of mucormycosis-The bitter and the sweet. PLoS pathog. 2017;13(8):e1006408. https://doi.org/10.1371/journal.ppat.1006408 Excellent review on the host pathogen interactions in mucormycosis and how the altered host factors like hyperglycemia and ketoacidosis lead to expression of receptors on endothelial cells and ligands on the pathogen, resulting in adhesion, angioinvasion and dissemination of the fungus.
Tissot F, Agrawal S, Pagano L, Petrikkos G, Groll AH, Skiada A, et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017;102(3):433–44. https://doi.org/10.3324/haematol.2016.152900.
Dignani MC. Epidemiology of invasive fungal diseases on the basis of autopsy reports. F1000Prime Rep. 2014;6:81. Published 2014 Sep 4. https://doi.org/10.12703/P6-81.
Kontoyiannis DP, Lionakis MS, Lewis RE, Chamilos G, Healy M, Perego C, et al. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J Infect Dis. 2005;191(8):1350–60.
Chamilos G, Luna M, Lewis RE, Bodey GP, Chemaly R, Tarrand JJ, et al. Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989-2003). Haematologica. 2006;91(7):986–9.
Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41(5):634–53 Review.
Chakrabarti A, Das A, Mandal J, Shivaprakash MR, George VK, Tarai B, et al. The rising trend of invasive zygomycosis in patients with uncontrolled diabetes mellitus. Med Mycol. 2006;44(4):335–42.
Chakrabarti A, Singh R. The emerging epidemiology of mould infections in developing countries. Curr Opin Infect Dis. 2011;24(6):521–6. https://doi.org/10.1097/QCO.0b013e32834ab21e Review.
Skiada A, Pagano L, Groll A, Zimmerli S, Dupont B, Lagrou K, et al. European Confederation of Medical Mycology Working Group on Zygomycosis. 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. Clin Microbiol Infect. 2011;17(12):1859–67. https://doi.org/10.1111/j.1469-0691.2010.03456.x.
•• Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh TJ, Kontoyiannis DP. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis. 2012;54(Suppl 1):S23–34. https://doi.org/10.1093/cid/cir866 Review. Excellent review on the epidemiology, risk factors, mode of spread and clinical manifestations of mucormycosis.
Kwon-Chung KJ. Taxonomy of fungi causing mucormycosis and entomophthoramycosis (zygomycosis) and nomenclature of the disease: molecular mycologic perspectives. Clin Infect Dis. 2012;54(Suppl 1):S8–S15. https://doi.org/10.1093/cid/cir864 Review.
• Park HR, Voigt K. Interaction of Zygomycetes with innate immune cells reconsidered with respect to ecology, morphology, evolution and infection biology: a mini-review. Mycoses. 2014;57(Suppl 3):31–9. https://doi.org/10.1111/myc.12235 Review. A review on the molecular classification of Zygomycetes and the separation of Mucorales from other genera. The review focuses on the innate immunity of the host against infection by Mucorales .
Farmakiotis D, Kontoyiannis DP. Mucormycoses. Infect Dis Clin N Am. 2016;30(1):143–63. https://doi.org/10.1016/j.idc.2015.10.011 Review.
Spellberg B, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis:pathophysiology, presentation, and management. Clin Microbiol Rev. 2005;18(3):556–69 Review.
Sun HY, Singh N. Mucormycosis: its contemporary face and management strategies. Lancet Infect Dis. 2011;11(4):301–11. https://doi.org/10.1016/S1473-3099(10)70316-9 Review.
Neblett Fanfair R, Benedict K, Bos J, Bennett SD, Lo YC, Adebanjo T, et al. Necrotizing cutaneous mucormycosis after a tornado in Joplin, Missouri, in 2011. N Engl J Med. 2012;367(23):2214–25.
•• Petrikkos G, Tsioutis C. Recent Advances in the Pathogenesis of Mucormycoses. Clin Ther. 2018;(6):40, 894–902. https://doi.org/10.1016/j.clinthera.2018.03.009 Review. Excellent review on the recent developments in the pathogenesis of mucormycosis which have implications in therapeutic interventions. The role of phagocytes, platelets and NK cells in host defenses and the mechanisms of iron uptake, pathogen-endothelial interaction, angioinvasion and dissemination are discussed in detail.
Hood MI, Skaar EP. Nutritional immunity: transition metals at the pathogen-host interface. Nat Rev Microbiol. 2012;10(8):525–37. https://doi.org/10.1038/nrmicro2836 Review.
Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections. Lancet. 2003;362(9398):1828–38 Review.
Chamilos G, Lewis RE, Lamaris G, Walsh TJ, Kontoyiannis DP. Zygomycetes hyphae trigger an early, robust proinflammatory response in human polymorphonuclear neutrophils through toll-like receptor 2 induction but display relative resistance to oxidative damage. Antimicrob Agents Chemother. 2008;52(2):722–4.
Ibrahim AS, Spellberg B, Walsh TJ, Kontoyiannis DP. Pathogenesis of mucormycosis. Clin Infect Dis. 2012;54(Suppl 1):S16–22. https://doi.org/10.1093/cid/cir865 Review.
Roilides E, Kontoyiannis DP, Walsh TJ. Host defenses against zygomycetes. Clin Infect Dis. 2012;54(Suppl 1):S61–6. https://doi.org/10.1093/cid/cir869 Review.
• Ibrahim AS, Voelz K. The mucormycete-host interface. Curr Opin Microbiol. 2017;40:40–5. https://doi.org/10.1016/j.mib.2017.10.010 Review. This review discusses the host pathogen interactions with particular emphasis on host defenses and risk fators. The iron acquisition mechanisms of the pathogen are discussed.
Perkhofer S, Kainzner B, Kehrel BE, Dierich MP, Nussbaumer W, Lass-Flörl C. Potential antifungal effects of human platelets against zygomycetes in vitro. J Infect Dis. 2009;200(7):1176–9. https://doi.org/10.1086/605607.
Speth C, Rambach G, Lass-Flörl C. Platelet immunology in fungal infections. Thromb Haemost. 2014;112(4):632–9. https://doi.org/10.1160/TH14-01-0074 Review.
Schmidt S, Tramsen L, Perkhofer S, Lass-Flörl C, Hanisch M, Röger F, et al. Rhizopus oryzae hyphae are damaged by human natural killer (NK) cells, but suppress NK cell mediated immunity. Immunobiology. 2013;218(7):939–44. https://doi.org/10.1016/j.imbio.2012.10.013.
Lamaris GA, Ben-Ami R, Lewis RE, Chamilos G, Samonis G, Kontoyiannis DP. Increased virulence of Zygomycetes organisms following exposure to voriconazole: a study involving fly and murine models of zygomycosis. J Infect Dis. 2009;199(9):1399–406. https://doi.org/10.1086/597615.
Ma L-J, Ibrahim AS, Skory C, et al. Genomic analysis of the basal lineage fungus rhizopus oryzae reveals a whole-genome duplication. Madhani HD, ed. PLoS Genet. 2009;5:e1000549.
Lewis RE, Lortholary O, Spellberg B, Roilides E, Kontoyiannis DP, Walsh TJ. How does antifungal pharmacology differ for mucormycosis versus aspergillosis? Clin Infect Dis. 2012;54(Suppl 1):S67–72. https://doi.org/10.1093/cid/cir884.
•• Binder U, Maurer E, Lass-Flörl C. Mucormycosis--from the pathogens to the disease. Clin Microbiol Infect. 2014;20(Suppl 6):60–6. https://doi.org/10.1111/1469-0691.12566 Review. Excellent review on the virulence of Mucorales in causing disease. The taxonomic classification, virulence factors, angioinvasion mechanisms and iron acquisition from host are described in detail. The different clinical forms of the disease and their manifestations are discussed.
Alastruey-Izquierdo A, Hoffmann K, de Hoog GS, Rodriguez-Tudela JL, Voigt K, Bibashi E, et al. Species recognition and clinical relevance of the zygomycetous genus Lichtheimia (syn. Absidia pro parte, Mycocladus). J Clin Microbiol. 2010;48(6):2154–70. https://doi.org/10.1128/JCM.01744-09.
Morace G, Borghi E. Invasive mold infections: virulence and pathogenesis of mucorales. Int J Microbiol. 2012;2012:349278. https://doi.org/10.1155/2012/349278.
Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. Clin Microbiol Rev. 2000;13(2):236–301 Review.
Schoen C, Reichard U, Monod M, Kratzin HD, Rüchel R. Molecular cloning of an extracellular aspartic proteinase from Rhizopus microsporus and evidence for its expression during infection. Med Mycol. 2002;40(1):61–71.
Spreer A, Rüchel R, Reichard U. Characterization of an extracellular subtilisin protease of Rhizopus microsporus and evidence for its expression during invasive rhinoorbital mycosis. Med Mycol. 2006;44(8):723–31.
• Chibucos MC, Soliman S, Gebremariam T, Lee H, Daugherty S, Orvis J, et al. An integrated genomic and transcriptomic survey of mucormycosis-causing fungi. Nat Commun. 2016;7:12218. https://doi.org/10.1038/ncomms12218 A review based on experimental studies on the genetic basis of virulence factors. The article brings about correlation between the number of CotH protein on the pathogen species and frequency of clinical invasive disease.
Roilides E, Antachopoulos C, Simitsopoulou M. Pathogenesis and host defence against Mucorales: the role of cytokines and interaction with antifungal drugs. Mycoses. 2014;57(Suppl 3):40–7. https://doi.org/10.1111/myc.12236 Review.
Liu M, Spellberg B, Phan QT, Fu Y, Fu Y, Lee AS, et al. The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice. J Clin Invest. 2010;120(6):1914–24. https://doi.org/10.1172/JCI42164.
Liu Y, Shetty AC, Schwartz JA, Bradford LL, Xu W, Phan QT, et al. New signaling pathways govern the host response to C. albicans infection in various niches. Genome Res. 2015;25(5):679–89. https://doi.org/10.1101/gr.187427.114.
Kovalenko M, Rönnstrand L, Heldin CH, Loubtchenkov M, Gazit A, Levitzki A, et al. Phosphorylation site-specific inhibition of platelet-derived growth factor beta-receptor autophosphorylation by the receptor blocking tyrphostin AG1296. Biochemistry. 1997;36(21):6260–9.
Cantinieaux B, Janssens A, Boelaert JR, Lejeune M, Vermylen C, Kerrels V, et al. Ferritin-associated iron induces neutrophil dysfunction in hemosiderosis. J Lab Clin Med. 1999;133(4):353–61.
Shirazi F, Kontoyiannis DP, Ibrahim AS. Iron starvation induces apoptosis in Rhizopus oryzae in vitro. Virulence. 2015;6(2):121–6. https://doi.org/10.1080/21505594.2015.1009732.
Artis WM, Fountain JA, Delcher HK, Jones HE. A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability. Diabetes. 1982;31(12):1109–14.
• Liu M, Lin L, Gebremariam T, Luo G, Skory CD, French SW, et al. Fob1 and Fob2 Proteins Are Virulence Determinants of Rhizopus oryzae via Facilitating Iron Uptake from Ferrioxamine. PLoS Pathog. 2015;11(5):e1004842. https://doi.org/10.1371/journal.ppat.1004842 A very good review on how Rhizopus oryzae expresses receptors Fob 1 and Fob 2 to derive iron from feroxamine in patients treated with deferoxamine and transports iron intracellularly by iron permease FTR1.
Gebremariam T, Lin L, Liu M, Kontoyiannis DP, French S, Edwards JE Jr, et al. Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis. J Clin Invest. 2016;126(6):2280–94. https://doi.org/10.1172/JCI82744.
de Locht M, Boelaert JR, Schneider YJ. Iron uptake from ferrioxamine and from ferrirhizoferrin by germinating spores of Rhizopus microsporus. Biochem Pharmacol. 1994;47(10):1843–50.
Ibrahim AS, Gebremariam T, Lin L, Luo G, Husseiny MI, Skory CD, et al. The high affinity iron permease is a key virulence factor required for Rhizopus oryzae pathogenesis. Mol Microbiol. 2010;77(3):587–604. https://doi.org/10.1111/j.1365-2958.2010.07234.x.
Calo S, Shertz-Wall C, Lee SC, Bastidas RJ, Nicolás FE, Granek JA, et al. Antifungal drug resistance evoked via RNAi-dependent epimutations. Nature. 2014;513(7519):555–8. https://doi.org/10.1038/nature13575.
Lee SC, Li A, Calo S, Inoue M, Tonthat NK, Bain JM, et al. Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides. Mol Microbiol. 2015;97(5):844–65. https://doi.org/10.1111/mmi.13071.
Lee SC, Li A, Calo S, Heitman J. Calcineurin plays key roles in the dimorphic transition and virulence of the human pathogenic zygomycete Mucor circinelloides. Andrianopoulos A, ed. PLoS Pathog. 2013;9:e1003625.
•• Calo S, Nicolás FE, Lee SC, Vila A, Cervantes M, Torres-Martinez S, et al. A non-canonical RNA degradation pathway suppresses RNAi-dependent epimutations in the human fungal pathogen Mucor circinelloides. PLoS Genet. 2017;13(3):e1006686. https://doi.org/10.1371/journal.pgen.1006686 An excellent paper on the epigenetic pathway involving RNAi for antifungal resistance.
Chang SS, Zhang Z, Liu Y. RNA interference pathways in fungi: mechanisms and functions. Annu Rev Microbiol. 2012;66:305–23. https://doi.org/10.1146/annurev-micro-092611-150138 Review.
Nicolás FE, Ruiz-Vázquez RM. Functional diversity of RNAi-associated sRNAs in fungi. Int J Mol Sci. 2013;14(8):15348–60. https://doi.org/10.3390/ijms140815348.Review.
Trieu TA, Calo S, Nicolás FE, Vila A, Moxon S, Dalmay T, et al. A non-canonical RNA silencing pathway promotes mRNA degradation in basal Fungi. PLoS Genet. 2015;11(4):e1005168. https://doi.org/10.1371/journal.pgen.1005168.
Cornely OA, Arikan-Akdagli S, Dannaoui E, Groll AH, Lagrou K, Chakrabarti A, et al. European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study Group; European Confederation of Medical Mycology. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. 2014;20(Suppl 3):5–26. https://doi.org/10.1111/1469-0691.12371.
Frater JL, Hall GS, Procop GW. Histologic features of zygomycosis: emphasis on perineural invasion and fungal morphology. Arch Pathol Lab Med. 2001;125(3):375–8.
Sravani T, Uppin SG, Uppin MS, Sundaram C. Rhinocerebral mucormycosis: pathology revisited with emphasis on perineural spread. Neurol India. 2014;62:383–6. https://doi.org/10.4103/0028-3886.141252.
Sundaram C, Mahadevan A, Laxmi V, Yasha TC, Santosh V, Murthy JM, et al. Cerebral zygomycosis. Mycoses. 2005;48(6):396–407.
Sundaram C, Umabala P, Laxmi V, Purohit AK, Prasad VS, Panigrahi M, et al. Pathology of fungal infections of the central nervous system: 17 years' experience from Southern India. Histopathology. 2006;49(4):396–405.
Shankar SK, Mahadevan A, Sundaram C, Sarkar C, Chacko G, Lanjewar DN, et al. Pathobiology of fungal infections of the central nervous system with special reference to the Indian scenario. Neurol India. 2007;55(3):198–215 Review.
Das A, Bal A, Chakrabarti A, Panda N, Joshi K. Spectrum of fungal rhinosinusitis; histopathologist's perspective. Histopathology. 2009;54(7):854–9. https://doi.org/10.1111/j.1365-2559.2009.03309.x.
Challa S, Uppin SG, Hanumanthu S, Panigrahi MK, Purohit AK, Sattaluri S, et al. Fungal rhinosinusitis: a clinicopathological study from South India. Eur Arch Otorhinolaryngol. 2010;267(8):1239–45. https://doi.org/10.1007/s00405-010-1202-6.
Hosseini SM, Borghei P. Rhinocerebral mucormycosis: pathways of spread. Eur Arch Otorhinolaryngol. 2005;262(11):932–8.
Sehgal A, Raghavendran M, Kumar D, Srivastava A, Dubey D, Kumar A. Rhinocerebral mucormycosis causing basilar artery aneurysm with concomitant fungal colonic perforation in renal allograft recipient: a case report. Transplantation. 2004;78(6):949–50.
Challa S, Uppin SG, Uppin MS, Paul RT, Prayaga AK, Rao MT. Pulmonary zygomycosis: a clinicopathological study. Lung India. 2011;28(1):25–9. https://doi.org/10.4103/0970-2113.76297.
Yamin HS, Alastal AY, Bakri I. Pulmonary Mucormycosis over 130 years: a case report and literature review. Turk Thorac J. 2017;18(1):1–5. https://doi.org/10.5152/TurkThoracJ.2017.16033 Review.
Wang XM, Guo LC, Xue SL, Chen YB. Pulmonary mucormycosis: a case report and review of the literature. Oncol Lett. 2016;11(5):3049–53.
Walsh TJ, Gamaletsou MN, McGinnis MR, Hayden RT, Kontoyiannis DP. Early clinical and laboratory diagnosis of invasive pulmonary, extrapulmonary, and disseminated mucormycosis (zygomycosis). Clin Infect Dis. 2012;54(Suppl 1):S55–60. https://doi.org/10.1093/cid/cir868.
Lakshmi V, Rani TS, Sharma S, Mohan VS, Sundaram C, Rao RR, et al. Zygomycotic necrotizing fasciitis caused by Apophysomyces elegans. J Clin Microbiol. 1993;31(5):1368–9.
Prasad RM, Bose SM, Vaiphei K, Verma GR. Post operative abdominal wall mucormycosis mimicking as bacterial necrotising fasciitis. J Postgrad Med. 2003;49(2):187–8.
de Oliveira-Neto MP, Da Silva M, Fialho Monteiro PC, Lazera M, de Almeida PR, Novellino AB, et al. Cutaneous mucormycosis in a young, immunocompetent girl. Med Mycol. 2006;44(6):567–70 Erratum in: Med Mycol. 2006 ;44(8):793.
Li H, Hwang SK, Zhou C, Du J, Zhang J. Gangrenous cutaneous mucormycosis caused by Rhizopus oryzae: a case report and review of primary cutaneous mucormycosis in China over past 20 years. Mycopathologia. 2013;176(1–2):123–8. https://doi.org/10.1007/s11046-013-9654-z Review.
Kontoyiannis DP, Lewis RE. Invasive zygomycosis: update on pathogenesis,clinical manifestations, and management. Infect Dis Clin N Am. 2006;20(3):581–607 vi. Review.
Shiva Prasad BN, Shenoy A, Nataraj KS. Primary gastrointestinal mucormycosis in an immunocompetent person. J Postgrad Med. 2008;54(3):211–3.
Uppin MS, Anuradha S, Uppin SG, Paul TR, Prayaga AK, Sundaram C. Fungal infections as a contributing cause of death: an autopsy study. Indian J Pathol Microbiol. 2011;54:344–9.
Siu KL, Lee WH. A rare cause of intestinal perforation in an extreme low birth weight infant-gastrointestinal mucormycosis: a case report. J Perinatol. 2004; 24(5);319–21.
Spellberg B. Gastrointestinal mucormycosis: an evolving disease. Gastroenterol Hepatol (N Y). 2012;8(2):140–2.
Virk SS, Singh RP, Arora AS, Grewal JS, Puri H. Gastric zygomycosis—an unusual cause of massive upper gastrointestinal bleed. Indian J Gastroenterol. 2004;23(4):146–7.
Geramizadeh B, Modjalal M, Nabai S, Banani A, Forootan HR, Hooshdaran F, et al. Gastrointestinal zygomycosis: a report of three cases. Mycopathologia. 2007;164(1):35–8.
Challa S, Prayaga AK, Vemu L, Sadasivan J, Murthy Jagarlapudi MK, Digumarti, et al. Fungal endocarditis: an autopsy study. Asian Cardiovasc Thorac Ann. 2004;12:95–8. https://doi.org/10.1177/021849230401200202.
Acknowledgements
The author acknowledges the faculty, residents and staff of department of Pathology, Nizam’s Institute of Medical Sciences, Hyderabad, India.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Clinical Pathology
Rights and permissions
About this article
Cite this article
Challa, S. Mucormycosis: Pathogenesis and Pathology. Curr Fungal Infect Rep 13, 11–20 (2019). https://doi.org/10.1007/s12281-019-0337-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12281-019-0337-1