Abstract
To assess the influence of diabetes mellitus in predisposing to pulmonary mucormycosis, a murine model of streptozotocin-induced diabetes was used. Intranasal inoculation of Rhizopus oryzae into diabetic mice resulted in mucormycotic infection with histopathology resembling pulmonary mucormycosis observed in humans. There was no mortality nor infection in inoculated normal mice. Diabetic mice had fatal infections caused by R. oryzae but significantly reduced mortality following inoculation with Aspergillus fumigatus. These findings reflect the specific enhanced susceptibility to mucormycosis observed in human diabetics. Normal bronchoalveolar macrophages formed part of an efficient defense against R. oryzae by inhibiting germination, the critical step in the conversion of R. oryzae to its tissue invasive phase. Bronchoalveolar macrophages inhibited spore germination in vitro and appeared to help prevent germination in vivo. In contrast, spore germination occurred in diabetic mice following intranasal inoculation. Diabetic bronchoalveolar macrophages had a decreased ability to attach to hyphae. In diabetic mice, bronchoalveolar macrophages could damage spores or hyphae of R. oryzae, but serum factors appeared to both promote spore germination and impair attachment of macrophages to spores. This murine model of diabetes mellitus provides an opportunity for evaluation of the relative importance of cell and serum-mediated host factors in the pathogenesis of mucormycosis.
Full text
PDF










Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Agarwal M. K. Streptozotocin: mechanisms of action: proceedings of a workshop held on 21 June 1980, Washington, DC. FEBS Lett. 1980 Oct 20;120(1):1–3. doi: 10.1016/0014-5793(80)81031-3. [DOI] [PubMed] [Google Scholar]
- Artis W. M., Fountain J. A., Delcher H. K., Jones H. E. A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability. Diabetes. 1982 Dec;31(12):1109–1114. doi: 10.2337/diacare.31.12.1109. [DOI] [PubMed] [Google Scholar]
- BAUER H., FLANAGAN J. F., SHELDON W. H. The effects of metabolic alterations on experimental Rhizopus oryzae (mucormycosis) infection. Yale J Biol Med. 1956 Sep;29(1):23–32. [PMC free article] [PubMed] [Google Scholar]
- Baker R. D., Linares G. Prednisolone-induced mucormycosis in rhesus monkeys. Sabouraudia. 1974 Mar;12(1):75–80. doi: 10.1080/00362177485380101. [DOI] [PubMed] [Google Scholar]
- Cohen H. J., Chovaniec M. E. Superoxide generation by digitonin-stimulated guinea pig granulocytes. A basis for a continuous assay for monitoring superoxide production and for the study of the activation of the generating system. J Clin Invest. 1978 Apr;61(4):1081–1087. doi: 10.1172/JCI109007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coonrod J. D., Yoneda K. Detection and partial characterization of antibacterial factor(s) in alveolar lining material of rats. J Clin Invest. 1983 Jan;71(1):129–141. doi: 10.1172/JCI110741. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Corbel M. J., Eades S. M. Experimental mucormycosis in congenitally athymic (nude) mice. Mycopathologia. 1977 Dec 16;62(2):117–120. doi: 10.1007/BF01259402. [DOI] [PubMed] [Google Scholar]
- Corbel M. J., Eades S. M. Factors determining the susceptibility of mice to experimental phycomycosis. J Med Microbiol. 1975 Nov;8(4):551–564. doi: 10.1099/00222615-8-4-551. [DOI] [PubMed] [Google Scholar]
- Corbel M. J., Eades S. M. The relative susceptibility of New Zealand black and CBA mice to infection with opportunistic fungal pathogens. Sabouraudia. 1976 Mar;14(1):17–32. doi: 10.1080/00362177685190051. [DOI] [PubMed] [Google Scholar]
- DeChatelet L. R., Long G. D., Shirley P. S., Bass D. A., Thomas M. J., Henderson F. W., Cohen M. S. Mechanism of the luminol-dependent chemiluminescence of human neutrophils. J Immunol. 1982 Oct;129(4):1589–1593. [PubMed] [Google Scholar]
- Diamond R. D., Clark R. A. Damage to Aspergillus fumigatus and Rhizopus oryzae hyphae by oxidative and nonoxidative microbicidal products of human neutrophils in vitro. Infect Immun. 1982 Nov;38(2):487–495. doi: 10.1128/iai.38.2.487-495.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Diamond R. D., Haudenschild C. C., Erickson N. F., 3rd Monocyte-mediated damage to Rhizopus oryzae hyphae in vitro. Infect Immun. 1982 Oct;38(1):292–297. doi: 10.1128/iai.38.1.292-297.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Diamond R. D., Krzesicki R., Epstein B., Jao W. Damage to hyphal forms of fungi by human leukocytes in vitro. A possible host defense mechanism in aspergillosis and mucormycosis. Am J Pathol. 1978 May;91(2):313–328. [PMC free article] [PubMed] [Google Scholar]
- Eades S. M., Corbel M. J. Enhancement of susceptibility to experimental phycomycosis by agents producing reticuloendothelial stimulation. Br Vet J. 1975 Sep-Oct;131(5):622–624. doi: 10.1016/s0007-1935(17)35201-6. [DOI] [PubMed] [Google Scholar]
- GALE G. R., WELCH A. M. Studies of opportunistic fungi. I. Inhibition of Rhizopus oryzae by human serum. Am J Med Sci. 1961 May;241:604–612. [PubMed] [Google Scholar]
- Goodwin J. F., Murphy B., Guillemette M. Direct measurement of serum iron and binding capacity. Clin Chem. 1966 Feb;12(2):47–57. [PubMed] [Google Scholar]
- Hart P. D., Russell E., Jr, Remington J. S. The compromised host and infection. II. Deep fungal infection. J Infect Dis. 1969 Aug;120(2):169–191. doi: 10.1093/infdis/120.2.169. [DOI] [PubMed] [Google Scholar]
- Hoidal J. R., Schmeling D., Peterson P. K. Phagocytosis, bacterial killing, and metabolism by purified human lung phagocytes. J Infect Dis. 1981 Jul;144(1):61–71. doi: 10.1093/infdis/144.1.61. [DOI] [PubMed] [Google Scholar]
- Holt P. G. Alveolar macrophages. I. A simple technique for the preparation of high numbers of viable alveolar macrophages from small laboratory animals. J Immunol Methods. 1979;27(2):189–198. doi: 10.1016/0022-1759(79)90264-3. [DOI] [PubMed] [Google Scholar]
- Juers J. A., Rogers R. M., McCurdy J. B., Cook W. W. Enhancement of bactericidal capacity of alveolar macrophages by human alveolar lining material. J Clin Invest. 1976 Aug;58(2):271–275. doi: 10.1172/JCI108468. [DOI] [PMC free article] [PubMed] [Google Scholar]
- LaForce F. M., Kelly W. J., Huber G. L. Inactivation of staphylococci by alveolar macrophages with preliminary observations on the importance of alveolar lining material. Am Rev Respir Dis. 1973 Oct;108(4):784–790. doi: 10.1164/arrd.1973.108.4.784. [DOI] [PubMed] [Google Scholar]
- Lundborg M., Holma B. In vitro phagocytosis of fungal spores by rabbit lung macrophages. Sabouraudia. 1972 Jul;10(2):152–156. doi: 10.1080/00362177285190301. [DOI] [PubMed] [Google Scholar]
- Marchevsky A. M., Bottone E. J., Geller S. A., Giger D. K. The changing spectrum of disease, etiology, and diagnosis of mucormycosis. Hum Pathol. 1980 Sep;11(5):457–464. doi: 10.1016/s0046-8177(80)80054-2. [DOI] [PubMed] [Google Scholar]
- Mickenberg I. D., Root R. K., Wolff S. M. Leukocytic function in hypogammaglobulinemia. J Clin Invest. 1970 Aug;49(8):1528–1538. doi: 10.1172/JCI106370. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oliver C. Cytochemical localization of acid phosphatase and trimetaphosphatase activities in exocrine acinar cells. J Histochem Cytochem. 1980 Jan;28(1):78–81. doi: 10.1177/28.1.6243325. [DOI] [PubMed] [Google Scholar]
- Owens A. W., Shacklette M. H., Baker R. D. An antifungal factor in human serum. I. Studies of Rhizopus rhizopodiformis. Sabouraudia. 1965 Oct;4(3):179–186. doi: 10.1080/00362176685190411. [DOI] [PubMed] [Google Scholar]
- Persijn J. P., van der Slik W., Riethorst A. Determination of serum iron and latent iron-binding capacity (LIBC). Clin Chim Acta. 1971 Nov;35(1):91–98. doi: 10.1016/0009-8981(71)90298-1. [DOI] [PubMed] [Google Scholar]
- Reinhardt D. J., Licata I., Kaplan W., Ajello L., Chandler F. W., Ellis J. J. Experimental cerebral zygomycosis in alloxan-diabetic rabbits: variation in virulence among zygomycetes. Sabouraudia. 1981 Dec;19(4):245–256. doi: 10.1080/00362178185380421. [DOI] [PubMed] [Google Scholar]
- SHELDON W. H., BAUER H. The development of the acute inflammatory response to experimental cutaneous mucormycosis in normal and diabetic rabbits. J Exp Med. 1959 Dec 1;110:845–852. doi: 10.1084/jem.110.6.845. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schaffner A., Douglas H., Braude A. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. J Clin Invest. 1982 Mar;69(3):617–631. doi: 10.1172/JCI110489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smith D. L., Rommel F. A rapid micro method for the simultaneous determination of phagocytic-microbiocidal activity of human peripheral blood leukocytes in vitro. J Immunol Methods. 1977;17(3-4):241–247. doi: 10.1016/0022-1759(77)90106-5. [DOI] [PubMed] [Google Scholar]
- Smith J. M. In vivo development of spores of Absidia ramosa. Sabouraudia. 1976 Mar;14(1):11–15. [PubMed] [Google Scholar]
- Waldorf A. R., Halde C., Vedros N. A. Murine model of pulmonary mucormycosis in cortisone-treated mice. Sabouraudia. 1982 Sep;20(3):217–224. doi: 10.1080/00362178285380321. [DOI] [PubMed] [Google Scholar]
- Waldorf A. R., Peter L., Polak A. Mucormycotic infection in mice following prolonged incubation of spores in vivo and the role of spore agglutinating antibodies on spore germination. Sabouraudia. 1984;22(2):101–108. doi: 10.1080/00362178485380171. [DOI] [PubMed] [Google Scholar]



