lID 1992; 166 (October)
Correspondence
Genetic Resistance to Candida albicans Infection Is Conferred by Cells Derived from the Bone Marrow Colleagues-The yeast Candida albieans is a major opportunistic fungal pathogen that commonly affects debilitated or imReprints or correspondence: Dr. R. B. Ashman. Pathology Department. University of Western Australia. Queen Elizabeth II Medical Centre. Nedlands, Western Australia, 6009. The Journal of Infectious Diseases 1992;166:947-8 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6604-0051 $0 1.00
munocompromised patients. However, despite intensive investigation, the mechanisms responsible for susceptibility and resistance to infection have not been fully elucidated. There is increasing evidence that cell-mediated immune responses are involved in recovery from primary infection in mice [I], but there are clear differences in the early response to infection in genetically defined mouse strains that cannot be accounted for by this mechanism. In contrast to classifications based on mortality or colony counts [2, 3], histopathologic examination of tissues from infected mice has shown that inbred strains segregate clearly into those that are susceptible (e.g., CBA/CaH) and resistant (e.g., BALB/c, BALB/c-H-2k) to C. albicans infection [4].
Downloaded from http://jid.oxfordjournals.org/ at University of Lethbridge on September 7, 2015
Figure 1. Brain lesions caused by systemic infection with Candida albicans in the following groups of mice: A, CBA/CaH; B, BALB/cH-2 k ; C, CBA/CaH lethally irradiated and reconstituted with syngeneic bone marrow; D, CBA/CaH lethally irradiated and reconstituted with BALB/c-H-2k bone marrow. Magnification x4.6. Bar = I mm.
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tible mouse. The result shows unequivocally that the cells mediating natural resistance, at least in the early stage of the infection, are (relatively) short lived and that they or their precursors are radiosensitive and derived from the bone marrow. The effector cells are probably polymorphonuclear leucocytes (PMNL), a postulate consistent with the demonstration that the enhanced susceptibility of beige mutant mice to systemic candidiasis is linked to a weakness in the generation of PMNL rather than to NK cells or monocyte/macrophage function [7]. There is no known defect in PMNL function in CBA mice [8], so the crucial variable may well be differences in the kinetics ofPMNL production or differentiation in the bone marrow.
R. B. Ashman and J. M. Papadimitriou Pathology Department, University of Western Australia, and Queen Elizabeth Medical Centre, Nedlands, Australia
References I. Ashman RB. Papadimitriou JM. Ott AK. Warmington JR. Antigens and immune responses in Candida albicans infection. Immunol Cell Bioi 1990;68: 1-13. 2. Hector RF. Domer JE. Carrow EW. Immune responses to Candida albicans in genetically distinct mice. Infect Immun 1982;38: 1020-8. 3. Marquis G. Montplasir S. Pelletier M. Auger P. Lapp WS. Genetics of resistance to infection with Candida albicans in mice. Br J Exp Pathol 1988;69:651-60. 4. Ashman RB. Papadimitriou JM. Murine candidiasis. Pathogenesis and host responses in genetically distinct inbred mice. Immunol Cell Bioi 1987;65: 163-71. 5. Ashman RB. Papadimitriou JM. Genetic regulation of pathogenesis and host responses in fungal infection. In: Kurstak E. Marquis G. eds. Immunology of fungal diseases. New York: Marcel Dekker. 1989:347-71. 6. Blasi E. Mazzolla R. Barluzzi R. Mosci P. Bartoli A. Bistoni F. Intracerebral transfer of an in vitro established microglial cell line: local induction of a protective state against lethal challenge with Candida albicans. J Neuroimmunol 1991;32:249-57. 7. Ashman RB. Papadimitriou JM. Susceptibility of beige mutant mice to candidiasis may be linked to a defect in granulocyte production by bone marrow stem cells. Infect Immun 1991;59:2140-6. 8. Festing MFW. Origins and characteristics of inbred strains of mice. Mouse Genome 1991;89:421-548.
Downloaded from http://jid.oxfordjournals.org/ at University of Lethbridge on September 7, 2015
The gene(s) determining susceptibility and resistance are codominant [5], and further analysis in 40 BALB/c X CBA/CaH F2 hybrid mice has shown a segregation pattern of 11 resistant, 20 intermediate, and 9 susceptible. This is not significantly different from the expected Mendelian ratio for a single genetic element. To address the nature of this genetic control of natural resistance to Candida infection, we sought to establish whether resistance was conferred by the bone marrow or was a property ofthe tissue framework of the mouse. We therefore constructed radiation chimeras by lethal irradiation (850 R) of susceptible CBA/ CaH mice, followed by reconstitution with 2 X 107 syngeneic bone marrow cells or marrow from resistant, MHC-compatible, BALB/c-H-2 k mice. Unirradiated CBA/CaH and BALB/c-H-2k mice were included as controls. The chimeras were rested for 8 weeks after irradiation and reconstitution before they were used in experiments. The protocol was repeated twice, with 5 mice per group in each experiment. The chimeras and their controls were challenged with a sublethal dose (3 X 105 viable blastospores) of C. albicans intravenously, and at 5 days after inoculation mice were killed and the brains removed for comparative histopathologic evaluation. Random transverse sections were cut and stained with hematoxylin-eosin and periodic acidSchiff. The sections were coded and examined blind, then reevaluated once the code had been broken. In our experience, tissue lesions are remarkably consistent within treatment groups. As reported previously [4], susceptible CBA/CaH mice showed many large abscesses in the brain, whereas resistant BALB/c-H-2k mice had small and infrequent lesions (figure lA, B). Numerous severe lesions were also found in the brains of lethally irradiated CBA/CaH mice reconstituted with syngeneic bone marrow, but animals given BALB/c-H-2k bone marrow exhibited fewer and smaller lesions (figure lC, D). This indicated that the bone marrow from phenotypically resistant mice had a protective effect against infection in the genetically susceptible CBA/CaH recipients. Brain lesions in both types of chimeras were detectably more severe than in the corresponding controls. This could have been due to the gradual loss of or failure to replace resident phagocytes, such as microglia [6], in the tissues. To our knowledge, this is the first model system in which it has been possible to transfer the resistant phenotype to a suscep-
110 1992; 166 (October)
Correspondence
Genetic Resistance to Candida albicans Infection Is Conferred by Cells Derived from the Bone Marrow Colleagues-The yeast Candida albieans is a major opportunistic fungal pathogen that commonly affects debilitated or imReprints or correspondence: Dr. R. B. Ashman. Pathology Department. University of Western Australia. Queen Elizabeth II Medical Centre. Nedlands, Western Australia, 6009. The Journal of Infectious Diseases 1992;166:947-8 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6604-0051 $0 1.00
munocompromised patients. However, despite intensive investigation, the mechanisms responsible for susceptibility and resistance to infection have not been fully elucidated. There is increasing evidence that cell-mediated immune responses are involved in recovery from primary infection in mice [I], but there are clear differences in the early response to infection in genetically defined mouse strains that cannot be accounted for by this mechanism. In contrast to classifications based on mortality or colony counts [2, 3], histopathologic examination of tissues from infected mice has shown that inbred strains segregate clearly into those that are susceptible (e.g., CBA/CaH) and resistant (e.g., BALB/c, BALB/c-H-2k) to C. albicans infection [4].
Downloaded from http://jid.oxfordjournals.org/ at University of Lethbridge on September 7, 2015
Figure 1. Brain lesions caused by systemic infection with Candida albicans in the following groups of mice: A, CBA/CaH; B, BALB/cH-2 k ; C, CBA/CaH lethally irradiated and reconstituted with syngeneic bone marrow; D, CBA/CaH lethally irradiated and reconstituted with BALB/c-H-2k bone marrow. Magnification x4.6. Bar = I mm.
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tible mouse. The result shows unequivocally that the cells mediating natural resistance, at least in the early stage of the infection, are (relatively) short lived and that they or their precursors are radiosensitive and derived from the bone marrow. The effector cells are probably polymorphonuclear leucocytes (PMNL), a postulate consistent with the demonstration that the enhanced susceptibility of beige mutant mice to systemic candidiasis is linked to a weakness in the generation of PMNL rather than to NK cells or monocyte/macrophage function [7]. There is no known defect in PMNL function in CBA mice [8], so the crucial variable may well be differences in the kinetics ofPMNL production or differentiation in the bone marrow.
R. B. Ashman and J. M. Papadimitriou Pathology Department, University of Western Australia, and Queen Elizabeth Medical Centre, Nedlands, Australia
References I. Ashman RB. Papadimitriou JM. Ott AK. Warmington JR. Antigens and immune responses in Candida albicans infection. Immunol Cell Bioi 1990;68: 1-13. 2. Hector RF. Domer JE. Carrow EW. Immune responses to Candida albicans in genetically distinct mice. Infect Immun 1982;38: 1020-8. 3. Marquis G. Montplasir S. Pelletier M. Auger P. Lapp WS. Genetics of resistance to infection with Candida albicans in mice. Br J Exp Pathol 1988;69:651-60. 4. Ashman RB. Papadimitriou JM. Murine candidiasis. Pathogenesis and host responses in genetically distinct inbred mice. Immunol Cell Bioi 1987;65: 163-71. 5. Ashman RB. Papadimitriou JM. Genetic regulation of pathogenesis and host responses in fungal infection. In: Kurstak E. Marquis G. eds. Immunology of fungal diseases. New York: Marcel Dekker. 1989:347-71. 6. Blasi E. Mazzolla R. Barluzzi R. Mosci P. Bartoli A. Bistoni F. Intracerebral transfer of an in vitro established microglial cell line: local induction of a protective state against lethal challenge with Candida albicans. J Neuroimmunol 1991;32:249-57. 7. Ashman RB. Papadimitriou JM. Susceptibility of beige mutant mice to candidiasis may be linked to a defect in granulocyte production by bone marrow stem cells. Infect Immun 1991;59:2140-6. 8. Festing MFW. Origins and characteristics of inbred strains of mice. Mouse Genome 1991;89:421-548.
Downloaded from http://jid.oxfordjournals.org/ at University of Lethbridge on September 7, 2015
The gene(s) determining susceptibility and resistance are codominant [5], and further analysis in 40 BALB/c X CBA/CaH F2 hybrid mice has shown a segregation pattern of 11 resistant, 20 intermediate, and 9 susceptible. This is not significantly different from the expected Mendelian ratio for a single genetic element. To address the nature of this genetic control of natural resistance to Candida infection, we sought to establish whether resistance was conferred by the bone marrow or was a property ofthe tissue framework of the mouse. We therefore constructed radiation chimeras by lethal irradiation (850 R) of susceptible CBA/ CaH mice, followed by reconstitution with 2 X 107 syngeneic bone marrow cells or marrow from resistant, MHC-compatible, BALB/c-H-2 k mice. Unirradiated CBA/CaH and BALB/c-H-2k mice were included as controls. The chimeras were rested for 8 weeks after irradiation and reconstitution before they were used in experiments. The protocol was repeated twice, with 5 mice per group in each experiment. The chimeras and their controls were challenged with a sublethal dose (3 X 105 viable blastospores) of C. albicans intravenously, and at 5 days after inoculation mice were killed and the brains removed for comparative histopathologic evaluation. Random transverse sections were cut and stained with hematoxylin-eosin and periodic acidSchiff. The sections were coded and examined blind, then reevaluated once the code had been broken. In our experience, tissue lesions are remarkably consistent within treatment groups. As reported previously [4], susceptible CBA/CaH mice showed many large abscesses in the brain, whereas resistant BALB/c-H-2k mice had small and infrequent lesions (figure lA, B). Numerous severe lesions were also found in the brains of lethally irradiated CBA/CaH mice reconstituted with syngeneic bone marrow, but animals given BALB/c-H-2k bone marrow exhibited fewer and smaller lesions (figure lC, D). This indicated that the bone marrow from phenotypically resistant mice had a protective effect against infection in the genetically susceptible CBA/CaH recipients. Brain lesions in both types of chimeras were detectably more severe than in the corresponding controls. This could have been due to the gradual loss of or failure to replace resident phagocytes, such as microglia [6], in the tissues. To our knowledge, this is the first model system in which it has been possible to transfer the resistant phenotype to a suscep-
110 1992; 166 (October)
