Abstract
Using a murine model, we have previously shown that brain resistance to local infection with opportunistic fungi is affected by manipulation of the host myelomonocytic compartment. Here, we demonstrate that intracerebral administration of heat-inactivated Cryptococcus neoformans (H-CN) yeast cells results in a consistent enhancement of mouse survival to subsequent local challenge with lethal doses of C. neoformans. The phenomenon, more pronounced upon double H-CN treatment, is associated with (i) massive local inflammatory response, (ii) reduced growth of the fungus within the brain, and (iii) induction of delayed-type hypersensitivity. Moreover, H-CN treatment confers protection against local heterologous challenges. Our data provide initial evidence that intracerebral administration of H-CN results in the establishment of aspecific and specific immune responses; the mechanisms of elicitation and relative contributions to host antimicrobial resistance remains to be elucidated.
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- Anderson D. M., Dykstra M. A. Resistance to challenge and macrophage activity in mice previously vaccinated with formalin-killed Cryptococcus neoformans. Mycopathologia. 1984 Jun 30;86(3):169–177. doi: 10.1007/BF00441128. [DOI] [PubMed] [Google Scholar]
- Blasi E., Barluzzi R., Mazzolla R., Mosci P., Bistoni F. Experimental model of intracerebral infection with Cryptococcus neoformans: roles of phagocytes and opsonization. Infect Immun. 1992 Sep;60(9):3682–3688. doi: 10.1128/iai.60.9.3682-3688.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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 Jun;32(3):249–257. doi: 10.1016/0165-5728(91)90195-d. [DOI] [PubMed] [Google Scholar]
- Blasi E., Mazzolla R., Pitzurra L., Barluzzi R., Bistoni F. Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicans. Antimicrob Agents Chemother. 1993 Nov;37(11):2422–2426. doi: 10.1128/aac.37.11.2422. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Buchanan K. L., Fidel P. L., Jr, Murphy J. W. Effects of Cryptococcus neoformans-specific suppressor T cells on the amplified anticryptococcal delayed-type hypersensitivity response. Infect Immun. 1991 Jan;59(1):29–35. doi: 10.1128/iai.59.1.29-35.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Buchanan K. L., Murphy J. W. Characterization of cellular infiltrates and cytokine production during the expression phase of the anticryptococcal delayed-type hypersensitivity response. Infect Immun. 1993 Jul;61(7):2854–2865. doi: 10.1128/iai.61.7.2854-2865.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cauley L. K., Murphy J. W. Response of congenitally athymic (nude) and phenotypically normal mice to Cryptococcus neoformans infection. Infect Immun. 1979 Mar;23(3):644–651. doi: 10.1128/iai.23.3.644-651.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chandler F. W. Pathology of the mycoses in patients with the acquired immunodeficiency syndrome (AIDS). Curr Top Med Mycol. 1985;1:1–23. doi: 10.1007/978-1-4613-9547-8_1. [DOI] [PubMed] [Google Scholar]
- Collins H. L., Bancroft G. J. Cytokine enhancement of complement-dependent phagocytosis by macrophages: synergy of tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor for phagocytosis of Cryptococcus neoformans. Eur J Immunol. 1992 Jun;22(6):1447–1454. doi: 10.1002/eji.1830220617. [DOI] [PubMed] [Google Scholar]
- Collins H. L., Bancroft G. J. Encapsulation of Cryptococcus neoformans impairs antigen-specific T-cell responses. Infect Immun. 1991 Nov;59(11):3883–3888. doi: 10.1128/iai.59.11.3883-3888.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Diamond R. D., May J. E., Kane M. A., Frank M. M., Bennett J. E. The role of the classical and alternate complement pathways in host defenses against Cryptococcus neoformans infection. J Immunol. 1974 Jun;112(6):2260–2270. [PubMed] [Google Scholar]
- Eng R. H., Bishburg E., Smith S. M., Kapila R. Cryptococcal infections in patients with acquired immune deficiency syndrome. Am J Med. 1986 Jul;81(1):19–23. doi: 10.1016/0002-9343(86)90176-2. [DOI] [PubMed] [Google Scholar]
- Fidel P. L., Jr, Murphy J. W. Characterization of a cell population which amplifies the anticryptococcal delayed-type hypersensitivity response. Infect Immun. 1990 Feb;58(2):393–398. doi: 10.1128/iai.58.2.393-398.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Granger D. L., Perfect J. R., Durack D. T. Macrophage-mediated fungistasis in vitro: requirements for intracellular and extracellular cytotoxicity. J Immunol. 1986 Jan;136(2):672–680. [PubMed] [Google Scholar]
- Hidore M. R., Murphy J. W. Correlation of natural killer cell activity and clearance of Cryptococcus neoformans from mice after adoptive transfer of splenic nylon wool-nonadherent cells. Infect Immun. 1986 Feb;51(2):547–555. doi: 10.1128/iai.51.2.547-555.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hidore M. R., Nabavi N., Sonleitner F., Murphy J. W. Murine natural killer cells are fungicidal to Cryptococcus neoformans. Infect Immun. 1991 May;59(5):1747–1754. doi: 10.1128/iai.59.5.1747-1754.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hill J. O., Harmsen A. G. Intrapulmonary growth and dissemination of an avirulent strain of Cryptococcus neoformans in mice depleted of CD4+ or CD8+ T cells. J Exp Med. 1991 Mar 1;173(3):755–758. doi: 10.1084/jem.173.3.755. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huffnagle G. B., Yates J. L., Lipscomb M. F. Immunity to a pulmonary Cryptococcus neoformans infection requires both CD4+ and CD8+ T cells. J Exp Med. 1991 Apr 1;173(4):793–800. doi: 10.1084/jem.173.4.793. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huffnagle G. B., Yates J. L., Lipscomb M. F. T cell-mediated immunity in the lung: a Cryptococcus neoformans pulmonary infection model using SCID and athymic nude mice. Infect Immun. 1991 Apr;59(4):1423–1433. doi: 10.1128/iai.59.4.1423-1433.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kovacs J. A., Kovacs A. A., Polis M., Wright W. C., Gill V. J., Tuazon C. U., Gelmann E. P., Lane H. C., Longfield R., Overturf G. Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med. 1985 Oct;103(4):533–538. doi: 10.7326/0003-4819-103-4-533. [DOI] [PubMed] [Google Scholar]
- Kozel T. R., Pfrommer G. S., Guerlain A. S., Highison B. A., Highison G. J. Strain variation in phagocytosis of Cryptococcus neoformans: dissociation of susceptibility to phagocytosis from activation and binding of opsonic fragments of C3. Infect Immun. 1988 Nov;56(11):2794–2800. doi: 10.1128/iai.56.11.2794-2800.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kozel T. R., Wilson M. A., Murphy J. W. Early events in initiation of alternative complement pathway activation by the capsule of Cryptococcus neoformans. Infect Immun. 1991 Sep;59(9):3101–3110. doi: 10.1128/iai.59.9.3101-3110.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Levitz S. M., DiBenedetto D. J. Differential stimulation of murine resident peritoneal cells by selectively opsonized encapsulated and acapsular Cryptococcus neoformans. Infect Immun. 1988 Oct;56(10):2544–2551. doi: 10.1128/iai.56.10.2544-2551.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lim T. S., Murphy J. W., Cauley L. K. Host-etiological agent interactions in intranasally and intraperitoneally induced Cryptococcosis in mice. Infect Immun. 1980 Aug;29(2):633–641. doi: 10.1128/iai.29.2.633-641.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mazzolla R., Barluzzi R., Romani L., Mosci P., Bistoni F. Anti-Candida resistance in the mouse brain and effect of intracerebral administration of interleukin 1. J Gen Microbiol. 1991 Aug;137(8):1799–1804. doi: 10.1099/00221287-137-8-1799. [DOI] [PubMed] [Google Scholar]
- Miller G. P., Puck J. In vitro human lymphocyte responses to Cryptococcus neoformans. Evidence for primary and secondary responses in normals and infected subjects. J Immunol. 1984 Jul;133(1):166–172. [PubMed] [Google Scholar]
- Miller M. F., Mitchell T. G. Killing of Cryptococcus neoformans strains by human neutrophils and monocytes. Infect Immun. 1991 Jan;59(1):24–28. doi: 10.1128/iai.59.1.24-28.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mody C. H., Lipscomb M. F., Street N. E., Toews G. B. Depletion of CD4+ (L3T4+) lymphocytes in vivo impairs murine host defense to Cryptococcus neoformans. J Immunol. 1990 Feb 15;144(4):1472–1477. [PubMed] [Google Scholar]
- Murphy J. W., McDaniel D. O. In vitro reactivity of natural killer (NK) cells against Cryptococcus neoformans. J Immunol. 1982 Apr;128(4):1577–1583. [PubMed] [Google Scholar]
- Perfect J. R., Hobbs M. M., Granger D. L., Durack D. T. Cerebrospinal fluid macrophage response to experimental cryptococcal meningitis: relationship between in vivo and in vitro measurements of cytotoxicity. Infect Immun. 1988 Apr;56(4):849–854. doi: 10.1128/iai.56.4.849-854.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Salkowski C. A., Balish E. A monoclonal antibody to gamma interferon blocks augmentation of natural killer cell activity induced during systemic cryptococcosis. Infect Immun. 1991 Feb;59(2):486–493. doi: 10.1128/iai.59.2.486-493.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Salkowski C. A., Balish E. Cryptococcosis in beige mice: the effect of congenital defects in innate immunity on susceptibility. Can J Microbiol. 1991 Feb;37(2):128–135. doi: 10.1139/m91-019. [DOI] [PubMed] [Google Scholar]
- Salkowski C. A., Balish E. Pathogenesis of Cryptococcus neoformans in congenitally immunodeficient beige athymic mice. Infect Immun. 1990 Oct;58(10):3300–3306. doi: 10.1128/iai.58.10.3300-3306.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Salkowski C. A., Balish E. Role of natural killer cells in resistance to systemic cryptococcosis. J Leukoc Biol. 1991 Aug;50(2):151–159. doi: 10.1002/jlb.50.2.151. [DOI] [PubMed] [Google Scholar]
- Zuger A., Louie E., Holzman R. S., Simberkoff M. S., Rahal J. J. Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of treatment. Ann Intern Med. 1986 Feb;104(2):234–240. doi: 10.7326/0003-4819-104-2-234. [DOI] [PubMed] [Google Scholar]