In a fatal mouse model of invasive candidiasis (IC), fungal burden changes with variable dynamics in the kidney, brain, spleen, and liver and declines in all organs except for the kidney, which inexorably loses function. Since leukocytes are required to control Candida, we hypothesized that differential leukocyte infiltration determines organ-specific outcome of the infection. We defined leukocyte accumulation in the blood, kidney, brain, spleen, and liver after infection using fluorescent-activated cell sorting (FACS) and immunohistochemistry. Accumulation of Ly6cintCD11b+ neutrophils predominated in all organs except the brain, where CD45intCD11b+CD11c– microglia were the major leukocytes detected, surrounding foci of invading Candida. Significantly more neutrophils accumulated in the spleen and liver than in the kidney during the first 24 h after infection, when neutrophil presence is critical for Candida control. Conversely, at later time points only the kidney continued to accumulate neutrophils, associated with immunopathology and organ failure. The distribution of neutrophils was completely different in each organ, with large abscesses exclusively forming in the kidney. Candida filamentation, an essential virulence factor, was seen in the kidney but not in the spleen or liver. IC induced Ly6chiCD11b+ inflammatory monocyte and NK1.1+ cell expansion in the blood and all organs tested, and MHCII+F4/80+CD11c– macrophage accumulation, mainly in the spleen and liver. This study is the first detailed analysis of leukocyte subsets accumulating in different target organs during IC. The results delineate immune responses to the same pathogen that are highly idiosyncratic for each organ tested. The work provides novel insights into the balance between effective host defense and immunopathology in IC.
© 2010 S. Karger AG, Basel
- Cellular immunology
- Flow cytometry
- Leukocyte trafficking
- Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C: The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis 2005;41:1232–1239.
- Papadimitriou JM, Ashman RB: The pathogenesis of acute systemic candidiasis in a susceptible inbred mouse strain. J Pathol 1986;150:257–265.
- Spellberg B, Ibrahim AS, Edwards JE Jr, Filler SG: Mice with disseminated candidiasis die of progressive sepsis. J Infect Dis 2005;192:336–343.
- MacCallum DM, Odds FC: Need for early antifungal treatment confirmed in experimental disseminated Candida albicans infection. Antimicrob Agents Chemother 2004;48:4911–4914.
- Fulurija A, Ashman RB, Papadimitriou JM: Neutrophil depletion increases susceptibility to systemic and vaginal candidiasis in mice, and reveals differences between brain and kidney in mechanisms of host resistance. Microbiology 1996;142:3487–3496.
- Romani L, Mencacci A, Cenci E, Del Sero G, Bistoni F, Puccetti P: An immunoregulatory role for neutrophils in CD4+ T helper subset selection in mice with candidiasis. J Immunol 1997;158:2356–2362.
- Qian Q, Jutila MA, Van Rooijen N, Cutler JE: Elimination of mouse splenic macrophages correlates with increased susceptibility to experimental disseminated candidiasis. J Immunol 1994;152:5000–5008.
- Vázquez-Torres A, Balish E: Macrophages in resistance to candidiasis. Microbiol Mol Biol Rev 1997;61:170–192.
- Mahanty S, Greenfield RA, Joyce WA, Kincade PW: Inoculation candidiasis in a murine model of severe combined immunodeficiency syndrome. Infect Immun 1988;56:3162–3166.
- Schuit KE: Phagocytosis and intracellular killing of pathogenic yeasts by human monocytes and neutrophils. Infect Immun 1979;24:932–938.
- Tsou CL, Peters W, Si Y, Slaymaker S, Slaymaker S, Aslanian AM, et al: Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Invest 2007;117:902–909.
- Sanos SL, Bui VL, Mortha A, Oberle K, Heners C, Johner C, et al: RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat Immunol 2009;10:83–91.
- Kanazawa H, Ohsawa K, Sasaki Y, Kohsaka S, Imai Y: Macrophage/microglia-specific protein Iba1 enhances membrane ruffling and Rac activation via phospholipase C-γ-dependent pathway. J Biol Chem 2002;277:20026–20032.
- Glass WG, Lim JK, Cholera R, Pletnev AG, Gao JL, Murphy PM: Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection. J Exp Med 2005;202:1087–1098.
- Salazar-Mather TP, Hamilton TA, Biron CA: A chemokine-to-cytokine-to-chemokine cascade critical in antiviral defense. J Clin Invest 2000;105:985–993.
- Sarin SK, Sabba C, Groszmann RJ: Splanchnic and systemic hemodynamics in mice using a radioactive microsphere technique. Am J Physiol 1990;258:G365–G369.
- Lo HJ, Köhler JR, DiDomenico B, Loebenberg D, Cacciapuoti A, Fink GR: Nonfilamentous C. albicans mutants are avirulent. Cell 1997;90:939–949.
- Sudbery P, Gow N, Berman J: The distinct morphogenic states of Candida albicans. Trends Microbiol 2004;12:317–324.
- 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;32:249–257.
- Lawson LJ, Perry VH, Gordon S: Turnover of resident microglia in the normal adult mouse brain. Neuroscience 1992;48:405–415.
- Garey KW, Rege M, Pai MP, Mingo DE, Suda KJ, Turpin RS, et al: Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 2006;43:25–31.
- Saville SP, Lazzell AL, Chaturvedi AK, Monteagudo C, Lopez-Ribot JL: Use of a genetically engineered strain to evaluate the pathogenic potential of yeast cell and filamentous forms during Candida albicans systemic infection in immunodeficient mice. Infect Immun 2008;76:97–102.
- Cutler JE, Poor AH: Effect of mouse phagocytes on Candida albicans in in vivo chambers. Infect Immun 1981;31:1110–1116.
- Diamond RD, Krzesicki R, Jao W: Damage to hyphal forms of Candida albicans by neutrophils in the absence of serum in vitro. J Clin Invest 1978;61:349–359.
- Weiss SJ: Tissue destruction by neutrophils. N Engl J Med 1989;320:365–376.
- Gargan RA, Hamilton-Miller JM, Brumfitt W: Effect of pH and osmolality on in vitro phagocytosis and killing by neutrophils in urine. Infect Immun 1993:61:8–12.
- Naglik J, Albrecht A, Bader O, Hube B: Candida albicans proteinases and host/pathogen interactions. Cell Microbiol 2004;6:915–926.
- Krause PJ, Malech HL, Kristie J, Kosciol CM, Herson VC, Eisenfeld L, et al: Polymorphonuclear leukocyte heterogeneity in neonates and adults. Blood 1986;68:200–204.
- Tsuda Y, Takahashi H, Kobayashi M, Hanafusa T, Herndon DN, Suzuki F: Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus. Immunity 2004;21:215–226.
- Mencacci A, Montagnoli C, Bacci A, Cenci E, Pitzurra L, Spreca A, et al: CD80+Gr-1+ myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis. J Immunol 2002;169:3180–3190.
- Romani L, Mencacci A, Cenci E, Spaccapelo R, Del Sero G, Nicoletti I, et al: Neutrophil production of IL-12 and IL-10 in candidiasis and efficacy of IL-12 therapy in neutropenic mice. J Immunol 1997;158:5349–5356.
- Redmond HP, Shou J, Gallagher HJ, Kelly CJ, Daly JM: Macrophage-dependent candidacidal mechanisms in the murine system. Comparison of murine Kupffer cell and peritoneal macrophage candidacidal mechanisms. J Immunol 1993;150:3427–3433.
- Serbina NV, Jia T, Hohl TM, Pamer EG: Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol 2008;26:421–452.
- Getts DR, Terry RL, Getts MT, Müller M, Rana S, Shrestha B, et al: Ly6c+ ‘inflammatory monocytes’ are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis. J Exp Med 2008;205:2319–2337.
- Romani L, Mencacci A, Cenci E, Spaccapelo R, Schiaffella E, Tonnetti L, et al: Natural killer cells do not play a dominant role in CD4+ subset differentiation in Candida albicans-infected mice. Infect Immun 1993;61:3769–3774.
- Algarra I, Ortega E, Serrano MJ, Alvarez de Cienfuegos G, Gaforio JJ: Suppression of splenic macrophage Candida albicans phagocytosis following in vivo depletion of natural killer cells in immunocompetent BALB/c mice and T-cell-deficient nude mice. FEMS Immunol Med Microbiol 2002;33:159–163.
- d’Ostiani CF, Del Sero G, Bacci A, Montagnoli C, Spreca A, Mencacci A, et al: Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans. Implications for initiation of T helper cell immunity in vitro and in vivo. J Exp Med 2000;191:1661–1674.
Dr. Philip M. Murphy
Molecular Signaling Section, Laboratory of Molecular Immunology
National Institutes of Health, Building 10, Room 11N113, 9000 Rockville Pike
Bethesda, MD 20892 (USA)
Tel. +1 301 496 8616, Fax +1 301 402 4369, E-Mail email@example.com
Presented in part at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 12–15, 2009 (late-breaker abstract M-1696b) and at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, September 12–15, 2010 (abstract M-1076).
Received: August 5, 2010
Accepted after revision: September 10, 2010
Published online: November 9, 2010
Number of Print Pages : 20
Number of Figures : 6, Number of Tables : 0, Number of References : 37
Journal of Innate Immunity
Vol. 3, No. 2, Year 2011 (Cover Date: February 2011)
Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)
For additional information: http://www.karger.com/JIN
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.