Discordant antibody and cellular responses to Pneumocystis major surface glycoprotein variants in mice

BMC Immunology

Joseph A Kovacs¹  Daniel Helman¹  Lisa R Bishop¹ 

[1] Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892-1662, USA

关键词: Pneumocystis;    Major surface glycoprotein;    Immune response;    Antigenic variation;   

Others  :  1077896
DOI  :  10.1186/1471-2172-13-39

 received in 2011-12-28, accepted in 2012-07-12,  发布年份 2012

【 摘 要 】

Background

The major surface glycoprotein (Msg) of Pneumocystis is encoded by approximately 50 to 80 unique but related genes. Msg diversity may represent a mechanism for immune escape from host T cell responses. We examined splenic T cell proliferative and cytokine as well as serum antibody responses to recombinant and native Pneumocystis antigens in immunized or Pneumocystis-infected mice. In addition, immune responses were examined in 5 healthy humans.

Results

Proliferative responses to each of two recombinant Msg variant proteins were seen in mice immunized with either recombinant protein, but no proliferation to these antigens was seen in mice immunized with crude Pneumocystis antigens or in mice that had cleared infection, although the latter animals demonstrated proliferative responses to crude Pneumocystis antigens and native Msg. IL-17 and MCP-3 were produced in previously infected animals in response to the same antigens, but not to recombinant antigens. Antibody responses to the recombinant P. murina Msg variant proteins were seen in all groups of animals, demonstrating that all groups were exposed to and mounted immune responses to Msg. No human PBMC samples proliferated following stimulation with P. jirovecii Msg, while antibody responses were detected in sera from 4 of 5 samples.

Conclusions

Cross-reactive antibody responses to Msg variants are common, while cross-reactive T cell responses are uncommon; these results support the hypothesis that Pneumocystis utilizes switching of Msg variant expression to avoid host T cell responses.

【 授权许可】

   
2012 Bishop et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Harmsen AG, Stankiewicz M: Requirement for CD4+ cells in resistance to Pneumocystis carinii pneumonia in mice. J Exp Med 1990, 172:937-945.
• [2]Roths JB, Sidman CL: Both immunity and hyperresponsiveness to Pneumocystis carinii result from transfer of CD4+ but not CD8+ T cells into severe combined immunodeficiency mice. J Clin Invest 1992, 90:673-678.
• [3]Meuwissen JH, Tauber I, Leeuwenberg AD, Beckers PJ, Sieben M: Parasitologic and serologic observations of infection with Pneumocystis in humans. J Infect Dis 1977, 136:43-49.
• [4]Lundgren B, Lipschik GY, Kovacs JA: Purification and characterization of a major human Pneumocystis carinii surface antigen. J Clin Invest 1991, 87:163-170.
• [5]Pottratz ST, Paulsrud J, Smith JS, Martin WJ: Pneumocystis carinii attachment to cultured lung cells by Pneumocystis gp 120, a fibronectin binding protein. J Clin Invest 1991, 88:403-407.
• [6]Neese LW, Standing JE, Olson EJ, Castro M, Limper AH: Vitronectin, fibronectin, and gp120 antibody enhance macrophage release of TNF-alpha in response to Pneumocystis carinii. J Immunol 1994, 152:4549-4556.
• [7]Kovacs JA, Powell F, Edman JC, Lundgren B, Martinez A, Drew B, Angus CW: Multiple genes encode the major surface glycoprotein of Pneumocystis carinii. J Biol Chem 1993, 268:6034-6040.
• [8]Stringer JR, Keely SP: Genetics of surface antigen expression in Pneumocystis carinii. Infect Immun 2001, 69:627-639.
• [9]Angus CW, Tu A, Vogel P, Qin M, Kovacs JA: Expression of variants of the major surface glycoprotein of Pneumocystis carinii. J Exp Med 1996, 183:1229-1234.
• [10]Keely SP, Linke MJ, Cushion MT, Stringer JR: Pneumocystis murina MSG gene family and the structure of the locus associated with its transcription. Fungal Genet Biol 2007, 44:905-919.
• [11]Edman JC, Hatton TW, Nam M, Turner R, Mei Q, Angus CW, Kovacs JA: A single expression site with a conserved leader sequence regulates variation of expression of the Pneumocystis carinii family of major surface glycoprotein genes. DNA Cell Biol 1996, 15:989-999.
• [12]Wada M, Sunkin SM, Stringer JR, Nakamura Y: Antigenic variation by positional control of major surface glycoprotein gene expression in Pneumocystis carinii. J Infect Dis 1995, 171:1563-1568.
• [13]Kutty G, Ma L, Kovacs JA: Characterization of the expression site of the major surface glycoprotein of human-derived Pneumocystis carinii. Mol Microbiol 2001, 42:183-193.
• [14]Barbour AG, Restrepo BI: Antigenic variation in vector-borne pathogens. Emerg Infect Dis 2000, 6:449-457.
• [15]Vestereng VH, Bishop LR, Hernandez B, Kutty G, Larsen HH, Kovacs JA: Quantitative real-time polymerase chain-reaction assay allows characterization of Pneumocystis infection in immunocompetent mice. J Infect Dis 2004, 189:1540-1544.
• [16]Hernandez-Novoa B, Bishop L, Logun C, Munson PJ, Elnekave E, Rangel ZG, Barb J, Danner RL, Kovacs JA: Immune responses to Pneumocystis murina are robust in healthy mice but largely absent in CD40 ligand-deficient mice. J Leukoc Biol 2008, 84:420-430.
• [17]Theus SA, Smulian AG, Steele P, Linke MJ, Walzer PD: Immunization with the major surface glycoprotein of Pneumocystis carinii elicits a protective response. Vaccine 1998, 16:1149-1157.
• [18]Gigliotti F, Wiley JA, Harmsen AG: Immunization with Pneumocystis carinii gpA is immunogenic but not protective in a mouse model of P. carinii pneumonia. Infect Immun 1998, 66:3179-3182.
• [19]Zheng M, Ramsay AJ, Robichaux MB, Norris KA, Kliment C, Crowe C, Rapaka RR, Steele C, McAllister F, Shellito JE, et al.: CD4+ T cell-independent DNA vaccination against opportunistic infections. J Clin Invest 2005, 115:3536-3544.
• [20]Kovacs JA, Halpern JL, Swan JC, Moss J, Parrillo JE, Masur H: Identification of antigens and antibodies specific for Pneumocystis carinii. J Immunol 1988, 140:2023-2031.
• [21]Smulian AG, Theus SA, Denko N, Walzer PD, Stringer JR: A 55 kDa antigen of Pneumocystis carinii: analysis of the cellular immune response and characterization of the gene. Mol Microbiol 1993, 7:745-753.
• [22]Theus SA, Sullivan DW, Walzer PD, Smulian AG: Cellular responses to a 55-kilodalton recombinant Pneumocystis carinii antigen. Infect Immun 1994, 62:3479-3484.
• [23]Russian DA, Andrawis-Sorial V, Goheen MP, Edman JC, Vogel P, Turner RE, Klivington DL, Angus CW, Kovacs JA: Characterization of a multicopy family of genes encoding a surface-expressed serine endoprotease in rat Pneumocystis carinii. Proc Assoc Am Physicians 1999, 111:347-356.
• [24]Theus SA, Andrews RP, Linke MJ, Walzer PD: Characterization of rat CD4 T cell clones specific for the major surface glycoprotein of Pneumocystis carinii. J Euk Microbiol 1997, 44:96-100.
• [25]Jambo KC, Sepako E, Fullerton DG, Mzinza D, Glennie S, Wright AK, Heyderman RS, Gordon SB: Bronchoalveolar CD4+ T cell responses to respiratory antigens are impaired in HIV-infected adults. Thorax 2011, 66:375-382.
• [26]Theus SA, Sawhney N, Smulian AG, Walzer PD: Proliferative and cytokine responses of human T lymphocytes isolated from human immunodeficiency virus-infected patients to the major surface glycoprotein of Pneumocystis carinii. J Infect Dis 1998, 177:238-241.
• [27]Atzori C, Clerici M, Trabattoni D, Fantoni G, Valerio A, Tronconi E, Cargnel A: Assessment of immune reconstitution to Pneumocystis carinii in HIV-1 patients under different highly active antiretroviral therapy regimens. J Antimicrob Chemother 2003, 52:276-281.
• [28]Forte M, Maartens G, Campbell F, Stubberfield C, Shahmanesh M, Kumararatne D, Gaston H: T-lymphocyte responses to Pneumocystis carinii in healthy and HIV-positive individuals. J Acquir Immune Defic Syndr 1992, 5:409-416.
• [29]Frangioni JV, Neel BG: Solubilization and purification of enzymatically active glutathione S-transferase (pGEX) fusion proteins. Anal Biochem 1993, 210:179-187.
• [30]Kohfeldt E, Maurer P, Vannahme C, Timpl R: Properties of the extracellular calcium binding module of the proteoglycan testican. FEBS Lett 1997, 414:557-561.
• [31]Liu S, Tobias R, McClure S, Styba G, Shi Q, Jackowski G: Removal of endotoxin from recombinant protein preparations. Clin Biochem 1997, 30:455-463.
• [32]Mei Q, Turner RE, Sorial V, Klivington D, Angus CW, Kovacs JA: Characterization of major surface glycoprotein genes of human Pneumocystis carinii and high-level expression of a conserved region. Infect Immun 1998, 66:4268-4273.
• [33]Bishop LR, Kovacs JA: Quantitation of anti-Pneumocystis jiroveci antibodies in healthy persons and immunocompromised patients. J Infect Dis 2003, 187:1844-1848.
• [34]Sims JT, Plattner R: MTT assays cannot be utilized to study the effects of STI571/Gleevec on the viability of solid tumor cell lines. Cancer Chemother Pharmacol 2009, 64:629-633.