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Chapter 27 : Cell Surface Determinants and Their Application in Vaccine Development

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Abstract:

The favored substrate of appears to be material with a high organic content, with the assumption frequently being made that it, too, must grow within the soil. Developing an understanding of the functions and regulation of such factors is integral to understanding the pathogenesis of disease and could serve as the foundation for innovative approaches to the treatment of fungal infections. The comparison of wild-type strains with strains lacking specific yeast-phase characteristics requires reliable, precise methods of genetic manipulation. Investigation of pathogenesis in has required the adaptation of a wide variety of molecular biology tools to this task. The indispensable role of BAD1 in virulence was highlighted through the agency of several molecular genetic tools newly available for use in studies of . Cellular immunity is critical in acquired resistance to . Mice immunized with either viable or merthiolate-killed yeast demonstrate peak delayed-type hypersensitivity (DTH) responses that coincide temporally with maximal resistance to a lethal challenge with live given intranasally, intraperitoneally, and intravenously. Depletion of T-cell subsets during the period of vaccination (defined as the induction phase of vaccine immunity) and throughout the period postinfection gave striking results. Understanding antigen processing and presentation mechanisms and the development of memory immunity under the unusual circumstances will allow the rational design of safe, effective vaccines that harness natural or unnatural lung immunity against and other fungal pathogens.

Citation: Klein B. 2006. Cell Surface Determinants and Their Application in Vaccine Development, p 393-406. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch27

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Figure 1

Overview of the role of BAD1 in the pathogenesis of blastomycosis. Linkage of BAD1 in with the phase transition of mold to yeast, adhesion, and modulation and evasion of host immunity is shown. After morphogenesis from mold to yeast (top), effects of BAD1 expression on wild-type yeast are shown on the left side of the figure, whereas effects of the null mutation in the isogenic knockout strain are shown on the right. BAD1 on wild-type yeast suppresses TNF-α production, which leads to progressive infection ( ). Surface BAD1 suppresses TNF-α production via TGF-α ( ), whereas soluble BAD1 suppresses TNF-α independently of TGF-α. BAD1 thus acts in multiple key ways to foster infection and disease progression. Adapted from reference with permission.

Citation: Klein B. 2006. Cell Surface Determinants and Their Application in Vaccine Development, p 393-406. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch27
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Image of Figure 2
Figure 2

BAD1 blocks TNF-α production by phagocytes. (A) Isogenic BAD1 plus and minus strains (ATCC 26199 and knockout strain 55) were cocultured in vitro with peritoneal macrophages, and TNF-α levels were measured at serial time points postincubation (denoted on the axis from 24 to 96 h). Wild-type strain ATCC 26199 blocks TNF-α production, and knockout strain 55 stimulates TNF-α. (B) Soluble purified BAD1 was added in vitro to wells where knockout strain 55 induced TNF-α production by macrophages. BAD1 blocked TNF-α production in a concentration-dependent manner. Note that BAD1 had previously been named WI-1. Adapted from reference with permission.

Citation: Klein B. 2006. Cell Surface Determinants and Their Application in Vaccine Development, p 393-406. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch27
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Figure 3

BAD1 suppresses TNF-α via TGF-β-dependent and -independent mechanisms. Isogenic BAD1 plus and minus strains (wild-type strain ATCC 26199 and BAD1 knockout 55) or BAD1-coated knockout yeasts were cocultured in vitro with peritoneal macrophages, and levels of TNF-α (black bars) and TGF-α (gray bars) were measured after 24 to 48 h. (Top) Wild-type yeast or BAD1-coated knockout yeast induced TGF-β and suppressed TNF-α. Soluble BAD1 failed to induce TGF-β but nevertheless suppressed TNF-α. (Bottom) Anti-TGF-β neutralized the product and restored TNF-α suppressed by yeast cell surface BAD1. Anti-TGF-β failed to restore TNF-α suppressed in response to soluble BAD1. Thus, surface BAD1 suppresses TNF-α in a TGF-β-dependent manner and soluble BAD1 suppresses TNF-α in a TGF-β-independent manner. Adapted from reference with permission.

Citation: Klein B. 2006. Cell Surface Determinants and Their Application in Vaccine Development, p 393-406. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch27
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Figure 4

Acquired resistance to blastomycosis after vaccination with a recombinant, live, attenuated strain of . (Top) DTH responses. C57BL/6 mice were vaccinated intranasally (i.n.), subcutaneously (s.c.), and intravenously (i.v.). After immunization, mice were injected with 10 dead yeast cells of strain 55 into one footpad or phosphate-buffered saline (PBS) into the other. Footpad swelling was measured 24 h later. Error bars show the standard error of the mean. (Center) Lung infection. At 2 weeks after immunization, mice were infected intranasally with 10 CFU of wild-type ATCC 26199 yeast. Lung CFU were measured 3 weeks later. Error bars show the standard error of the mean. values are for comparison of each immunized group versus nonimmune controls. (Bottom) Survival analysis. Groups of C57BL/6 mice were infected as above and monitored for survival. values are for comparison of each immunized group versus nonimmune mice. Reprinted from reference with permission.

Citation: Klein B. 2006. Cell Surface Determinants and Their Application in Vaccine Development, p 393-406. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch27
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Figure 5

IFN-γ and TNF-α are dispensable in vaccine immunity. Knockout and wild-type mice were analyzed for lung CFU 2 weeks after infection or monitored for survival. Mean lung CFU ± standard error of the mean and mean survival time ± standard error of the mean are shown. %, percentage alive 50 days postinfection. *, < 0.007 versus unvaccinated controls; **, < 0.012 versus vaccinated transgenic mice; ***, < 0.005 versus unvaccinated wild-type mice. Reprinted from reference with permission.

Citation: Klein B. 2006. Cell Surface Determinants and Their Application in Vaccine Development, p 393-406. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch27
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Figure 6

Role of CD4 and CD8 T cells during induction of vaccine immunity. (A) Lung CFU. Vaccinated mice were depleted of T cells during vaccination and infection. *, = 0.1983 versus IgG control; **, = 0.9825 versus control; ***, = 0.7 versus unvaccinated mice. (B) Survival of vaccinated, CD4 mice and wild-type mice. Vaccinated CD4/CD8 mice were depleted of CD8 cells after vaccination and through infection. *, < 0.0001 versus unvaccinated mice; **, = 0.008 versus vaccinated CD4 mice. (C) CD8 T cells mediate vaccine immunity to . Anti-CD4/anti-CD8 denotes vaccinated CD4-depleted mice, depleted of CD8 T cells after vaccination and through infection. *, < 0.0002 versus unvaccinated mice or anti-CD4/anti-CD8-treated mice. Reprinted from reference with permission.

Citation: Klein B. 2006. Cell Surface Determinants and Their Application in Vaccine Development, p 393-406. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch27
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Tables

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Table 1.

Approaches available for genetic manipulation of

Citation: Klein B. 2006. Cell Surface Determinants and Their Application in Vaccine Development, p 393-406. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch27

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