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      Vaccine-Mediated Immune Responses to Experimental Pulmonary Cryptococcus gattii Infection in Mice

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          Abstract

          Cryptococcus gattii is a fungal pathogen that can cause life-threatening respiratory and disseminated infections in immune-competent and immune-suppressed individuals. Currently, there are no standardized vaccines against cryptococcosis in humans, underlying an urgent need for effective therapies and/or vaccines. In this study, we evaluated the efficacy of intranasal immunization with C. gattii cell wall associated (CW) and/or cytoplasmic (CP) protein preparations to induce protection against experimental pulmonary C. gattii infection in mice. BALB/c mice immunized with C. gattii CW and/or CP protein preparations exhibited a significant reduction in pulmonary fungal burden and prolonged survival following pulmonary challenge with C. gattii. Protection was associated with significantly increased pro-inflammatory and Th1-type cytokine recall responses, in vitro and increased C. gattii-specific antibody production in immunized mice challenged with C. gattii. A number of immunodominant proteins were identified following immunoblot analysis of C. gattii CW and CP protein preparations using sera from immunized mice. Immunization with a combined CW and CP protein preparation resulted in an early increase in pulmonary T cell infiltrates following challenge with C. gattii. Overall, our studies show that C. gattii CW and CP protein preparations contain antigens that may be included in a subunit vaccine to induce prolonged protection against pulmonary C. gattii infection.

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          Most cited references52

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          Cryptococcosis in the era of AIDS--100 years after the discovery of Cryptococcus neoformans.

          Although Cryptococcus neoformans and cryptococcosis have existed for several millennia, a century has passed since the discovery of this encapsulated yeast and its devastating disease. With the advent of the AIDS pandemic, cryptococcal meningitis has emerged as a leading cause of infectious morbidity and mortality and a frequently life-threatening opportunistic mycosis among patients with AIDS. Both basic and clinical research have accelerated in the 1990s, and this review attempts to highlight some of these advances. The discussion covers recent findings, current concepts, controversies, and unresolved issues related to the ecology and genetics of C. neoformans; the surface structure of the yeast; and the mechanisms of host defense. Regarding cell-mediated immunity, CD4+ T cells are crucial for successful resistance, but CD8+ T cells may also participate significantly in the cytokine-mediated activation of anticryptococcal effector cells. In addition to cell-mediated immunity, monoclonal antibodies to the major capsular polysaccharide, the glucuronoxylomannan, offer some protection in murine models of cryptococcosis. Clinical concepts are presented that relate to the distinctive features of cryptococcosis in patients with AIDS and the diagnosis, treatment, and prevention of cryptococcosis in AIDS patients.
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            Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box.

            Cryptococcus neoformans is generally considered to be an opportunistic fungal pathogen because of its tendency to infect immunocompromised individuals, particularly those infected with HIV. However, this view has been challenged by the recent discovery of specialized interactions between the fungus and its mammalian hosts, and by the emergence of the related species Cryptococcus gattii as a primary pathogen of immunocompetent populations. In this Review, we highlight features of cryptococcal pathogens that reveal their adaptation to the mammalian environment. These features include not only remarkably sophisticated interactions with phagocytic cells to promote intracellular survival, dissemination to the central nervous system and escape, but also surprising morphological and genomic adaptations such as the formation of polyploid giant cells in the lung.
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              Cell wall and secreted proteins of Candida albicans: identification, function, and expression.

              The cell wall is essential to nearly every aspect of the biology and pathogenicity of Candida albicans. Although it was initially considered an almost inert cellular structure that protected the protoplast against osmotic offense, more recent studies have demonstrated that it is a dynamic organelle. The major components of the cell wall are glucan and chitin, which are associated with structural rigidity, and mannoproteins. The protein component, including both mannoprotein and nonmannoproteins, comprises some 40 or more moieties. Wall proteins may differ in their expression, secretion, or topological location within the wall structure. Proteins may be modified by glycosylation (primarily addition of mannose residues), phosphorylation, and ubiquitination. Among the secreted enzymes are those that are postulated to have substrates within the cell wall and those that find substrates in the extracellular environment. Cell wall proteins have been implicated in adhesion to host tissues and ligands. Fibrinogen, complement fragments, and several extracellular matrix components are among the host proteins bound by cell wall proteins. Proteins related to the hsp70 and hsp90 families of conserved stress proteins and some glycolytic enzyme proteins are also found in the cell wall, apparently as bona fide components. In addition, the expression of some proteins is associated with the morphological growth form of the fungus and may play a role in morphogenesis. Finally, surface mannoproteins are strong immunogens that trigger and modulate the host immune response during candidiasis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                13 August 2014
                : 9
                : 8
                : e104316
                Affiliations
                [1 ]Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, United States of America
                [2 ]The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, United States of America
                [3 ]Department of Biochemistry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
                Geisel School of Medicine at Dartmouth, United States of America
                Author notes

                Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: FW is a member of the PLoS One editorial board. However, this does not alter the authors' adherence to PLOS ONE Editorial policies and criteria.

                Conceived and designed the experiments: AC KW FW. Performed the experiments: AC RH KW CH CL. Analyzed the data: AC KW FW SW JL. Contributed reagents/materials/analysis tools: SW. Contributed to the writing of the manuscript: AC KW SW JL FW.

                Article
                PONE-D-14-17441
                10.1371/journal.pone.0104316
                4132117
                25119981
                4fe2a308-80f9-442f-a513-bf3ff0073900
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 April 2014
                : 7 July 2014
                Page count
                Pages: 13
                Funding
                This work was supported by the Army Research Office of the Department of Defense under Contract No. W911NF-11-1-0136 awarded to FW and JL ( http://www.defense.gov/) and grants 2RO1 AI071752 and R21 AI083718 from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) awarded to FW ( http://www.nih.gov/). Protein identifications were accomplished at the Institutional Mass Spectrometry Laboratory at The University of Texas Health Science Center at San Antonio with support by UTHSCSA and NIH (1 S10 RR021160-01) awarded to SW ( http://www.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Immunology
                Microbiology
                Mycology
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

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