Publications by authors named "Jessica Lopes da Rosa"

7 Publications

  • Page 1 of 1

Chromatin-mediated Candida albicans virulence.

Biochim Biophys Acta 2013 Mar-Apr;1819(3-4):349-55

Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605-2324, USA.

Candida albicans is the most prevalent human fungal pathogen. To successfully propagate an infection, this organism relies on the ability to change morphology, express virulence-associated genes and resist DNA damage caused by the host immune system. Many of these events involve chromatin alterations that are crucial for virulence. This review will focus on the studies that have been conducted on how chromatin function affects pathogenicity of C. albicans and other fungi. This article is part of a Special Issue entitled: Histone chaperones and Chromatin assembly.
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February 2014

A small molecule inhibitor of fungal histone acetyltransferase Rtt109.

Bioorg Med Chem Lett 2013 May 4;23(10):2853-9. Epub 2013 Apr 4.

Program in Gene Function and Expression, Program in Molecular Medicine, University of Massachusetts Medical School, 364 Plantation St., LRB506, Worcester, MA 01605, USA.

The histone acetyltransferase Rtt109 is the sole enzyme responsible for acetylation of histone H3 lysine 56 (H3K56) in fungal organisms. Loss of Rtt109 renders fungal cells extremely sensitive to genotoxic agents, and prevents pathogenesis in several clinically important species. Here, via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of Rtt109 that does not inhibit other acetyltransferase enzymes. This compound inhibits Rtt109 regardless of which histone chaperone cofactor protein (Asf1 or Vps75) is present, and appears to inhibit Rtt109 via a tight-binding, uncompetitive mechanism.
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http://dx.doi.org/10.1016/j.bmcl.2013.03.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654155PMC
May 2013

Chromatin-mediated Candida albicans virulence.

Biochim Biophys Acta 2012 Mar 24;1819(3-4):349-55. Epub 2011 Aug 24.

Candida albicans is the most prevalent human fungal pathogen. To successfully propagate an infection, this organism relies on the ability to change morphology, express virulence-associated genes and resist DNA damage caused by the host immune system. Many of these events involve chromatin alterations that are crucial for virulence. This review will focus on the studies that have been conducted on how chromatin function affects pathogenicity of C. albicans and other fungi. This article is part of a Special Issue entitled: Histone chaperones and Chromatin assembly.
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http://dx.doi.org/10.1016/j.bbagrm.2011.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243783PMC
March 2012

Overlapping regulation of CenH3 localization and histone H3 turnover by CAF-1 and HIR proteins in Saccharomyces cerevisiae.

Genetics 2011 Jan 13;187(1):9-19. Epub 2010 Oct 13.

Department of Molecular and Cell Biology, University of California, Berkeley, California 947202, USA.

Accurate chromosome segregation is dependent on the centromere-specific histone H3 isoform known generally as CenH3, or as Cse4 in budding yeast. Cytological experiments have shown that Cse4 appears at extracentromeric loci in yeast cells deficient for both the CAF-1 and HIR histone H3/H4 deposition complexes, consistent with increased nondisjunction in these double mutant cells. Here, we examined molecular aspects of this Cse4 mislocalization. Genome-scale chromatin immunoprecipitation analyses demonstrated broader distribution of Cse4 outside of centromeres in cac1Δ hir1Δ double mutant cells that lack both CAF-1 and HIR complexes than in either single mutant. However, cytological localization showed that the essential inner kinetochore component Mif2 (CENP-C) was not recruited to extracentromeric Cse4 in cac1Δ hir1Δ double mutant cells. We also observed that rpb1-1 mutants displayed a modestly increased Cse4 half-life at nonpermissive temperatures, suggesting that turnover of Cse4 is partially dependent on Pol II transcription. We used genome-scale assays to demonstrate that the CAF-1 and HIR complexes independently stimulate replication-independent histone H3 turnover rates. We discuss ways in which altered histone exchange kinetics may affect eviction of Cse4 from noncentromeric loci.
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http://dx.doi.org/10.1534/genetics.110.123117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018296PMC
January 2011

Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis.

Proc Natl Acad Sci U S A 2010 Jan 4;107(4):1594-9. Epub 2010 Jan 4.

Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605-2324, USA.

Candida albicans is a ubiquitous opportunistic pathogen that is the most prevalent cause of hospital-acquired fungal infections. In mammalian hosts, C. albicans is engulfed by phagocytes that attack the pathogen with DNA-damaging reactive oxygen species (ROS). Acetylation of histone H3 lysine 56 (H3K56) by the fungal-specific histone acetyltransferase Rtt109 is important for yeast model organisms to survive DNA damage and maintain genome integrity. To assess the importance of Rtt109 for C. albicans pathogenicity, we deleted the predicted homolog of Rtt109 in the clinical C. albicans isolate, SC5314. C. albicans rtt109(-/-) mutant cells lack acetylated H3K56 (H3K56ac) and are hypersensitive to genotoxic agents. Additionally, rtt109(-/-) mutant cells constitutively display increased H2A S129 phosphorylation and elevated DNA repair gene expression, consistent with endogenous DNA damage. Importantly, C. albicans rtt109(-/-) cells are significantly less pathogenic in mice and more susceptible to killing by macrophages in vitro than are wild-type cells. Via pharmacological inhibition of the host NADPH oxidase enzyme, we show that the increased sensitivity of rtt109(-/-) cells to macrophages depends on the host's ability to generate ROS, providing a mechanistic link between the drug sensitivity, gene expression, and pathogenesis phenotypes. We conclude that Rtt109 is particularly important for fungal pathogenicity, suggesting a unique target for therapeutic antifungal compounds.
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http://dx.doi.org/10.1073/pnas.0912427107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824404PMC
January 2010

Severe CD4 T cell-mediated immunopathology in murine schistosomiasis is dependent on IL-12p40 and correlates with high levels of IL-17.

J Immunol 2005 Sep;175(6):3920-6

Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.

C57BL/6 mice infected with the helminth Schistosoma mansoni develop small hepatic granulomas around parasite eggs, but concomitant immunization with soluble schistosome egg Ags (SEA) in CFA (SEA/CFA) causes marked exacerbation of the lesions in a Th1-dominated environment characterized by high levels of IFN-gamma. We explored the cause of the severe immunopathology by using IL-12p40(-/-) and IL-12p35(-/-) mice. SEA/CFA-immunized IL-12p40(-/-) mice, incapable of making IL-12 or IL-23, were completely resistant to high pathology, and their SEA-stimulated lymphoid cells failed to secrete significant IFN-gamma or IL-17. In contrast, SEA/CFA-immunized IL-12p35(-/-) mice, able to make IL-23 but not IL-12, developed severe lesions that correlated with high levels of IL-17, low IFN-gamma, and an expansion of activated CD4 T cells with a CD44(high)/CD62L(low) memory phenotype. In vivo administration of neutralizing anti-IL-17 mAb markedly inhibited hepatic granulomatous inflammation. Importantly, CBA mice, a naturally high pathology strain, also displayed elevated IL-17 levels comparable to those seen in the SEA/CFA-immunized BL/6 mice, and their lesions were similarly reduced by in vivo treatment with anti-IL-17. Our findings indicate that an IL-17-producing T cell population, likely driven by IL-23, significantly contributes to severe immunopathology in schistosomiasis.
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http://dx.doi.org/10.4049/jimmunol.175.6.3920DOI Listing
September 2005

Murine immune responses to a novel schistosome egg antigen, SmEP25.

Int J Parasitol 2005 Jul;35(8):875-82

Department of Biological Sciences, Illinois State University, Normal, IL 61790, USA.

Pathology in schistosomiasis consists of granuloma formation around parasite eggs. There is considerable variation in the severity of disease in individuals with schistosomiasis, which may result from differential responses to egg antigens. The egg-induced immunopathology is mediated by CD4+ T helper cells sensitised to egg antigens. In this study, cellular responses to a 25-kDa fraction of egg proteins identified a novel T-cell antigen, SmEP25. The native SmEP25 elicited significant proliferative responses as well as gamma interferon (IFN-gamma), IL-2, IL-4, and IL-5 secretion in CD4+ cells from 8.5-week infected CBA and C57BL/6 mice. In C57BL/6 mice, proliferative responses to SmEP25 were relatively stronger than those directed against the major egg antigen Sm-p40, whereas in CBA mice the reverse was found. SmEP25 elicited stronger Th2 type response than Sm-p40 in both mouse strains. By comparison, recombinant SmEP25 elicited a smaller, Th1-polarised response, with significant IFN-gamma, low levels of IL-5 and essentially no IL-4. B-cell responses to SmEP25 coincided with the start of parasite egg production and SmEP25 protein was restricted to parasite eggs. The systematic identification of T-cell-sensitising egg components will lead to a better understanding of the processes involved in granuloma formation.
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http://dx.doi.org/10.1016/j.ijpara.2005.03.012DOI Listing
July 2005