Because of advances in highly active antiretroviral therapy (HAART), the incidence of oral and esophageal candidiasis and other opportunistic infections is currently reduced in HIV+ individuals compared to previous years. Unfortunately the reduced incidence is not correlated with major advances in preventive or treatment methodologies for candidiasis, but rather with the ability to suppress HIV infection and restore adequate anti-fungal immunity by lifelong administration of HAART. The uncertainties that accompany the long-term success of HAART, the inability of some individuals to tolerate or accept the therapy, and the lack of availability of HAART therapy to the majority of the global population point to the need for a basic understanding of the pathogenesis of oral and esophageal candidiasis that can be applied to prevention in those at risk and therapy in infected HIV+ individuals. The recognition of Hwpl as an adhesin and virulence factor and the involvement of mammalian transglutaminases in adhesion have posed important new questions and have opened new avenues of exploration that will benefit our understanding of the pathogenic mechanisms of candidiasis.
New aims are proposed that explore mammalian parameters that lead to stabilized adhesion. These include characterizing adherent buccal epithelial cells (BECs) and identifying BEC proteins that become cross-linked to rHwpl. With the availability of new technologies including bioinformatics, cell biology and microarray analyses that build upon molecular genetic and biochemical tools recently acquired, we currently have unprecedented opportunities to decipher the complexities of candidiasis and develop non-toxic therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011375-12
Application #
7048634
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Nokta, Mostafa A
Project Start
1994-09-30
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
12
Fiscal Year
2006
Total Cost
$390,356
Indirect Cost
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Wollert, Torsten; Rollenhagen, Christiane; Langford, George M et al. (2012) Human oral keratinocytes: a model system to analyze host-pathogen interactions. Methods Mol Biol 845:289-302
Rollenhagen, Christiane; Wollert, Torsten; Langford, George M et al. (2009) Stimulation of cell motility and expression of late markers of differentiation in human oral keratinocytes by Candida albicans. Cell Microbiol 11:946-66
Ponniah, Gomathinayagam; Rollenhagen, Christiane; Bahn, Yong-Sun et al. (2007) State of differentiation defines buccal epithelial cell affinity for cross-linking to Candida albicans Hwp1. J Oral Pathol Med 36:456-67
Naglik, Julian R; Fostira, Florentia; Ruprai, Jasmeet et al. (2006) Candida albicans HWP1 gene expression and host antibody responses in colonization and disease. J Med Microbiol 55:1323-7
Staab, Janet F; Bahn, Yong-Sun; Tai, Chia-Hui et al. (2004) Expression of transglutaminase substrate activity on Candida albicans germ tubes through a coiled, disulfide-bonded N-terminal domain of Hwp1 requires C-terminal glycosylphosphatidylinositol modification. J Biol Chem 279:40737-47
Daniels, Karla J; Lockhart, Shawn R; Staab, Janet F et al. (2003) The adhesin Hwp1 and the first daughter cell localize to the a/a portion of the conjugation bridge during Candida albicans mating. Mol Biol Cell 14:4920-30
Staab, Janet F; Sundstrom, Paula (2003) URA3 as a selectable marker for disruption and virulence assessment of Candida albicans genes. Trends Microbiol 11:69-73
Sundstrom, Paula; Cutler, Jim E; Staab, Janet F (2002) Reevaluation of the role of HWP1 in systemic candidiasis by use of Candida albicans strains with selectable marker URA3 targeted to the ENO1 locus. Infect Immun 70:3281-3
Sundstrom, Paula (2002) Adhesion in Candida spp. Cell Microbiol 4:461-9
Sundstrom, Paula; Balish, Edward; Allen, Carl M (2002) Essential role of the Candida albicans transglutaminase substrate, hyphal wall protein 1, in lethal oroesophageal candidiasis in immunodeficient mice. J Infect Dis 185:521-30

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