Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-10-01
2002-02-05
Houtteman, Scott W. (Department: 1656)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S006120
Reexamination Certificate
active
06344554
ABSTRACT:
TECHNICAL FIELD
This invention relates to polynucleotides and protein products encoded thereby. More specifically, the invention relates to polynucleotides of
C. albicans
and polypeptides encoded by the polynucleotides, which are associated with TUP1 gene fimction, particularly, gene repression and morphological transition, particularly to a filamentous form.
BACKGROUND OF INVENTION
The yeast Candida is a ubiquitous human commensal, known as the causative agent of candidiasis. The majority of the diseases are caused by the species
Candida albicans
. It is the most prevalent commensal and opportunistic fungal pathogen of humans, causing common superficial infections as well as more serious systemic and organ infections. Cannon et al. (1995)
J. Dental Research
74:1152-1161. Exposure to
C. albicans
at or shortly after birth results in lifelong colonization in the host tissues, such as the gastrointestinal tract, oral cavity and genital area. It has been noted that approximately 75% of women would suffer from vaginal candidiasis at some stage in their lifetime. Bossche et al. (1993)
Fungal Dimorphism
3-10; Fidel et al. (1996)
Clin. Micro. Rev
. 9(3):335-348. Whereas
C. albicans
infection often remains localized to the initial sites of contact in healthy individuals,
C. albicans
cells can invade submucosal vessels, disseminate hematogenously and become life-threatening, especially to immunocompromised patients. The invasive forms of
C. albicans
infection are not only dangerous in their own right, but they are believed to facilitate infections by other opportunistic pathogens.
In the last decades, the incidence of severe and systemic candidiasis has increased dramatically because of the growing number of immunocompromised patients suffering from AIDS, diabetes, cancer and other conditions. In addition, the widespread use of immunosuppressants for organ transplant patients, the common practice of radiation and chemotherapy for treating malignancies, as well as the growing size of the aging population have increased the morbidity of this opportunistic pathogen. For reviews, see Rubin et al. (1993)
Eur. J. Clin. Microbiol. Infect. Dis
. 12 Suppl. 1, 542; Dudley et al. (1990)
Pharmacotherapy
10
:
133
; Paya (1993)
Clin. Infect. Dis
. 16:677-688; Rubin (1993)
Eur. J. Clin. Micro. Infect. Dis
. 12 Suppl. 1:S42-S48.
Despite decades of intensive study, the properties of
C. albicans
that contribute to its virulence are only beginning to be understood. Among the most investigated virulence factors are adherence, production of hydrolytic enzymes and adoption of various cell morphologies. Odds et al. (1994)
Am. Soc. Microbiol. News
60:313-318. The ability of
C. albicans
to adhere to the host surfaces probably allows initial colonization and infection of the host tissues. Secretion of a variety of hydrolytic enzymes which are capable of degrading proteins and lipids is thought to generate tissue cavitation and thereby facilitate deeper penetration. The morphological transition between various forms of
C. albicans
is also considered a key determinant of virulence.
C. albicans
cells can exist in a variety of shapes, ranging from ellipsoidal budding yeast cells (also known as blastospores) to filamentous forms in which cells remain attached to each other after dividing and thereby form long branched strings of connected cells. These filamentous forms include both pseudohyphae (where cells that form filaments are elongated, but still ellipsoidal) and true hyphae (where highly elongated cells that form the filaments are cylindrical and are separated by perpendicular septal walls). Transitions between the ellipsoidal and filamentous forms take place by outgrowth of new cells with the altered morphology, rather than remodeling of pre-existing cells. The ability of
C. albicans
to adopt these different morphologies is thought to allow the fungus to adapt to, and possibly travel to, different host micro-environments. Odds et al. (1988)
Candida and Candidosis
(Bailliere Tindall, London, 2nd ed.); Odds et al. (1994); Odds et al. (1994)
J. Am. Acad. Dermatol
. 31:52. The regulation of cellular morphology is in response to environmental conditions. In vitro studies have shown that most
C. albicans
strains assume filamentous forms when they are subjected to either unfavorable growth conditions, such as nutrient-poor media and high CO
2
:O
2
ratio, or host-mimicking conditions, such as high temperature (37° C.) and mammalian serum (10%). Conversely, rich media, low temperatures and aerated conditions promote blastospore growth. Intermediate conditions can induce various pseudohyphal forms as well as true hyphae. For reviews, see Odds et al. (1988)
Candida and Candidosis
, Bailliere Tindall, London, ed. 2nd; Odds et al
Crit. Rev Microbiol
. (1985) 12:45; Gow et al. (1984)
Sabouraudia
22:137. Very little is known about the genetic identity of regulators controlling the morphological transition of
C. albicans.
The ability of
C. albicans
to adopt these different morphologies is thought to contribute to colonization and dissemination within host tissues and thereby to promote infection. Odds (1988); Odds (1994)
J. Am. Acad. Dermatol
. 31:S2. It has been commonly suggested that the hyphal form is invasive and pathogenic, while the blastospore is the commensal, non-pathogenic form. However, all morphological forms have been found within infected tissues. Histopathological examination of candidiasis lesions indicates that hyphae are not always present. More recent studies have shown that commensal
C. albicans
does not exist uniquely in the blastospore form. In fact, sometimes invading
C. albicans
cells are seen exclusively as the budding yeast form. Odds et al. (1994)
Am. Soc. Microbiol. News
60:313-318. Despite the uncertainty with regard to the relative roles these two distinct forms of
C. albicans
have in fungal virulence, phenotypic switching represents a remarkable adaptation that
C. albicans
has acquired to cope with different host microenvironments.
The TUP1 gene of
C. albicans
appears to be a key regulator of filamentous growth. Braun et al. (1997)
Science
277:105-109. Cells in which TUP1 function is disrupted grow exclusively as filaments in all conditions tested (e.g., nutrient-rich and nutrient-poor media, in the presence and absence of mammalian serum, aerobic and micro-aerobic conditions, throughout the range of temperature and pH values). These results suggest that the gene product Tup1 is a repressor of filamentous development. This function for the Tup1 protein may occur through transcriptional repression of genes whose expression is required to initiate and/or maintain filamentous growth. This conclusion is supported by: (1) the amino acid sequence of
C. albicans
Tup1 protein is very similar (67% identity) to that of the
S. cerevisiae
Tup1 protein, a known transcriptional repressor, and (2) expression of the
C. albicans
TUP1 gene is
S. cerevisiae
lacking TUP1 function restored wild type cell shape and growth behavior to the
S. cerevisiae
cells indicating that
C. albicans
TUP1 gene product functionally complements (i.e., substitutes for)
S. cerevisiae
tupl (i.e., lacking Tup1 fimction). For papers describing
S. cerevisiae
TUP1, see Tzamarias et al. (1994)
Nature
369: 758; Komachi et al.
Genes Dev
. 8: 2857; Wahi et al. (1995)
Genetics
140: 79-90; Edmondson et al. (1996)
Genes Dev
. 10: 1247.
Current therapy available for systemic candidiasis is limited to the use of anti-fungal agents. In practice, the arsenal of anti-fingal drugs is based on a few antimycotics, such as flucytosine, amphotericin B and azole derivatives. Many of these antimycotics are somewhat water insoluble which restrict their bioavailability and present problems in intravenous formulation. In addition, they cause serious and often difficult side effects, such as renal toxicity, bone marrow destruction, as well as unpleasant symptoms such as fever and shivering. Furthermore, the chronic use of these anti-fungal agents has led to the emergence of drug-r
Braun Burkhard
Johnson Alexander D.
Houtteman Scott W.
Regents of the University of California
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