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Chapter 18 : Specific Chromosome Alterations of Candida albicans: Mechanisms for Adaptation to Pathogenicity
Category: Fungi and Fungal Pathogenesis; Bacterial Pathogenesis
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This chapter reviews the examples of Candida albicans survival resulting from specific chromosome alterations in vitro, as well as recent advances in understanding this regulation. Previously classified as asexual, C. albicans belongs to the genus Candida, which is composed of approximately 159 species of lower fungi reproducing by multilateral budding. Development of fluconazole resistance has been extensively studied in clinical settings and in laboratories. Series of matched clinical isolates became an important tool in these studies. Matched series are usually represented by the isolates, which were sampled from the same patient either at a certain time during infection or during recurrent episodes and which were derived from the same strain. Study of the deletion in one of the mutants confirmed the loss of at least a 305-kbp portion adjacent to the right telomere. The reason this deletion confers the Sou+ phenotype is discussed in the section Ch5 carries functionally redundant regulatory genes. In fact, an uncharacterized rearrangement of one mutant of strain CAF4-2 is probably the only true exception from the Ch5 monosomy. The major control of sorbose utilization (CSUs) on Ch5 that are controlled by this chromosome copy number, apparently can 'override' secondary CSUs, thus allowing ready adaptation to sorbose. Universality of the control caused by aneuploidy implies that C. albicans regulatory and metabolic genes are distributed nonrandomly over the chromosomes.
Schematic representation of Ch5 showing regions that are responsible for different phenotypes. Included are the length (1,295 kbp); centromere (C); telomeres (T); and the mjor repeat sequence (MRS). See Lephart et al. (2005) for the orientation of MRS. The contigs, including their names, are indicated under the diagram of the chromosome. The aligned contigs are presented as arrows. Orientation of the contigs flanking MRS is explained by Wu et al. (2005). Also shown are 2 portions, approximately 305 kbp adjacent to the right telomere or the entire left arm, loss or duplication of which confers the Sou+ or Flur phenotype, respectively, in naturally occurring mutants. CSU51 to CSU55 in five unique functional regions 140 (B and A), 135, C, and 139 are shown within an approximately 209-kb critical portion of the right arm of Ch5. The regions are organized in two redundant regulatory pathways, I and II. Also shown are the contig positions of the unique sequences 133, 134, 137, 141, 142, and 148, which were cloned from DNA library of Ch5 due to their repression of growth on sorbose medium (Kabir et al., 2005). Also shown are ERG11 in contig 19-10080 and TAC1 and MTL in contig 19-10170 on the left arm of Ch5. Not shown is an unknown portion, amplication of which confers Foar. Also, loss of an entire homolog of Ch5 confers Sou+. (Adapted from Wu et al., 2005, and Kabir et al., 2005).
Schematic presentation of the electrophoretic karyotype of C. albicans strain CAF4-2 and the chromosome assignment of the genes, which are implicated with the resistance to fluconazole in clinical isolates. Metabolic genes are underlined; the regulatory gene is not. Dotted line corresponds to one homolog. Continuous line corresponds to two comigrating homologs.
Examples of specific chromosome alterations, which allow survival in four specific adverse environments. Portions of chromosome patterns are precisely separated using different conditions of orthogonal-field-alternation gel electrophoresis. (A) Ch5 alterations in sequential series of Sou+ and Sou− derivatives from strain 3153A. Shown are the Sou− parental strain 3153A, its Sou+ derivative Sor55; the Sou− phenotypic revertant of the previous Sor55-1, and the Sou+ derivative of the revertant Sor55-1-1. Short Ch7, Ch6, and Ch5, or the bottom group of chromosomes, (B) are separated precisely, whereas the middle-sized or middle group, (M) and long chromosomes, or top group, (T) are compressed. (B) and (C) An approximately 250-kbp enlargement of Ch5 and trisomy of Ch4, respectively, in two classes of Foar derivatives of strain 3153A are shown. The Ch4 and Ch3 of the M-group are separated precisely. The T-group is compressed. The B-group is poorly separated, although Ch5 is clearly observed. (D) and (E) Reduction of Ch4 and concomitant reduction of Ch4 and trisomy of Ch3 in Flur derivatives of strain SGY-243 appearing after, respectively, short and long exposure to fluconazole. See explanations in (A) for the chromosome separation in (D). See explanations in (B) and (C) for the chromosome separation in (E). Note that patterns of chromosomes in parental strains 3153A and SGY-243 are different (see schematics in Fig. 2A and M for the comparison). (F) Trisomy of Ch2 coupled with an approximately 1-Mbp deletion in Aru+ derivatives of strain 3153A. (G) Hybridization of the blot in (F) to probe HIS3, revealing formation of an additional truncated homolog of Ch2. Note that two regular copies of Ch2 are compressed in the T-group of chromosomes in (F). Arrows indicate normal and altered copies of specific chromosomes. (Adapted from Rustchenko et al., 1994; Janbon et al., 1998; Perepnikhatka et al., 1999; and Wellington and Rustchenko, 2005.)
Cartoon showing tandemly positioned SOU1 and SOU2 on Ch4. The C-rich region between the genes is also indicated.
The schematic presentation of the electrophoretic karyotype of C. albicans CAF4-2 and the chromosome assignment of the genes, which are implicated with the resistance to sorbose. Metabolic gene is underlined; regulatory genes are not. Major regulatory genes CSU51 to CSU55 on Ch5 are in bold (Fig. 1). For more details see the legend of Fig. 2.
Specific chromosome alterations confer four specific phenotypes