Relationship of the glyoxylate pathway to the pathogenesis of Cryptococcus neoformans.
Functional genomics has become a major focus in the study of microbial pathogenesis. This study used a functional genomic tool, differential display reverse transcription-PCR, to identify a transcriptional profile of Cryptococcus neoformans cells as they produced meningitis in an immunosuppressed host. This serial global gene expression during infection allowed for the identification of up- and down-regulated genes during infection. During this profiling, a single gene for the enzyme isocitrate lyase (ICL1) was found to be up regulated at 1 week of infection in a rabbit meningitis model and during a time of maximum host cellular response. The finding suggested that this enzyme and the glyoxylate shunt pathway are important to this yeast's energy production during infection. However, site-directed icl1 mutants had no apparent virulence defect in two animal models and no growth defect within macrophages. These observations suggest that although the yeast responded to a certain environmental cue(s) by an increase in ICL1 expression during infection, this gene was not necessary for progression of a C. neoformans infection. Compounds that specifically target only ICL1 are unlikely to cripple C. neoformans growth in vivo.
Rude
Thomas H
TH
Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Toffaletti
Dena L
DL
Cox
Gary M
GM
Perfect
John R
JR
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003453:Cryptococcosis / Q000209:etiology; D003455:Cryptococcus neoformans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity*; D004271:DNA, Fungal / Q000235:genetics; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005800:Genes, Fungal; D006038:Glyoxylates / Q000378:metabolism*; D006801:Humans; D007522:Isocitrate Lyase / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology; D016919:Meningitis, Cryptococcal / Q000209:etiology; D051379:Mice; D008805:Mice, Inbred A; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D014774:Virulence / Q000235:genetics / Q000502:physiology
D004271:DNA, Fungal; D005656:Fungal Proteins; D006038:Glyoxylates; D007522:Isocitrate Lyase; C031150:glyoxylic acid