Metabolic adaptation in Cryptococcus neoformans during early murine pulmonary infection

Abstract

SummaryThe pathogenic fungus Cryptococcus neoformans generally initiates infection in mammalian lung tissue and subsequently disseminates to the brain. We performed serial analysis of gene expression (SAGE) on C. neoformans cells recovered from the lungs of mice and found elevated expression of genes for central carbon metabolism including functions for acetylCoA production and utilization. Deletion of the highly expressed ACS1 gene encoding acetyl-CoA synthetase revealed a requirement for growth on acetate and for full virulence. Transcripts for transporters (e.g. for monosaccharides, iron, copper and acetate) and for stress-response proteins were also elevated thus indicating a nutrient-limited and hostile host environment. The pattern of regulation was reminiscent of the control of alternative carbon source utilization and stress response by the Snf1 protein kinase in Saccharomyces cerevisiae. A snf1 mutant of C. neoformans showed defects in alternative carbon source utilization, the response to nitrosative stress, melanin production and virulence. However, loss of Snf1 did not influence the expression of a set of genes for carbon metabolism that were elevated upon lung infection. Taken together, the results reveal specific metabolic adaptations of C. neoformans during pulmonary infection and indicate a role for ACS1 and SNF1 in virulence.

Peroxisomal and Mitochondrial β-Oxidation Pathways Influence the Virulence of the Pathogenic Fungus Cryptococcus neoformans

“…Alternative carbon sources such as fatty acids may be important during infection and may be particularly relevant for the proliferation of intracellular pathogens following phagocytosis by macrophages (17,24,43,71). We therefore examined the expression of ␤-oxidation genes during lung infection of mice by C. neoformans (Fig.…”

“…To examine the expression of the C. neoformans ␤-oxidation genes in vivo, cells were pregrown in YPD, transferred to LIM for 24 h, washed three times in phosphate-buffered saline (PBS), and inoculated by intranasal instillation in AJcr mice; subsequently, 1 ϫ 10 8 cells were retrieved from the lungs of mice by lavage at 0 h, 8 h, and 24 h after infection, as described by Hu et al (24). The cells were washed three times with ice-cold water and lyophilized.…”

“…C. neoformans survives within macrophages and may use host lipids for intracellular proliferation and to modulate the host immune response (14,82). In particular, transcription profiling revealed that cryptococcal genes for peroxisomal ␤-oxidation, fatty acid import, and lipid degradation are upregulated upon macrophage internalization and during pulmonary infection (17,24). Thus, fatty acid metabolism may be important for the virulence of C. neoformans in mammals.…”

Biochemical and Kinetic Characterization of Xylulose 5-Phosphate/Fructose 6-Phosphate Phosphoketolase 2 (Xfp2) from Cryptococcus neoformans

“…Genes encoding enzymes from three putative acetateproducing pathways and two putative acetate transporters have been shown to be upregulated during cryptococcal infection (6), suggesting acetate production and transport may be a necessary and required part of the pathogenic process.…”

Preferential transcription of Paracoccidioides brasiliensis genes: host niche and time-dependent expression

“…The high-affinity system of iron uptake, which envolves a member of the copper oxidase family, is present in fungi (Stearman et al 1996) and requires efficient copper uptake, since maturation of the copper protein in the secretory apparatus requires the acquisition of copper and the absence of genes related to this activity results in a decrease in high affinity iron transport (Dancis et al 1994). Transcripts for iron and copper transporters were elevated in C. neoformans during early murine pulmonary infection, indicating a nutrient-limited host environment (Hu et al 2008). The transport of copper seems to be exacerbated in P. brasiliensis yeast cells recovered from liver of infected mice.…”