Thiol peroxidase is critical for virulence and resistance to nitric oxide and peroxide in the fungal pathogen, Cryptococcus neoformans

Abstract

SummaryCryptococcus neoformans is a fungal pathogen most commonly causing meningitis in immunocompromised patients. Current therapies are inadequate, and novel antifungal targets are needed. We have identified by proteomics two thiol peroxidases that are differentially expressed at 37 ∞ ∞ ∞ ∞ C, the temperature of the mammalian host. Consistent with their antioxidant role, we show that the genes encoding these thiolspecific antioxidants, TSA1 and TSA3 , are transcriptionally induced when C. neoformans is exposed to hydrogen peroxide. Genome sequence analysis of C. neoformans revealed a third thiol peroxidase, TSA4 .

Two glutathione peroxidases in the fungal pathogen Cryptococcus neoformans are expressed in the presence of specific substrates

“…Since mutation of the GPX genes does not affect virulence or resistance to hydrogen peroxide and nitric oxide, it is plausible that these two compounds, and not the more complex alkyl or aromatic peroxides to which the gpx mutants are sensitive, are more important to the host defence against C. neoformans. Both the thiol peroxidase Tsa1, which is important for hydrogen peroxide, t-butylhydroperoxide and nitric oxide resistance, and the flavohaemoglobin denitrosylase Fhb1, which is important specifically for nitric oxide resistance, are important to the virulence of C. neoformans (de Jesus-Berrios et al, 2003;Missall et al, 2004b). Another possibility is that in the absence of a GPX, other antioxidant enzyme(s) are upregulated in vivo to compensate for the lack of Gpx activity.…”

“…But since the double mutant is also not sensitive to hydrogen peroxide, this suggests that another peroxide defence system in C. neoformans, such as catalases, glutaredoxins or other peroxidases, is more efficient and specific for the stress induced by hydrogen peroxide compared to more complex hydroperoxides. In previous work, we have shown the importance of the thiol peroxidase Tsa1 to the hydrogen peroxide stress resistance of C. neoformans (Missall et al, 2004b).…”

“…For example, flavohaemoglobin denitrosylase, Fhb1, which is necessary for nitric oxide resistance (de Jesus-Berrios et al, 2003), and the thiol peroxidase, Tsa1, which is important for both oxidative and nitrosative stress resistance (Missall et al, 2004b), contribute significantly to virulence in C. neoformans. In addition, thioredoxin reductase, upon which Tsa1 is thought ultimately to be dependent for reduction, has been shown to be induced during oxidative and nitrosative stress and to be necessary for viability in C. neoformans .…”

“…The glutathione system has not been studied in any fungal pathogen to date, but enzymes important for resistance to oxidative and nitrosative stress have been linked to both virulence and viability of Cryptococcus neoformans (de JesusBerrios et al, 2003;Cox et al, 2003;Missall et al, 2004b. For example, flavohaemoglobin denitrosylase, Fhb1, which is necessary for nitric oxide resistance (de Jesus-Berrios et al, 2003), and the thiol peroxidase, Tsa1, which is important for both oxidative and nitrosative stress resistance (Missall et al, 2004b), contribute significantly to virulence in C. neoformans.…”

Eca1, a Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase, Is Involved in Stress Tolerance and Virulence inCryptococcus neoformans

“…Tolerance to thermal stress (caused by body temperature) and oxidative stresses (from mammalian host defenses) is critical for successful infection. C. neoformans mutants with increased sensitivity to oxidative or nitrosative challenge, including those lacking superoxide dismutase Sod1 or Sod2 (18,35), alternative oxidase Aox1 (2), flavohemoglobin denitrosylase Fhb1 (23), thiol peroxidase Tsa1 (48), or thioredoxin Trx1 (47), exhibit attenuated virulence. Temperature-sensitive mutants have been isolated in C. neoformans, including cna1 (calcineurin catalytic subunit), cnb1 (calcineurin regulatory subunit), cpa1 (cyclophilin A), and ras1 strains, and all of these have reduced virulence in mammalian host models (3,29,55,73).…”