Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages

Gary M. Cox, Thomas S. Harrison, Henry C. McDade, Carlos P. Taborda, Garrett Heinrich, Arturo Casadevall, John R. Perfect

Research output: Contribution to journalArticle

Abstract

Superoxide dismutase (SOD) is an enzyme that converts superoxide radicals into hydrogen peroxide and molecular oxygen and has been shown to contribute to the virulence of many human-pathogenic bacteria through its ability to neutralize toxic levels of reactive oxygen species generated by the host. SOD has also been speculated to be important in the pathogenesis of fungal infections, but the role of this enzyme has not been rigorously investigated. To examine the contribution of SOD to the pathogenesis of fungal infections, we cloned the Cu,Zn SOD-encoding gene (SOD1) from the human-pathogenic yeast Cryptococcus neoformans and made mutants via targeted disruption. The sod1 mutant strains had marked decreases in SOD activity and were strikingly more susceptible to reactive oxygen species in vitro. A sod1 mutant was significantly less virulent than the wild-type strain and two independent reconstituted strains, as measured by cumulative survival in the mouse inhalational model. In vitro studies established that the sod1 strain had attenuated growth compared to the growth of the wild type and a reconstituted strain inside macrophages producing reduced amounts of nitric oxide. These findings demonstrate that (i) the Cu,Zn SOD contributes to virulence but is not required for pathogenicity in C. neoformans; (ii) the decreased virulence of the sod1 strain may be due to increased susceptibility to oxygen radicals within macrophages; and (iii) other antioxidant defense systems in C. neoformans can compensate for the loss of the Cu,Zn SOD in vivo.

Original languageEnglish (US)
Pages (from-to)173-180
Number of pages8
JournalInfection and Immunity
Volume71
Issue number1
DOIs
StatePublished - Jan 1 2003
Externally publishedYes

Fingerprint

Cryptococcus neoformans
Superoxide Dismutase
Virulence
Macrophages
Reactive Oxygen Species
Mycoses
Growth
Poisons
Enzymes
Superoxides
Hydrogen Peroxide
Nitric Oxide
Antioxidants
Yeasts
Oxygen
Bacteria
Survival
Genes
Superoxide Dismutase-1
In Vitro Techniques

ASJC Scopus subject areas

  • Immunology

Cite this

Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages. / Cox, Gary M.; Harrison, Thomas S.; McDade, Henry C.; Taborda, Carlos P.; Heinrich, Garrett; Casadevall, Arturo; Perfect, John R.

In: Infection and Immunity, Vol. 71, No. 1, 01.01.2003, p. 173-180.

Research output: Contribution to journalArticle

Cox, Gary M. ; Harrison, Thomas S. ; McDade, Henry C. ; Taborda, Carlos P. ; Heinrich, Garrett ; Casadevall, Arturo ; Perfect, John R. / Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages. In: Infection and Immunity. 2003 ; Vol. 71, No. 1. pp. 173-180.
@article{af0cb2ccacb84ebe96f7c89a6841b419,
title = "Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages",
abstract = "Superoxide dismutase (SOD) is an enzyme that converts superoxide radicals into hydrogen peroxide and molecular oxygen and has been shown to contribute to the virulence of many human-pathogenic bacteria through its ability to neutralize toxic levels of reactive oxygen species generated by the host. SOD has also been speculated to be important in the pathogenesis of fungal infections, but the role of this enzyme has not been rigorously investigated. To examine the contribution of SOD to the pathogenesis of fungal infections, we cloned the Cu,Zn SOD-encoding gene (SOD1) from the human-pathogenic yeast Cryptococcus neoformans and made mutants via targeted disruption. The sod1 mutant strains had marked decreases in SOD activity and were strikingly more susceptible to reactive oxygen species in vitro. A sod1 mutant was significantly less virulent than the wild-type strain and two independent reconstituted strains, as measured by cumulative survival in the mouse inhalational model. In vitro studies established that the sod1 strain had attenuated growth compared to the growth of the wild type and a reconstituted strain inside macrophages producing reduced amounts of nitric oxide. These findings demonstrate that (i) the Cu,Zn SOD contributes to virulence but is not required for pathogenicity in C. neoformans; (ii) the decreased virulence of the sod1 strain may be due to increased susceptibility to oxygen radicals within macrophages; and (iii) other antioxidant defense systems in C. neoformans can compensate for the loss of the Cu,Zn SOD in vivo.",
author = "Cox, {Gary M.} and Harrison, {Thomas S.} and McDade, {Henry C.} and Taborda, {Carlos P.} and Garrett Heinrich and Arturo Casadevall and Perfect, {John R.}",
year = "2003",
month = "1",
day = "1",
doi = "10.1128/IAI.71.1.173-180.2003",
language = "English (US)",
volume = "71",
pages = "173--180",
journal = "Infection and Immunity",
issn = "0019-9567",
publisher = "American Society for Microbiology",
number = "1",

}

TY - JOUR

T1 - Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages

AU - Cox, Gary M.

AU - Harrison, Thomas S.

AU - McDade, Henry C.

AU - Taborda, Carlos P.

AU - Heinrich, Garrett

AU - Casadevall, Arturo

AU - Perfect, John R.

PY - 2003/1/1

Y1 - 2003/1/1

N2 - Superoxide dismutase (SOD) is an enzyme that converts superoxide radicals into hydrogen peroxide and molecular oxygen and has been shown to contribute to the virulence of many human-pathogenic bacteria through its ability to neutralize toxic levels of reactive oxygen species generated by the host. SOD has also been speculated to be important in the pathogenesis of fungal infections, but the role of this enzyme has not been rigorously investigated. To examine the contribution of SOD to the pathogenesis of fungal infections, we cloned the Cu,Zn SOD-encoding gene (SOD1) from the human-pathogenic yeast Cryptococcus neoformans and made mutants via targeted disruption. The sod1 mutant strains had marked decreases in SOD activity and were strikingly more susceptible to reactive oxygen species in vitro. A sod1 mutant was significantly less virulent than the wild-type strain and two independent reconstituted strains, as measured by cumulative survival in the mouse inhalational model. In vitro studies established that the sod1 strain had attenuated growth compared to the growth of the wild type and a reconstituted strain inside macrophages producing reduced amounts of nitric oxide. These findings demonstrate that (i) the Cu,Zn SOD contributes to virulence but is not required for pathogenicity in C. neoformans; (ii) the decreased virulence of the sod1 strain may be due to increased susceptibility to oxygen radicals within macrophages; and (iii) other antioxidant defense systems in C. neoformans can compensate for the loss of the Cu,Zn SOD in vivo.

AB - Superoxide dismutase (SOD) is an enzyme that converts superoxide radicals into hydrogen peroxide and molecular oxygen and has been shown to contribute to the virulence of many human-pathogenic bacteria through its ability to neutralize toxic levels of reactive oxygen species generated by the host. SOD has also been speculated to be important in the pathogenesis of fungal infections, but the role of this enzyme has not been rigorously investigated. To examine the contribution of SOD to the pathogenesis of fungal infections, we cloned the Cu,Zn SOD-encoding gene (SOD1) from the human-pathogenic yeast Cryptococcus neoformans and made mutants via targeted disruption. The sod1 mutant strains had marked decreases in SOD activity and were strikingly more susceptible to reactive oxygen species in vitro. A sod1 mutant was significantly less virulent than the wild-type strain and two independent reconstituted strains, as measured by cumulative survival in the mouse inhalational model. In vitro studies established that the sod1 strain had attenuated growth compared to the growth of the wild type and a reconstituted strain inside macrophages producing reduced amounts of nitric oxide. These findings demonstrate that (i) the Cu,Zn SOD contributes to virulence but is not required for pathogenicity in C. neoformans; (ii) the decreased virulence of the sod1 strain may be due to increased susceptibility to oxygen radicals within macrophages; and (iii) other antioxidant defense systems in C. neoformans can compensate for the loss of the Cu,Zn SOD in vivo.

UR - http://www.scopus.com/inward/record.url?scp=0037218164&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037218164&partnerID=8YFLogxK

U2 - 10.1128/IAI.71.1.173-180.2003

DO - 10.1128/IAI.71.1.173-180.2003

M3 - Article

C2 - 12496163

AN - SCOPUS:0037218164

VL - 71

SP - 173

EP - 180

JO - Infection and Immunity

JF - Infection and Immunity

SN - 0019-9567

IS - 1

ER -