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In the Absence of Reactive Oxygen Species, T Cells Default to a Th1 Phenotype and Mediate Protection against Pulmonary Cryptococcus neoformans Infection

Robert J. Snelgrove^*, Lorna Edwards^*, Andrew E. Williams^*, Aaron J. Rae and Tracy Hussell^1,*

^* Kennedy Institute of Rheumatology, Imperial College London, Hammersmith, and Center for Molecular Microbiology and Infection, Imperial College London, London, United Kingdom

In recent years, the prevalence of invasive fungal infections has increased, attributed mostly to the rising population of immunocompromised individuals. Cryptococcus neoformans has been one of the most devastating, with an estimated 6–8% of AIDS-infected patients succumbing to Cryptococcus-associated meningitis. Reactive oxygen species (ROS) are potent antimicrobial agents but also play a significant role in regulating immune cell phenotype, but cause immunopathology when produced in excess. We now show that mice lacking phagocyte NADPH oxidase have heightened macrophage and Th1 responses and improved pathogen containment within pulmonary granulomatous lesions. Consequently, dissemination of this fungus to the brain is diminished, an effect that is independent of IL-12. Similar results are described using the metalloporphyrin antioxidant manganese(III) tetrakis(N-ethyl pyridinium-2-yl)porphyrin, which also promoted a protective Th1 response and reduced dissemination to the brain. These findings are in sharp contrast to the protective potential of ROS against other fungal pathogens, and highlight the pivotal role that ROS can fulfill in shaping the profile of the host’s immune response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Tracy Hussell, Kennedy Institute of Rheumatology, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, U.K. E-mail address: t.hussell{at}ic.ac.uk

² Abbreviations used in this paper: CBA, cytometric bead array; ROS, reactive oxygen species; CGD, chronic granulomatous disease; SOD, superoxide dismutase; MnTE-2-PyP, manganese(III) tetrakis(N-ethyl pyridinium-2-yl)porphyrin; i.n., intranasal(ly); BAL, bronchoalveolar lavage; LDH, lactate dehydrogenase; MHC-II, MHC class II.

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