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

Abstract

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.

NOX Enzymes and Pulmonary Disease

“…Studies in mice deficient in the p47 phox subunit indicate a role for NOX isoforms, requiring this subunit for enzyme activation in host defense against Pseudomonas pneumonia (103) and M. tuberculosis pneumonia (21); a potential role of NOX-derived ROS in suppressing neutrophilic inflammation also was suggested (21). Similar findings of a putative ''antiinflammatory'' role for p47 phox =NOX2 are reported in mice challenged with intraperitoneal live Escherichia coli to induce sepsis (35), and in murine models of pneumococcal pneumonia (72), influenza pneumonia (109), and disseminated Cryptococcus neoformans infection (110).…”

Reactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia

“…However, antioxidants do not selectively inhibit NADPH oxidase activation. Prior models enforce the concept that manipulation of the NADPH oxidase complex does not produce the same phenotype as antioxidant treatment after infection (46). A future therapeutic approach would be to specifically target the neutrophil NAPDH oxidase complex, potentially by targeting regulatory small GTPases (47).…”

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

“…Attempts to implicate NOX2 or p47phox in models of lung inflammation and injury, using gp91phox−/− or p47phox−/− mice, demonstrated that genetic NADPH oxidase deficiency was in many cases associated with enhanced inflammation and injury (200)(201)(202)(203), implicating that NOX2 also has beneficial functions in regulating inflammatoryimmune responses. For example, infection of gp91phox−/− mice with the yeast C. neoformans or with influenza virus was in either case found to result in increased Th1-skewed inflammation and granuloma formation, compared to their wild-type counterparts, which led to increased influenza clearance and protection against C. neoformans infection (204,205). Studies using chimera of gp91phox−/− mice indicated a contribution of non-hemapoetic cell NADPH oxidase to development of airways eosinophilia in a mouse model of allergic inflammation, suggesting a role for NOX2 within the vascular endothelium (206).…”