Absence of Respiratory Burst in X-linked Chronic Granulomatous Disease Mice Leads to Abnormalities in Both Host Defense and Inflammatory Response to Aspergillus fumigatus

Abstract

Mice with X-linked chronic granulomatous disease (CGD) generated by targeted disruption of the gp91phox subunit of the NADPH–oxidase complex (X-CGD mice) were examined for their response to respiratory challenge with Aspergillus fumigatus. This opportunistic fungal pathogen causes infection in CGD patients due to the deficient generation of neutrophil respiratory burst oxidants important for damaging A. fumigatus hyphae. Alveolar macrophages from X-CGD mice were found to kill A. fumigatus conidia in vitro as effectively as alveolar macrophages from wild-type mice. Pulmonary disease in X-CGD mice was observed after administration of doses ranging from 105 to 48 spores, none of which produced disease in wild-type mice. Higher doses produced a rapidly fatal bronchopneumonia in X-CGD mice, whereas progression of disease was slower at lower doses, with development of chronic inflammatory lesions. Marked differences were also observed in the response of X-CGD mice to the administration of sterilized Aspergillus hyphae into the lung. Within 24 hours of administration, X-CGD mice had significantly higher numbers of alveolar neutrophils and increased expression of the proinflammatory cytokines IL-1β and TNF-α relative to the responses seen in wild-type mice. By one week after administration, pulmonary inflammation was resolving in wild-type mice, whereas X-CGD mice developed chronic granulomatous lesions that persisted for at least six weeks. This is the first experimental evidence that chronic inflammation in CGD does not always result from persistent infection, and suggests that the clinical manifestations of this disorder reflect both impaired microbial killing as well as other abnormalities in the inflammatory response in the absence of a respiratory burst.

Suppression of Microglial Inflammatory Activity by Myelin Phagocytosis: Role of p47-PHOX-Mediated Generation of Reactive Oxygen Species

“…In the context of the autoimmune attack in MS, ROS generation induced by phagocytosis of myelin debris may represent a negative feedback loop to self-limit cytokine-driven neuroinflammation. This view correlates with previous observations that the genetic defect of p47-PHOX enhances autoimmune encephalomyelitis and arthritis in animal models (Hultqvist et al, 2004) and leads to chronic non-infectious inflammation in chronic granulomatous disease (Morgenstern et al, 1997). Additional support for this hypothesis comes from a recently published study showing that p47-PHOX-mediated ROS negatively regulate expression of IL-8 and IL-1␤ in human neutrophils (Lekstrom-Himes et al, 2005).…”

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

“…Genetic mutations in NOX2 (gp91phox), p47phox, p67phox and p22phox are known to be responsible for development of CGD, but minimal evidence exists for associations of these polymorphisms with other diseases, and a recent analysis failed to show an association of polymorphisms within gp91phox, p47phox, p67phox or p22phox with infectious or non-infectious lung diseases, such as tuberculosis or sarcoidosis (199). 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).…”

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

“…The superoxide generated by the phagocyte NADPH oxidase exhibits potent antipathogenic actions, mediating the destruction of a host of invading microorganisms. Furthermore, superoxide can subsequently be converted to a vast array of other reactive oxygen species (ROS) that are detrimental to the invading organism (9,10). The critical role fulfilled by ROS species in the control of pathogen burden is made clearly apparent by the genetic condition chronic granulomatous disease (CGD), characterized by deficiency of a functional phagocytic oxidase, and greater susceptibility to infection with bacterial and fungal pathogens (9,11).…”