Cited by 370Neutrophil, Myeloperoxidase and Oxidative MechanismsImmunodeficiency and Autoimmune DisordersAntifungal resistance and susceptibility

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

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Morgenstern, David E., Gifford, Mary A.C., Li, Ling Lin, Doerschuk, Claire M., Dinauer, Mary C.·1997·The Journal of Experimental Medicine

DOI 10.1084/jem.185.2.207PMC PMC2196125

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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 10(5) 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-1 beta and TNF-alpha 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.

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Authors: Morgenstern, D. E., Gifford, M. A. C., Li, L. L., Doerschuk, C. M., & Dinauer, M. C.
Affiliations: Riley Hospital for Children (US)
ORCID: Morgenstern, David E.
Doerschuk, Claire M.
Dinauer, Mary C.
Venue: The Journal of Experimental Medicine
Publisher: Rockefeller University Press
Published: 1997-01-20
Volume: 185
Issue: 2
Pages: 207-218
ISSN: 0022-1007 (ISSN-L)
1540-9538
DOI: 10.1084/jem.185.2.207
PMC: PMC2196125
OpenAlex: W2138396364
Cited by: 370
References: 51
Citations by year: 2026: 5 · 2025: 5 · 2024: 2 · 2023: 4 · 2022: 9 · 2021: 13 · 2020: 7 · 2019: 11 · 2018: 11 · 2017: 18 · 2016: 12 · 2015: 11 · 2014: 22 · 2013: 18 · 2012: 17
FWCI: 5.40
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: The Journal of Experimental Medicine (publishedVersion)
PubMed Central (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-sa)
UNC Libraries
Funders: Arthritis Foundation
National Institutes of Health (5r01hl052565-05)
National Heart, Lung, and Blood Institute (R01 HL52565)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Keywords: X-linked chronic granulomatous disease, Aspergillus fumigatus, respiratory burst, NADPH oxidase, gp91phox, alveolar macrophages, neutrophils, lung inflammation, IL-1β, TNF-α, fungal infection, bronchopneumonia
MeSH terms: NADPH Oxidase 2, Animals, Aspergillus fumigatus, Granulomatous Disease, Chronic, Inflammation, Genetic Linkage, Lung Diseases, Membrane Glycoproteins, Phagocytosis, X Chromosome, Cytokines, Macrophages, Alveolar, Respiratory Burst, NADPH Oxidases, Mice

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

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