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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.

Morgenstern DE, Gifford MA, Li LL, Doerschuk CM, Dinauer MC - J. Exp. Med. (1997)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics (Hematology-Oncology), Indiana University Medical Center, Indianapolis 46202, USA.

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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Survival curve of X-CGD mice receiving from 1 × 105 to  48 A. fumigatus conidia. Mice were examined daily and the percent of  mice surviving in each treatment group was plotted versus time from intratracheal administration of the indicated dose of conidia (day 0). ○, 1 ×  105 conidia/mouse (n = 5); ▿, 7 × 103 conidia/mouse (n = 5); ▵, 1 ×  103 conidia/mouse (n = 8); □, 540 conidia/mouse (n = 5); ⋄, 48  conidia/mouse (n = 5).
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Figure 1: Survival curve of X-CGD mice receiving from 1 × 105 to 48 A. fumigatus conidia. Mice were examined daily and the percent of mice surviving in each treatment group was plotted versus time from intratracheal administration of the indicated dose of conidia (day 0). ○, 1 × 105 conidia/mouse (n = 5); ▿, 7 × 103 conidia/mouse (n = 5); ▵, 1 × 103 conidia/mouse (n = 8); □, 540 conidia/mouse (n = 5); ⋄, 48 conidia/mouse (n = 5).

Mentions: Wild-type and X-CGD mice were challenged with A. fumigatus conidia at doses ranging from 1 × 105 to 48 per animal, as administered by intratracheal instillation. No mortality was observed in wild-type mice, even at the highest dose tested. In contrast, pulmonary disease occurred in all X-CGD mice after Aspergillus exposure, with 24 of the 28 mice dead or moribund within 11–21 d due to progressive lung disease (Fig. 1). X-CGD mice given 1 × 105 conidia developed a rapidly progressing and uniformly fatal bronchopneumonia with all mice dead or moribund by the fourth day after infection, similar to what was previously observed with exposure to 3 × 106 conidia (15). Administration of lower doses resulted in a longer asymptomatic period and survival of a small number of mice (Fig. 1).


Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus.

Morgenstern DE, Gifford MA, Li LL, Doerschuk CM, Dinauer MC - J. Exp. Med. (1997)

Survival curve of X-CGD mice receiving from 1 × 105 to  48 A. fumigatus conidia. Mice were examined daily and the percent of  mice surviving in each treatment group was plotted versus time from intratracheal administration of the indicated dose of conidia (day 0). ○, 1 ×  105 conidia/mouse (n = 5); ▿, 7 × 103 conidia/mouse (n = 5); ▵, 1 ×  103 conidia/mouse (n = 8); □, 540 conidia/mouse (n = 5); ⋄, 48  conidia/mouse (n = 5).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196125&req=5

Figure 1: Survival curve of X-CGD mice receiving from 1 × 105 to 48 A. fumigatus conidia. Mice were examined daily and the percent of mice surviving in each treatment group was plotted versus time from intratracheal administration of the indicated dose of conidia (day 0). ○, 1 × 105 conidia/mouse (n = 5); ▿, 7 × 103 conidia/mouse (n = 5); ▵, 1 × 103 conidia/mouse (n = 8); □, 540 conidia/mouse (n = 5); ⋄, 48 conidia/mouse (n = 5).
Mentions: Wild-type and X-CGD mice were challenged with A. fumigatus conidia at doses ranging from 1 × 105 to 48 per animal, as administered by intratracheal instillation. No mortality was observed in wild-type mice, even at the highest dose tested. In contrast, pulmonary disease occurred in all X-CGD mice after Aspergillus exposure, with 24 of the 28 mice dead or moribund within 11–21 d due to progressive lung disease (Fig. 1). X-CGD mice given 1 × 105 conidia developed a rapidly progressing and uniformly fatal bronchopneumonia with all mice dead or moribund by the fourth day after infection, similar to what was previously observed with exposure to 3 × 106 conidia (15). Administration of lower doses resulted in a longer asymptomatic period and survival of a small number of mice (Fig. 1).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics (Hematology-Oncology), Indiana University Medical Center, Indianapolis 46202, USA.

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.

Show MeSH
Related in: MedlinePlus