The immune response to chronic <i>Pseudomonas aeruginosa</i> lung infection in cystic fibrosis patients is predominantly of the Th2 type

Moser, Claus; Kjærgaard, Susanne; Pressler, Tacjana; Kharazmi, Arsalan; Koch, Christian; Høiby, Niels

doi:10.1034/j.1600-0463.2000.d01-64.x

Cited by 147 publications

(157 citation statements)

References 23 publications

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“…For example, Moser et al (43) have shown that the PBMCs of Pseudomonas-infected patients to have lower IFN-g and higher IL-4 production compared with cells from noninfected patients; they also showed that IFN-g production positively correlated with lung function. In addition, Hartl et al (7) reported that the bronchoalveolar lavage from chronically Pseudomonas-infected CF patients had significantly higher levels of Th2 lymphocytes, IL-4, and IL-13, while having lower levels of IFN-g compared with noninfected patients, and the levels of IL-4 and IL-13 correlated inversely with lung function (7).…”

Section: Discussionmentioning

confidence: 99%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

The Journal of Immunology

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We previously observed the lungs of naive BALB/cJ Cftrtm1UNC mice to have greater numbers of lymphocytes, by immunohistochemical staining, than did BALB wild type littermates or C57BL/6J Cftrtm1UNC mice. In the present study, we initially investigated whether this mutation in Cftr alters the adaptive immunity phenotype by measuring the lymphocyte populations in the lungs and spleens by FACS and by evaluating CD3-stimulated cytokine secretion, proliferation, and apoptosis responses. Next, we assessed a potential influence of this lymphocyte phenotype on lung function through airway resistance measures. Finally, we mapped the phenotype of pulmonary lymphocyte counts in BALB × C57BL/6J F2 Cftrtm1UNC mice and reviewed positional candidate genes. By FACS analysis, both the lungs and spleens of BALB Cftrtm1UNC mice had more CD3+ (both CD4+ and CD8+) cells than did littermates or C57BL/6J Cftrtm1UNC mice. Cftrtm1UNC and littermate mice of either strain did not differ in anti-CD3–stimulated apoptosis or proliferation levels. Lymphocytes from BALB Cftrtm1UNC mice produced more IL-4 and IL-5 and reduced levels of IFN-γ than did littermates, whereas lymphocytes from C57BL/6J Cftrtm1UNC mice demonstrated increased Il-17 secretion. BALB Cftrtm1UNC mice presented an enhanced airway hyperresponsiveness to methacholine challenge compared with littermates and C57BL/6J Cftrtm1UNC mice. A chromosome 7 locus was identified to be linked to lymphocyte numbers, and genetic evaluation of the interval suggests Itgal and Il4ra as candidate genes for this trait. We conclude that the pulmonary phenotype of BALB Cftrtm1UNC mice includes airway hyperresponsiveness and increased lymphocyte numbers, with the latter trait being influenced by a chromosome 7 locus.

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Section: Discussionmentioning

confidence: 99%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

The Journal of Immunology

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“…Our previous report on Staphylococcus aureus demonstrated that secretion of this cytokine by human leukocytes was induced within 2 h of exposure to S. aureus biofilms (7). Interestingly, Moser et al (48,49) have demonstrated that P. aeruginosa induces a Th2 type response in mouse models of CF yet to clear the infections, a Th1 response is required. IFN-␥, a Th1-type cytokine, was vital to P. aeruginosa algD Ϫ biofilm bacterial killing in this study.…”

Section: Discussionmentioning

confidence: 99%

The Exopolysaccharide Alginate Protects Pseudomonas aeruginosa Biofilm Bacteria from IFN-γ-Mediated Macrophage Killing

Leid

Willson

Shirtliff

et al. 2005

The Journal of Immunology

465

308

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The ability of Pseudomonas aeruginosa to form biofilms and cause chronic infections in the lungs of cystic fibrosis patients is well documented. Numerous studies have revealed that P. aeruginosa biofilms are highly refractory to antibiotics. However, dramatically fewer studies have addressed P. aeruginosa biofilm resistance to the host’s immune system. In planktonic, unattached (nonbiofilm) P. aeruginosa, the exopolysaccharide alginate provides protection against a variety of host factors yet the role of alginate in protection of biofilm bacteria is unclear. To address this issue, we tested wild-type strains PAO1, PA14, the mucoid cystic fibrosis isolate, FRD1 (mucA22+), and the respective isogenic mutants which lacked the ability to produce alginate, for their susceptibility to human leukocytes in the presence and absence of IFN-γ. Human leukocytes, in the presence of recombinant human IFN-γ, killed biofilm bacteria lacking alginate after a 4-h challenge at 37°C. Bacterial killing was dependent on the presence of IFN-γ. Killing of the alginate-negative biofilm bacteria was mediated through mononuclear cell phagocytosis since treatment with cytochalasin B, which prevents actin polymerization, inhibited leukocyte-specific bacterial killing. By direct microscopic observation, phagocytosis of alginate-negative biofilm bacteria was significantly increased in the presence of IFN-γ vs all other treatments. Addition of exogenous, purified alginate to the alginate-negative biofilms restored resistance to human leukocyte killing. Our results suggest that although alginate may not play a significant role in bacterial attachment, biofilm development, and formation, it may play an important role in protecting mucoid P. aeruginosa biofilm bacteria from the human immune system.

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“…The significant increase in these ratios between the 24 and 48 h time-points is indicative of a Th1-based immune response (Table 3). The immune response in CF patients with chronic P. aeruginosa infections is predominantly a Th2 response and is correlated with a poor prognosis (Moser et al, 2000). It has been proposed that shifting the immune response to Th1 may help to combat P. aeruginosa infection (Høiby et al, 2001).…”

Section: Th1 Cytokines Are Up-regulated At 48 H Postinfectionmentioning

confidence: 99%

Pseudomonas aeruginosa alginate is refractory to Th1 immune response and impedes host immune clearance in a mouse model of acute lung infection

Song

Ciofu

et al. 2003

Journal of Medical Microbiology

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Pseudomonas aeruginosa is an opportunistic respiratory pathogen that accounts for most of the morbidity and mortality in cystic fibrosis (CF) patients. In CF-affected lungs, the bacteria undergo conversion from a non-mucoid to a non-tractable mucoid phenotype, due to overproduction of alginate. The effect of alginate production on pathogenicity was investigated by using an acute lung infection mouse model that compared a non-mucoid P. aeruginosa strain, PAO1, to its constitutive alginate-overproducing derivative, Alg þ PAOmucA22, and an alginate-defective strain, Alg À PAOalgD. Bacterial suspensions were instilled into the left bronchus and examined 24 and 48 h post-infection. The highest bacterial loads and the most severe lung pathology were observed with strain Alg À PAOalgD at 24 h post-infection, which may have been due to an increase in expression of bacterial elastase by the mutant. Significantly lower lung and spleen bacterial loads were found in the two non-mucoid (PAO1 and Alg À PAOalgD) groups, compared to the mucoid Alg þ PAOmucA22 group, between 24 and 48 h post-infection. The positive correlation between lung bacteriology and lung macroscopic pathology in the Alg þ PAOmucA22 group suggests that alginate production not only impedes pulmonary clearing, but also results in severe lung damage. Positive correlations between IL12 levels and lung macroscopic pathology, and between IL12 and IFN-ª levels in the Alg þ PAOmucA22 group, suggested a possible contribution of these pro-inflammatory cytokines to tissue damage. No significant differences were found between the three groups in lung cytokine responses at 24 or 48 h post-infection. However, on comparison within each group at 24 and 48 h post-infection, a significant increase in the pro-inflammatory cytokine IFN-ª was observed. Higher ratios of IFN-ª/IL4 and IFN-ª/IL10, but lower IL10 levels, were also found in all three groups. These results indicate a Th1-predominated immune response in these animals. Such cytokine responses could have aided the clearance of non-mucoid P. aeruginosa, but were not sufficient to alleviate infection by the mucoid variants. Alginate production may promote survival and persistence of this pathogenic micro-organism in the lung.

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The immune response to chronic Pseudomonas aeruginosa lung infection in cystic fibrosis patients is predominantly of the Th2 type

Cited by 147 publications

References 23 publications

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

The Exopolysaccharide Alginate Protects Pseudomonas aeruginosa Biofilm Bacteria from IFN-γ-Mediated Macrophage Killing

Pseudomonas aeruginosa alginate is refractory to Th1 immune response and impedes host immune clearance in a mouse model of acute lung infection

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