Chronic Pseudomonas aeruginosa lung infection is more severe in Th2 responding BALB/c mice compared to Th1 responding C3H/HeN mice

Moser, Claus; Johansen, Helle Krogh; Song, Zhijun; Hougen, Hans Petter; Rygaard, Jørgen; Høiby, Niels

doi:10.1111/j.1699-0463.1997.tb05092.x

Cited by 114 publications

(114 citation statements)

References 18 publications

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“…Previous studies have characterized the T cell response in human CF patients (33,34) (24,26,27,30) (35) and murine P. aeruginosa (36)(37)(38)(39)(40) or Aspergillus fumigatus infection models (41)(42)(43), providing evidence that the adaptive T cell response in CF is altered at several levels. CF T cells were found to be prone to a Th2 phenotype, with the CFTR mutation itself and/or chronic infections with P. aeruginosa as possible underlying factors (42,(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Rieber

Brand

Hector

et al. 2013

The Journal of Immunology

118

127

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Pseudomonas aeruginosa persists in patients with cystic fibrosis (CF) and drives CF lung disease progression. P. aeruginosa potently activates the innate immune system, mainly mediated through pathogen-associated molecular patterns, such as flagellin. However, the host is unable to eradicate this flagellated bacterium efficiently. The underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in cancer and proinflammatory microenvironments and are capable of suppressing T cell responses. We hypothesized that P. aeruginosa induces MDSCs to escape T cell immunity. In this article, we demonstrate that granulocytic MDSCs accumulate in CF patients chronically infected with P. aeruginosa and correlate with CF lung disease activity. Flagellated P. aeruginosa culture supernatants induced the generation of MDSCs, an effect that was 1) dose-dependently mimicked by purified flagellin protein, 2) significantly reduced using flagellin-deficient P. aeruginosa bacteria, and 3) corresponded to TLR5 expression on MDSCs in vitro and in vivo. Both purified flagellin and flagellated P. aeruginosa induced an MDSC phenotype distinct from that of the previously described MDSC-inducing cytokine GM-CSF, characterized by an upregulation of the chemokine receptor CXCR4 on the surface of MDSCs. Functionally, P. aeruginosa–infected CF patient ex vivo–isolated as well as flagellin or P. aeruginosa in vitro–generated MDSCs efficiently suppressed polyclonal T cell proliferation in a dose-dependent manner and modulated Th17 responses. These studies demonstrate that flagellin induces the generation of MDSCs and suggest that P. aeruginosa uses this mechanism to undermine T cell–mediated host defense in CF and other P. aeruginosa–associated chronic lung diseases.

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Section: Discussionmentioning

confidence: 99%

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Rieber

Brand

Hector

et al. 2013

The Journal of Immunology

118

127

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“…Before challenge, all mice were anaesthetized subcutaneously with a 1 : 1 (v/v) mixture of etomidate (Janssen) and midazolam (Roche) at a dose of 10 ml (kg body wt) À1 and then tracheotomized (Moser et al, 1997). Each mouse was challenged intratracheally with 0·04 ml bacterial suspension as described previously (Moser et al, 1997).…”

Section: Methodsmentioning

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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“…Cystic fibrosis is the most common and fatal autosomal-recessive disease in the Caucasian population affecting ≈70,000 individuals worldwide (20) and is caused by a dysfunctional CF transmembrane conductance regulator (CFTR) (21,22) resulting in increased mucous secretion in the alveolar spaces that provide an ideal environment for bacterial colonization and biofilm formation (23). This biofilm protects bacteria from host immune cells and antibiotics by encapsulation and sequestration (24,25) and thus co-induces the typically persistent type of lung inflammation observed in CF patients (26). Moreover, VAP pathogenesis is also closely linked to biofilm forming organisms colonizing the endotracheal tube (ETT) such as P. aeruginosa, and the presence of P. aeruginosa in the biofilm on the ETT microbiome negatively correlates with patient prognosis (27).…”

Section: Etiology Of Hospital Acquired Pneumoniamentioning

confidence: 99%

Animal models of hospital-acquired pneumonia: current practices and future perspectives

Bielen¹,

Jongers²,

Malhotra-Kumar³

et al. 2017

Ann. Transl. Med.

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Lower respiratory tract infections are amongst the leading causes of mortality and morbidity worldwide. Especially in hospital settings and more particularly in critically ill ventilated patients, nosocomial pneumonia is one of the most serious infectious complications frequently caused by opportunistic pathogens.Pseudomonas aeruginosa is one of the most important causes of ventilator-associated pneumonia as well as the major cause of chronic pneumonia in cystic fibrosis patients. Animal models of pneumonia allow us to investigate distinct types of pneumonia at various disease stages, studies that are not possible in patients.Different animal models of pneumonia such as one-hit acute pneumonia models, ventilator-associated pneumonia models and biofilm pneumonia models associated with cystic fibrosis have been extensively studied and have considerably aided our understanding of disease pathogenesis and testing and developing new treatment strategies. The present review aims to guide investigators in choosing appropriate animal pneumonia models by describing and comparing the relevant characteristics of each model using P. aeruginosa as a model etiology for hospital-acquired pneumonia. Key to establishing and studying these animal models of infection are well-defined end-points that allow precise monitoring and characterization of disease development that could ultimately aid in translating these findings to patient populations in order to guide therapy. In this respect, and discussed here, is the development of humanized animal models of bacterial pneumonia that could offer unique advantages to study bacterial virulence factor expression and host cytokine production for translational purposes.

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Chronic Pseudomonas aeruginosa lung infection is more severe in Th₂ responding BALB/c mice compared to Th₁ responding C₃H/HeN mice

Cited by 114 publications

References 18 publications

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

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

Animal models of hospital-acquired pneumonia: current practices and future perspectives

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