Infection and Immunity to Pseudomonas

Sorensen, Ricardo U.; Waller, Robert L.; Klinger, Jeffrey D.

doi:10.1007/978-1-4612-0475-6_4

Cited by 4 publications

(5 citation statements)

References 143 publications

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“…Consequently, MDSCs, as key interface cells between innate and adaptive immunity, may represent a novel therapeutic target in CF and other P. aeruginosa-associated pulmonary diseases, such as chronic obstructive pulmonary disease or ventilator-associated pneumonia. Beyond these lung diseases and wound infections, in which P. aeruginosa also plays an important part, our findings may have an even broader immunological relevance for understanding host-pathogen interactions, because P. aeruginosa infection was previously found to cross-suppress T cell responses and immunity to other bacterial pathogens in vivo (8,32). Although direct effects of P. aeruginosa toxins on T cells probably also have a function in this setting (8,32), our finding that MDSCs directly isolated from P. aeruginosa-infected patients potently suppressed T cells ex vivo in the absence of P. aeruginosa products supports the notion that MDSCs represent a distinct mechanism mediating flagellated P. aeruginosa-induced immune suppression.…”

Section: Discussionmentioning

confidence: 89%

“…aeruginosa is known to suppress T cell responses in vivo, and lymphocytes isolated from P. aeruginosa-infected CF patients show a blunted T cell proliferation capability ex vivo (7,8). Beyond direct effects of P. aeruginosa on T cells (7,8), this flagellated bacterium activates TLR5 on innate myeloid cells. Myeloid-derived suppressor cells (MDSCs) represent a novel innate immune cell subset generated in tumor, infective, and proinflammatory microenvironments (9,10).…”

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confidence: 99%

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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

116

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: 89%

mentioning

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

116

127

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“…This is also in accordance with Heiby ef ul. (25) and Sorensen et al (53), who both found that the cell-mediated immunity in chronically infected, clinically stable patients was not significantly different from that in normal persons. The explanation why the athymic rats are able to manage the lung infections although they are severely immune deficient is probably that their polymorphonuclear leukocyte recruitment and function is normal (32).…”

Section: Discussionmentioning

confidence: 97%

Chronic Pseudomonas aeruginosa lung infection in normal and athymic rats

Johansen

Espersen

Pedersen

et al. 1993

APMIS

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We have compared a chronic lung infection with Pseudomonas aeruginosa embedded in alginate beads in normal and athymic rats with an acute infection with free live P. aeruginosa bacteria. The following parameters were observed and described: mortality, macroscopic and microscopic pathologic changes, and antibody responses. The rats challenged with P. aeruginosa alginate beads experienced a generally more severe lung pathology and the antibody responses were more homogeneous with less dispersion as compared to the rats having free live P. aeruginosa bacteria. In general, manifestations were more severe in the athymic rats compared to the normal rats. It is, however, notable that the athymic rats developed similar microscopic lung manifestations as the normal rats when given a large number of P. aeruginosa in the beads, with dense accumulation of neutrophil granulocytes and microcolonies comparable to the lesions seen in cystic fibrosis (CF) patients. Early transitory IgM titers were demonstrated in both normal and athymic rats. Whilst athymic rats produced much lower IgG titers than the normal rats, presumably due to the absence of CD4+ cells, higher primary IgA titers were achieved. These two models in normal and athymic rats of the chronic lung infection resembling that seen in CF lungs make it possible to study the influence of the various components of the specific and nonspecific defence systems on the course of the chronic P. aeruginosa lung infection and to evaluate the effect of various immunization schedules and immunomodulatory drugs.

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“…45 This essential role of GSH in immunity might explain why in many diseases, not only AIDS, decreased GSH levels are associated with an increased susceptibility to infection. These include COPD, 46 cystic f ibrosis, 47,48 influenza infection, 49 and alcoholism, 50,51 as ethanol impairs Th1/Th2 balance via GSH depletion 52 (Table 3).…”

Section: Gsh Is Essential For Innate and Adaptive Immune Functionsmentioning

confidence: 99%

Role of glutathione in immunity and inflammation in the lung

Ghezzi¹

2011

IJGM

200

138

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Reactive oxygen species and thiol antioxidants, including glutathione (GSH), regulate innate immunity at various levels. This review outlines the redox-sensitive steps of the cellular mechanisms implicated in inflammation and host defense against infection, and describes how GSH is not only important as an antioxidant but also as a signaling molecule. There is an extensive literature of the role of GSH in immunity. Most reviews are biased by an oversimplified picture where “bad” free radicals cause all sorts of diseases and “good” antioxidants protect from them and prevent oxidative stress. While this may be the case in certain fields (eg, toxicology), the role of thiols (the topic of this review) in immunity certainly requires wearing scientist’s goggles and being prepared to accept a more complex picture. This review aims at describing the role of GSH in the lung in the context of immunity and inflammation. The first part summarizes the history and basic concepts of this picture. The second part focuses on GSH metabolism/levels in pathology, the third on the role of GSH in innate immunity and inflammation, and the fourth gives 4 examples describing the importance of GSH in the response to infections.

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Infection and Immunity to Pseudomonas

Cited by 4 publications

References 143 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

Chronic Pseudomonas aeruginosa lung infection in normal and athymic rats

Role of glutathione in immunity and inflammation in the lung

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