Strain differences in the immune mechanisms of resistance of immunocompetent rats to pulmonary aspergillosis

Mirkov, Ivana; Demenesku, Jelena; Aleksandrov, Aleksandra Popov; Ninkov, Marina; Glamočlija, Jasmina; Kataranovski, Dragan; Kataranovski, Milena

doi:10.1016/j.imbio.2015.05.007

Cited by 17 publications

(8 citation statements)

References 43 publications

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“…Limited data from human studies have identified polymorphisms in the IL-10 gene associated with increased susceptibility to invasive candidiasis [83], whereas polymorphisms in the IL-10 promoter have been associated with either resistance or susceptibility to invasive pulmonary aspergillosis [84]. In murine studies, IL-10 expression also occurs in response to murine infection with C. albicans [85], H. capsulatum [86] and A. fumigatus [87] and the absence of IL-10 is associated with improved fungal clearance. In particular, intravenous infection with C. albicans is quickly cleared in IL-10 −/− mice compared to wild-type mice, which is attributed to more efficient fungal killing by neutrophils [85].…”

Section: Immunoregulatory Signaling Pathwaysmentioning

confidence: 99%

Immunoregulation in Fungal Diseases

2016

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This review addresses specific regulatory mechanisms involved in the host immune response to fungal organisms. We focus on key cells and regulatory pathways involved in these responses, including a brief overview of their broader function preceding a discussion of their specific relevance to fungal disease. Important cell types discussed include dendritic cells and regulatory T cells, with a focus on specific studies relating to their effects on immune responses to fungi. We highlight the interleukin-10, programmed cell death 1, and cytotoxic T lymphocyte-associated protein 4 signaling pathways and emphasize interrelationships between these pathways and the regulatory functions of dendritic cells and regulatory T cells. Throughout our discussion, we identify selected studies best illustrating the role of these cells and pathways in response to specific fungal pathogens to provide a contextual understanding of the tightly-controlled network of regulatory mechanisms critical to determining the outcome of exposure to fungal pathogens. Lastly, we discuss two unique phenomena relating to immunoregulation, protective tolerance and immune reactivation inflammatory syndrome. These two clinically-relevant conditions provide perspective as to the range of immunoregulatory mechanisms active in response to fungi.

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Section: Immunoregulatory Signaling Pathwaysmentioning

confidence: 99%

Immunoregulation in Fungal Diseases

2016

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“…The strain of A. fumigatus used was Af293 with the required specifications for infections and cultivation as previously described [18]. Briefly, conidia were matured on Sabouraud Dextrose Agar plates for seven days at 37°C and 5% CO 2 .…”

Section: Strains Of Fungi and Conditions For Cultivationmentioning

confidence: 99%

Aspergillus fumigatus Influences Gasdermin-D-Dependent Pyroptosis of the Lung via Regulating Toll-Like Receptor 2-Mediated Regulatory T Cell Differentiation

Yan

Zhao

Xie

et al. 2021

Journal of Immunology Research

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Purpose. Aspergillus fumigatus, as an opportunistic fungus, has developed a series of escape mechanisms under the host’s immune response to obtain nutrients and promote fungal growth in the hostile environment. The immune escape of pathogens may be through suppressing the inflammatory response mediated by regulatory T cells (Tregs). The aim of this study was to explore whether A. fumigatus influences Gasdermin-D-dependent pyroptosis of the lung by regulating Toll-like receptor 2-mediated regulatory T cell differentiation. Methods. Collect peripheral blood from patients with A. fumigatus. ELISA kits we used to detect the expression levels of IL-1β, IL-6, IL-2R, and IL-10 in the serum and flow cytometry to detect the percentage of CD4+CD25+Foxp3+ Tregs in the patients’ peripheral blood mononuclear cells (PBMCs). The mouse model of A. fumigatus infection was constructed by tracheal instillation. The pathological changes in the lungs of the mice were observed under a microscope. The fungal load in the lung tissue was determined by the plate colony count. ELISA kit was used to detect the lung tissue homogenate proinflammatory cytokines TNF-α, IL-6, CCL2, and VEGF. Q-PCR was used for the detection of the expression of Foxp3 and TLR2 genes in the lung. Western blot was used for the detection of the expression of TLR2, Gasdermin-D (GSDMD), IL-1α, and IL-1β in the lung. Flow cytometry was used to detect splenic CD4+CD25+FOXP3+ Tregs. Using magnetic beads to extract CD4+ T cells from mice spleen, the effects of A. fumigatus conidia or TLR2 inhibitor (C29) to differentiate CD4+ T cells in vitro were tested. Results. The expression of Foxp3 and TLR2 in the lung tissue of mice infected with A. fumigatus increased, and we observed that the proportion of Tregs in both A. fumigatus infection patients and mice was upregulated. After using the CD25 neutralizing antibody, the number of Tregs in the mice spleen was significantly reduced. However, lung damage was reduced and the ability to clear lung fungi was enhanced. We found that the Tregs in TLR 2 − / − mice were significantly reduced and the nonlethal dose of A. fumigatus conidia did not cause severe lung damage in TLR 2 − / − mice. Compared with that of wild-type mice, the fungal burden in the lung of TLR2-deficient mice was reduced and the knockout of TLR2 changed the expression of GSDMD, IL-1α, and IL-1β in A. fumigatus. In in vitro experiments, we found that the inhibition of TLR2 can reduce Treg differentiation. Conclusions. A. fumigatus triggers CD4+CD25+FOXP3+ Treg proliferation and differentiation by activating the TLR2 pathway, which may be a potential mechanism for evading host defenses in A. fumigatus. This effect can modulate GSDMD-dependent pyroptosis and may partly involve TRL2 signaling.

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“…The strain of A. fumigatus used was Af293 with the required speci cations for infections and cultivation were as previously described [(Mirkov et al 2015)]. Brie y, conidia were matured on Sabouraud dextrose agar plates for seven days at 37 °C and 5% CO 2 .…”

Section: Strains Of Fungi and Conditions For Cultivationmentioning

confidence: 99%

Aspergillus fumigatus change Gasdermin-D-dependent pyrolysis of the lung through regulating TRL2-dependent Regulatory T cells differentiation

Wei¹,

Xing²,

Ke³

et al. 2020

Preprint

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Aspergillus fumigatus, as opportunistic fungi, lead to infection in the lungs and even systemic infection. The A. fumigatus interacts with the body through a series of complex and dynamic processes. After the fungi have invaded the host, it has a series of adaptive mechanisms which it applies to evade being detected by a host immune system also ways to retaliate against the immune responses. Regulatory T cells (Tregs) in enhancing immune tolerance and immune escape by inhibiting the body's immune response are concerned. It could increase the sensitivity of bacterial infections. When A. fumigatus enters the host, it stimulates Toll-like receptor 2 (TLR2) and triggers the signal transduction pathway. However, how Tregs affects susceptibility to A. fumigatus and TLR2 changes Tregs in A. fumigatus infection is unclear. We examined whether A. fumigatus induces Tregs proliferation in vivo, molecular mechanisms underlying A. fumigatus-stimulated TLR2 activation and the contribution of Tregs activation to susceptibility to A. fumigatus. We observed that Tregs to CD4+T cells ratio increased in samples from patients infected with Aspergillus fumigatus. After conducting tests in mice, it was revealed that when mice were infected with A. fumigatus, there was an enhancement in the Tregs to CD4+T cells ratio and Foxp3 expression levels which happen in the lungs also up-regulate. Inhibited Tregs by using CD25 neutralizing antibodies, and we found that the number of fungal burdens in the lung was decreased when these CD25 neutralizing antibodies are used. In our research, A. fumigatus infection can indeed stimulate TLR2 expression to increase, and for the lungs, damages and fungal burden caused by TLR2−/−mice were reduced. Then it also found that in TLR2−/-mice, pyrolysis-related proteins (GSDMD, IL-1α, and IL-1β) changed. It was concluded that for TLR2 knockout animals, the Treg cells quantities are significantly linked to vulnerability to be infected with A. fumigatus. The infection triggered the proliferation and differentiation of CD4+CD25+Foxp3+ Tregs through the activation of TLR2 pathway. It is a potential mechanism to evade host defense in A. fumigatus infection of the lung. And this effect can regulate GSDMD-dependent pyrolysis, and may involve TRL2 signals partially.

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Strain differences in the immune mechanisms of resistance of immunocompetent rats to pulmonary aspergillosis

Cited by 17 publications

References 43 publications

Immunoregulation in Fungal Diseases

Immunoregulation in Fungal Diseases

Aspergillus fumigatus Influences Gasdermin-D-Dependent Pyroptosis of the Lung via Regulating Toll-Like Receptor 2-Mediated Regulatory T Cell Differentiation

Aspergillus fumigatus change Gasdermin-D-dependent pyrolysis of the lung through regulating TRL2-dependent Regulatory T cells differentiation

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