Bone marrow transplant-induced alterations in Notch signaling promote pathologic Th17 responses to γ-herpesvirus infection

Gurczynski, Stephen J.; Zhou, Xiaofeng; Flaherty, Melanie; Wilke, Carol A.; Moore, Bethany B.

doi:10.1038/mi.2017.85

Cited by 17 publications

(17 citation statements)

References 47 publications

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“…Alveolar Macrophages (AMs) were isolated by bronchoalveolar lavage performed with supplemented Dulbecco’s Modified Eagle Medium (DMEM) (89% DMEM, 10% fetal bovine serum (FBS), and 1% penicillin-streptomycin (Pen-Strep) mixture) containing 5mM of ethylenediaminetetraacetic acid (EDTA). Total lung leukocytes were obtained by perfusing the lung with PBS followed by digesting the whole lung with Collagenase A and DNAse followed by Ficoll density separation as we have described [33]. Lung monocyte/macrophages were selected from these lung leukocytes by adherence to tissue culture plastic for 1 h and then cells were washed twice with PBS.…”

Section: Methodsmentioning

confidence: 99%

Influenza-induced immune suppression to methicillin-resistant Staphylococcus aureus is mediated by TLR9

et al. 2019

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Bacterial lung infections, particularly with methicillin-resistant Staphylococcus aureus (MRSA), increase mortality following influenza infection, but the mechanisms remain unclear. Here we show that expression of TLR9, a microbial DNA sensor, is increased in murine lung macrophages, dendritic cells, CD8+ T cells and epithelial cells post-influenza infection. TLR9-/- mice did not show differences in handling influenza nor MRSA infection alone. However, TLR9-/- mice have improved survival and bacterial clearance in the lung post-influenza and MRSA dual infection, with no difference in viral load during dual infection. We demonstrate that TLR9 is upregulated on macrophages even when they are not themselves infected, suggesting that TLR9 upregulation is related to soluble mediators. We rule out a role for elevations in interferon-γ (IFNγ) in mediating the beneficial MRSA clearance in TLR9-/- mice. While macrophages from WT and TLR9-/- mice show similar phagocytosis and bacterial killing to MRSA alone, following influenza infection, there is a marked upregulation of scavenger receptor A and MRSA phagocytosis as well as inducible nitric oxide synthase (Inos) and improved bacterial killing that is specific to TLR9-deficient cells. Bone marrow transplant chimera experiments and in vitro experiments using TLR9 antagonists suggest TLR9 expression on non-hematopoietic cells, rather than the macrophages themselves, is important for regulating myeloid cell function. Interestingly, improved bacterial clearance post-dual infection was restricted to MRSA, as there was no difference in the clearance of Streptococcus pneumoniae. Taken together these data show a surprising inhibitory role for TLR9 signaling in mediating clearance of MRSA that manifests following influenza infection.

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Section: Methodsmentioning

confidence: 99%

Influenza-induced immune suppression to methicillin-resistant Staphylococcus aureus is mediated by TLR9

et al. 2019

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“…Collagenase digestion of mouse lung tissue and flow cytometry were performed as previously described (25). See the online supplement for details.…”

Section: Preparation Of Single-cell Suspensions From Lung Tissue and mentioning

confidence: 99%

Lung Microbiota Contribute to Pulmonary Inflammation and Disease Progression in Pulmonary Fibrosis

O’Dwyer

Ashley

Gurczynski

et al. 2019

Am J Respir Crit Care Med

255

263

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Rationale: Idiopathic pulmonary fibrosis (IPF) causes considerable global morbidity and mortality, and its mechanisms of disease progression are poorly understood. Recent observational studies have reported associations between lung dysbiosis, mortality, and altered host defense gene expression, supporting a role for lung microbiota in IPF. However, the causal significance of altered lung microbiota in disease progression is undetermined. Objectives: To examine the effect of microbiota on local alveolar inflammation and disease progression using both animal models and human subjects with IPF. Methods: For human studies, we characterized lung microbiota in BAL fluid from 68 patients with IPF. For animal modeling, we used a murine model of pulmonary fibrosis in conventional and germ-free mice. Lung bacteria were characterized using 16S rRNA gene sequencing with novel techniques optimized for low-biomass sample load. Microbiota were correlated with alveolar inflammation, measures of pulmonary fibrosis, and disease progression. Measurements and Main Results: Disruption of the lung microbiome predicts disease progression, correlates with local host inflammation, and participates in disease progression. In patients with IPF, lung bacterial burden predicts fibrosis progression, and microbiota diversity and composition correlate with increased alveolar profibrotic cytokines. In murine models of fibrosis, lung dysbiosis precedes peak lung injury and is persistent. In germ-free animals, the absence of a microbiome protects against mortality. Conclusions: Our results demonstrate that lung microbiota contribute to the progression of IPF. We provide biological plausibility for the hypothesis that lung dysbiosis promotes alveolar inflammation and aberrant repair. Manipulation of lung microbiota may represent a novel target for the treatment of IPF.

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“…However, these alterations may be impacted more by the process of stem cell transplant rather than by the alterations in lung ECM and further research is needed to evaluate this. This model has also been shown to be impacted by alterations in Notch signalling, specifically by loss of delta‐like 4 ligand on dendritic cells and loss of the Notch 1 and Notch 2 receptors on T cells . This loss of Notch signalling which appears to be a consequence of both the radiation conditioning and the viral infection drives the increased IL‐17 to promote fibrogenesis.…”

Section: Effects Of Fibrosis On Innate Immunitymentioning

confidence: 99%

“…This model has also been shown to be impacted by alterations in Notch signalling, specifically by loss of delta-like 4 ligand on dendritic cells and loss of the Notch 1 and Notch 2 receptors on T cells. 86 This loss of Notch signalling which appears to be a consequence of both the radiation conditioning and the viral infection drives the increased IL-17 to promote fibrogenesis.…”

Section: Effects Of Fibrosis On Innate Immunitymentioning

confidence: 99%

A pathologic two‐way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity

2019

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Lung fibrosis is characterised by the accumulation of extracellular matrix within the lung and is secondary to both known and unknown aetiologies. This accumulation of scar tissue limits gas exchange causing respiratory insufficiency. The pathogenesis of lung fibrosis is poorly understood, but immunologic‐based treatments have been largely ineffective. Despite this, accumulating evidence suggests that innate immune cells and receptors play important modulatory roles in the initiation and propagation of the disease. Paradoxically, while innate immune signalling may be important for the pathogenesis of fibrosis, there is also evidence to suggest that innate immune function against pathogens may be impaired, leading to dysregulated and/or impaired host defence. This review summarises the evidence for this pathologic two‐way street, highlights new concepts of pathogenesis and recommends future directions for research emphasis.

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Bone marrow transplant-induced alterations in Notch signaling promote pathologic Th17 responses to γ-herpesvirus infection

Cited by 17 publications

References 47 publications

Influenza-induced immune suppression to methicillin-resistant Staphylococcus aureus is mediated by TLR9

Influenza-induced immune suppression to methicillin-resistant Staphylococcus aureus is mediated by TLR9

Lung Microbiota Contribute to Pulmonary Inflammation and Disease Progression in Pulmonary Fibrosis

A pathologic two‐way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity

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