Validation Of Anti-Host Cell Influenza Targets Using A Novel Human Lung Tissue Model

Nicholas, Ben; Staples, Karl J.; Moese, Stefan; Ward, James E.; North, Malcolm; Wilkinson, Tom; Pink, Sandra; Djukanović, Ratko

doi:10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a5716

Cited by 2 publications

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“…Resected human lung tissue was obtained from patients undergoing airway re-section surgery at our regional thoracic surgical unit. Ex vivo infection of resected lung tissue was carried out as previously described[ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…Whilst PDL1 expression has been shown to be increased on human airway macrophages in response to respiratory viral infections[ 7 ], the mechanisms of the expression of this ligand on macrophages in response to influenza has not been fully elucidated. Therefore we used a validated ex vivo human lung model of influenza infection[ 14 ], where we have demonstrated infection of resected lung tissue using immunohistochemistry and flow cytometry, by the expression of viral nucleoprotein (NP)-1[ 14 ]. In this ex vivo model we have observed NP1 positivity only in epithelial cells and macrophages suggesting that these are the two major cell types for which the virus has tropism.…”

Section: Introductionmentioning

confidence: 99%

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Viral Infection of Human Lung Macrophages Increases PDL1 Expression via IFNβ

et al. 2015

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Lung macrophages are an important defence against respiratory viral infection and recent work has demonstrated that influenza-induced macrophage PDL1 expression in the murine lung leads to rapid modulation of CD8+ T cell responses via the PD1 receptor. This PD1/PDL1 pathway may downregulate acute inflammatory responses to prevent tissue damage. The aim of this study was to investigate the mechanisms of PDL1 regulation by human macrophages in response to viral infection. Ex-vivo viral infection models using influenza and RSV were established in human lung explants, isolated lung macrophages and monocyte-derived macrophages (MDM) and analysed by flow cytometry and RT-PCR. Incubation of lung explants, lung macrophages and MDM with X31 resulted in mean cellular infection rates of 18%, 18% and 29% respectively. Viral infection significantly increased cell surface expression of PDL1 on explant macrophages, lung macrophages and MDM but not explant epithelial cells. Infected MDM induced IFNγ release from autologous CD8+ T cells, an effect enhanced by PDL1 blockade. We observed increases in PDL1 mRNA and IFNβ mRNA and protein release by MDM in response to influenza infection. Knockdown of IFNβ by siRNA, resulted in a 37.5% reduction in IFNβ gene expression in response to infection, and a significant decrease in PDL1 mRNA. Furthermore, when MDM were incubated with IFNβ, this cytokine caused increased expression of PDL1 mRNA. These data indicate that human macrophage PDL1 expression modulates CD8+ cell IFNγ release in response to virus and that this expression is regulated by autologous IFNβ production.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Viral Infection of Human Lung Macrophages Increases PDL1 Expression via IFNβ

et al. 2015

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“…To assess the functional consequences of a viral infection on the activation of T cells, we used a previously validated ex vivo model of lung explant infection (11,14,15). In a previous study, X31 was shown to infect epithelial cells and macrophages in human bronchial and parenchymal tissues (11,15).…”

Section: Influenza Infection Of Lung Explantsmentioning

confidence: 99%

“…In a previous study, X31 was shown to infect epithelial cells and macrophages in human bronchial and parenchymal tissues (11,15). Endothelium, fibroblasts, B cells, and T cells were not infected by X31 (14). Therefore, infection of epithelial cells and macrophages was quantified using the gating strategy with the expression of influenza nucleoprotein (NP)-1, outlined in Figure 3A.…”

Section: Influenza Infection Of Lung Explantsmentioning

confidence: 99%

Dysregulation of Antiviral Function of CD8⁺T Cells in the Chronic Obstructive Pulmonary Disease Lung. Role of the PD-1–PD-L1 Axis

McKendry

Spalluto

Burke

et al. 2016

Am J Respir Crit Care Med

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Rationale: Patients with chronic obstructive pulmonary disease (COPD) are susceptible to respiratory viral infections that cause exacerbations. The mechanisms underlying this susceptibility are not understood. Effectors of the adaptive immune response-CD8 1 T cells that clear viral infections-are present in increased numbers in the lungs of patients with COPD, but they fail to protect against infection and may contribute to the immunopathology of the disease. Objectives: CD81 function and signaling through the programmed cell death protein (PD)-1 exhaustion pathway were investigated as a potential key mechanism of viral exacerbation of the COPD lung.Methods: Tissue from control subjects and patients with COPD undergoing lung resection was infected with live influenza virus ex vivo. Viral infection and expression of lung cell markers were analyzed using flow cytometry. Measurements and Main Results:The proportion of lung CD8 1 T cells expressing PD-1 was greater in COPD (mean, 16.2%) than in controls (4.4%, P = 0.029). Only epithelial cells and macrophages were infected with influenza, and there was no difference in the proportion of infected cells between controls and COPD. Infection up-regulated T-cell PD-1 expression in control and COPD samples. Concurrently, influenza significantly up-regulated the marker of cytotoxic degranulation (CD107a) on CD81 T cells (P = 0.03) from control subjects but not on those from patients with COPD. Virus-induced expression of the ligand PD-L1 was decreased on COPD macrophages (P = 0.04) with a corresponding increase in IFN-g release from infected COPD explants compared with controls (P = 0.04).Conclusions: This study has established a signal of cytotoxic immune dysfunction and aberrant immune regulation in the COPD lung that may explain both the susceptibility to viral infection and the excessive inflammation associated with exacerbations.

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Validation Of Anti-Host Cell Influenza Targets Using A Novel Human Lung Tissue Model

Cited by 2 publications

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Viral Infection of Human Lung Macrophages Increases PDL1 Expression via IFNβ

Viral Infection of Human Lung Macrophages Increases PDL1 Expression via IFNβ

Dysregulation of Antiviral Function of CD8⁺T Cells in the Chronic Obstructive Pulmonary Disease Lung. Role of the PD-1–PD-L1 Axis

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Validation Of Anti-Host Cell Influenza Targets Using A Novel Human Lung Tissue Model

Cited by 2 publications

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Viral Infection of Human Lung Macrophages Increases PDL1 Expression via IFNβ

Viral Infection of Human Lung Macrophages Increases PDL1 Expression via IFNβ

Dysregulation of Antiviral Function of CD8+T Cells in the Chronic Obstructive Pulmonary Disease Lung. Role of the PD-1–PD-L1 Axis

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Dysregulation of Antiviral Function of CD8⁺T Cells in the Chronic Obstructive Pulmonary Disease Lung. Role of the PD-1–PD-L1 Axis