Virus-specific effector T cells impair airway secretory cell-mediated alveolar regeneration []
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE276810 | GEO | 2026/01/22
REPOSITORIES: GEO
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Project description:Severe respiratory viral infection leads to extensive damage to the alveolar epithelium and also induce a robust immune response. How immune response impacts alveolar regeneration, especially how immune microenvironment interacts with lung stem/progenitor cells is poorly understood. Here, we find that dysplastic Krt5+ basal-like cells, which emerge after severe viral infection, preferably recruit and maintain the tissue residence of both CD4+ effector T cells and CD8+ T cells in a CXCR3- and Integrin α4/β2-dependent manner after viral clearance. Persistent CD4+ and CD8+ T cells impair alveolar regeneration mediated by airway secretory cells, thus inhibiting lung functional repair. Mechanically, CD4+ and CD8+ T cells function by secreting IFNγ rather than direct interactions with epithelial cells. Importantly, anti-IFNγ treatment promotes alveolar regeneration and functional recovery in vivo. Overall, our study reveals the pathogenetic role of Krt5+ pods in lung regeneration, providing new insights into how dysplastic repair impairs functional regeneration of the alveolar epithelium via interactions with immune cells.
2026-01-22 | GSE276808 | GEO
Project description:Severe respiratory viral infection leads to extensive damage to the alveolar epithelium and also induce a robust immune response. How immune response impacts alveolar regeneration, especially how immune microenvironment interacts with lung stem/progenitor cells is poorly understood. Here, we find that dysplastic Krt5+ basal-like cells, which emerge after severe viral infection, preferably recruit and maintain the tissue residence of both CD4+ effector T cells and CD8+ T cells in a CXCR3- and Integrin α4/β2-dependent manner after viral clearance. Persistent CD4+ and CD8+ T cells impair alveolar regeneration mediated by airway secretory cells, thus inhibiting lung functional repair. Mechanically, CD4+ and CD8+ T cells function by secreting IFNγ rather than direct interactions with epithelial cells. Importantly, anti-IFNγ treatment promotes alveolar regeneration and functional recovery in vivo. Overall, our study reveals the pathogenetic role of Krt5+ pods in lung regeneration, providing new insights into how dysplastic repair impairs functional regeneration of the alveolar epithelium via interactions with immune cells.
2026-01-22 | GSE294184 | GEO
Project description:While the lung bears significant regenerative capacity, severe viral pneumonia can chronically impair lung function by triggering dysplastic remodeling. The connection between these enduring changes and chronic disease remains poorly understood. We recently described the emergence of tuft cells within Krt5+ dysplastic regions after influenza injury. Using bulk and single cell transcriptomics, we characterized and delineated multiple distinct tuft cell populations that arise following influenza clearance. Distinct from intestinal tuft cells which rely on Type 2 immune signals for their expansion, neither IL-25 nor IL-4Ra signaling are required to drive tuft cell development in dysplastic/injured lungs. Furthermore, tuft cells were also observed upon bleomycin injury, suggesting that their development may be a general response to severe lung injury. While intestinal tuft cells promote growth and differentiation of surrounding epithelial cells, in the lungs of tuft cell deficient mice, Krt5+ dysplasia still occurs, goblet cell production is unchanged, and there remains no appreciable contribution of Krt5+ cells into more regionally appropriate alveolar Type 2 cells. Together, these findings highlight unexpected differences in signals necessary for lung tuft cell amplification and establish a framework for future elucidation of tuft cell functions in pulmonary health and disease.
2022-09-14 | GSE197162 | GEO
Project description:While the lung bears significant regenerative capacity, severe viral pneumonia can chronically impair lung function by triggering dysplastic remodeling. The connection between these enduring changes and chronic disease remains poorly understood. We recently described the emergence of tuft cells within Krt5+ dysplastic regions after influenza injury. Using bulk and single cell transcriptomics, we characterized and delineated multiple distinct tuft cell populations that arise following influenza clearance. Distinct from intestinal tuft cells which rely on Type 2 immune signals for their expansion, neither IL-25 nor IL-4Ra signaling are required to drive tuft cell development in dysplastic/injured lungs. Furthermore, tuft cells were also observed upon bleomycin injury, suggesting that their development may be a general response to severe lung injury. While intestinal tuft cells promote growth and differentiation of surrounding epithelial cells, in the lungs of tuft cell deficient mice, Krt5+ dysplasia still occurs, goblet cell production is unchanged, and there remains no appreciable contribution of Krt5+ cells into more regionally appropriate alveolar Type 2 cells. Together, these findings highlight unexpected differences in signals necessary for lung tuft cell amplification and establish a framework for future elucidation of tuft cell functions in pulmonary health and disease.
2022-09-14 | GSE197156 | GEO
Project description:Respiratory viral infections are being increasingly recognized not just for their acute impact but also as potential triggers of long-term health conditions. The recent COVID-19 pandemic in particular has highlighted the prevalence of this phenomenon, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), which has rapidly evolved into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or impaired organ recovery post infection. Yet, the precise mechanisms linking non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC. Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. CD8+ T cell derived IFN-γ and TNF stimulated local macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate an aberrant immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.
2024-08-25 | GSE267226 | GEO
Project description:Respiratory viral infections are being increasingly recognized not just for their acute impact but also as potential triggers of long-term health conditions. The recent COVID-19 pandemic in particular has highlighted the prevalence of this phenomenon, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), which has rapidly evolved into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or impaired organ recovery post infection. Yet, the precise mechanisms linking non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC. Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. CD8+ T cell derived IFN-γ and TNF stimulated local macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate an aberrant immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.
2024-08-25 | GSE267228 | GEO
Project description:A single-cell transcriptional analysis was performed on lung immune cellsisolated from influenza PR8 infected mice at 14 days post injury. The goal is to investigate the potential signaling pathway that regulates dysplastic KRT5 cells expansion. The left lung lobe from influenza infected mice were dissociated to single cells and subjected to fluorescence activated cell sorting (FACS) to select all CD45+ cells. We found that the regulation of actin cytoskeleton, focal adhesion, Hippo signaling pathway are highly activated in dysplastic KRT5+ cells, suggesting that these signaling pathway may play a role in the expansion of dysplastic KRT5 cells in influenza infected lungs.
2025-05-01 | GSE237155 | GEO
Project description:The extent of lung regeneration following catastrophic damage and the potential role of adult stem cells in such a process remains obscure. Sublethal infection of mice with an H1N1 influenza virus related to that of the 1918 pandemic triggers massive airway damage followed by apparent regeneration. We show here that p63-expressing stem cells in the bronchiolar epithelium undergo rapid proliferation after infection and radiate to interbronchiolar regions of alveolar ablation. Once there, these cells assemble into discrete, Krt5+ pods and initiate expression of markers typical of alveoli. Gene expression profiles of these pods suggest that they are intermediates in the reconstitution of the alveolar-capillary network eradicated by viral infection. The dynamics of this p63-expressing stem cell in lung regeneration mirrors our parallel findings that defined pedigrees of human distal airway stem cells assemble alveoli-like structures in vitro and suggests new therapeutic avenues to acute and chronic airway disease. H1N1 infected mice were sacrificed at 25 dpi and the lungs were snap frozen and embedded in OCT. Sections were cut and stained for several markers and consecutive sections were used for Laser Capture Microdissection.The PALMM-BM-. Robot Microbeam laser microdissection system (P.A.L.M. GmbH, Bernried, Germany) in combination with a Zeiss microscope was used to dissect out desired cells.Four population of cells were collected namely alveoli, Krt5+,Spc+ and K5&SPC-. Isolated cells were collected in adhesive caps (Carl Zeiss, Inc.) and RNA was extracted using the Pico Pure RNA extraction kit (Arcturus).
2011-11-01 | E-GEOD-32602 | biostudies-arrayexpress
Project description:The extent of lung regeneration following catastrophic damage and the potential role of adult stem cells in such a process remains obscure. Sublethal infection of mice with an H1N1 influenza virus related to that of the 1918 pandemic triggers massive airway damage followed by apparent regeneration. We show here that p63-expressing stem cells in the bronchiolar epithelium undergo rapid proliferation after infection and radiate to interbronchiolar regions of alveolar ablation. Once there, these cells assemble into discrete, Krt5+ pods and initiate expression of markers typical of alveoli. Gene expression profiles of these pods suggest that they are intermediates in the reconstitution of the alveolar-capillary network eradicated by viral infection. The dynamics of this p63-expressing stem cell in lung regeneration mirrors our parallel findings that defined pedigrees of human distal airway stem cells assemble alveoli-like structures in vitro and suggests new therapeutic avenues to acute and chronic airway disease. 3 colonies fron control and H1N1 influenza treated lungs (12 dpi) ,each were picked for whole genome microarray analysis
2011-11-01 | E-GEOD-32600 | biostudies-arrayexpress
Project description:A single-cell transcriptional analysis was performed on lung epithelial cells isolated from influenza PR8 infected mice at 14 days post injury. The goal is to investigate the potential signaling pathway that regulates dysplastic KRT5 cells expansion. The left lung lobe from influenza infected mice were dissociated to single cells and subjected to fluorescence activated cell sorting (FACS) to select all Epcam+ cells. We found that the regulation of actin cytoskeleton, focal adhesion, Hippo signaling pathway are highly activated in dysplastic KRT5+ cells, suggesting that these signaling pathway may play a role in the expansion of dysplastic KRT5 cells in influenza infected lungs.
2024-07-31 | GSE234082 | GEO