Dataset Information

Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19.

ABSTRACT: Prolonged lung pathology has been associated with COVID-19, yet the cellular and molecular mechanisms behind this chronic inflammatory disease are poorly understood. In this study, we combine advanced imaging and spatial transcriptomics to shed light on the local immune response in severe COVID-19. We show that activated adventitial niches are crucial microenvironments contributing to the orchestration of prolonged lung immunopathology. Up-regulation of the chemokines CCL21 and CCL18 associates to endothelial-to-mesenchymal transition and tissue fibrosis within these niches. CCL21 over-expression additionally links to the local accumulation of T cells expressing the cognate receptor CCR7. These T cells are imprinted with an exhausted phenotype and form lymphoid aggregates that can organize in ectopic lymphoid structures. Our work proposes immune-stromal interaction mechanisms promoting a self-sustained and non-resolving local immune response that extends beyond active viral infection and perpetuates tissue remodeling.

SUBMITTER: Mothes R

PROVIDER: S-EPMC9922044 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19.

Mothes Ronja R Pascual-Reguant Anna A Koehler Ralf R Liebeskind Juliane J Liebheit Alina A Bauherr Sandy S Philipsen Lars L Dittmayer Carsten C Laue Michael M von Manitius Regina R Elezkurtaj Sefer S Durek Pawel P Heinrich Frederik F Heinz Gitta A GA Guerra Gabriela M GM Obermayer Benedikt B Meinhardt Jenny J Ihlow Jana J Radke Josefine J Heppner Frank L FL Enghard Philipp P Stockmann Helena H Aschman Tom T Schneider Julia J Corman Victor M VM Sander Leif E LE Mashreghi Mir-Farzin MF Conrad Thomas T Hocke Andreas C AC Niesner Raluca A RA Radbruch Helena H Hauser Anja E AE

Nature communications 20230211 1

Prolonged lung pathology has been associated with COVID-19, yet the cellular and molecular mechanisms behind this chronic inflammatory disease are poorly understood. In this study, we combine advanced imaging and spatial transcriptomics to shed light on the local immune response in severe COVID-19. We show that activated adventitial niches are crucial microenvironments contributing to the orchestration of prolonged lung immunopathology. Up-regulation of the chemokines CCL21 and CCL18 associates ...[more]

PMID: 36774347

Similar Datasets

Project description:BackgroundInfluenza A viruses (IAVs) have long posed a threat to humans, occasionally causing significant morbidity and mortality. The initial immune response is triggered by infected epithelial cells, alveolar macrophages and dendritic cells. However, an exaggerated innate immune response can result in severe lung injury and even host mortality. One notable pathology observed in hosts succumbing to severe influenza is the excessive influx of neutrophils and monocytes into the lung. In this study, we investigated a strategy for controlling lung immunopathology following severe influenza infection.ResultsTo evaluate the impact of innate immunity on influenza-associated lung injury, we employed CB17.SCID and NOD.SCID mice. NOD.SCID mice exhibited slower weight loss and longer survival than CB17.SCID mice following influenza infection. Lung inflammation was reduced in NOD.SCID mice compared to CB17.SCID mice. Bulk RNA sequencing analysis of lung tissue showed significant downregulation of 827 genes, and differentially expressed gene analysis indicated that the cytokine-cytokine receptor interaction pathway was predominantly downregulated in NOD.SCID mice. Interestingly, the expression of the Cxcl14 gene was higher in the lungs of influenza-infected NOD.SCID mice than in CB17.SCID mice. Therefore, we induced overexpression of the Cxcl14 gene in the lung using the adeno-associated virus 9 (AAV9)-vector system for target gene delivery. However, when we administered the AAV9 vector carrying the Cxcl14 gene or a control AAV9 vector to BALB/c mice from both groups, the morbidity and mortality rates remained similar. Both groups exhibited lower morbidity and mortality than the naive group that did not receive the AAV9 vector prior to IAV infection, suggesting that the pre-administration of the AAV9 vector conferred protection against lethal influenza infection, irrespective of Cxcl14 overexpression. Furthermore, we found that pre-inoculation of BALB/c mice with AAV9 attenuated the infiltration of trans-macrophages, neutrophils and monocytes in the lungs following IAV infection. Although there was no difference in lung viral titers between the naive group and the AAV9 pre-inoculated group, pre-inoculation with AAV9 conferred lung injury protection against lethal influenza infection in mice.ConclusionsOur study demonstrated that pre-inoculation with AAV9 prior to IAV infection protected mouse lungs from immunopathology by reducing the recruitment of inflammatory cells.

Dataset Information

Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19.

Publications

Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets