Organ-specific immunity: A tissue analysis framework for investigating local immune responses to SARS-CoV-2.

Local immune activation at mucosal surfaces, mediated by mucosal lymphoid tissues, is vital for effective immune responses against pathogens. While pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can spread to multiple organs, patients with coronavirus disease 2019 (COVID-19) primarily experience inflammation and damage in their lungs. To investigate this apparent organ-specific immune response, we develop an analytical framework that recognizes the significance of mucosal lymphoid tissues. This framework combines histology, immunofluorescence, spatial transcript profiling, and mathematical modeling to identify cellular and gene expression differences between the lymphoid tissues of the lung and the gut and predict the determinants of those differences. Our findings indicate that mucosal lymphoid tissues are pivotal in organ-specific immune response to SARS-CoV-2, mediating local inflammation and tissue damage and contributing to immune dysfunction. The framework developed here has potential utility in the study of long COVID and may streamline biomarker discovery and treatment design for diseases with differential pathologies at the organ level.

Role of urokinase plasminogen activator receptor-associated protein in mouse lung.

Urokinase plasminogen activator receptor-associated protein (uPARAP, or Endo180) is a transmembrane endocytic receptor that mediates collagen internalization and degradation. uPARAP may be a novel pathway for collagen turnover and matrix remodeling in the lung. The function of uPARAP in lung injury has not been described. We analyzed the pulmonary mechanics of uPARAP(-/-) and wild-type mice at baseline and examined their response after bleomycin instillation. We compared collagen internalization in primary mouse lung fibroblasts (MLFs) from wild-type and uPARAP(-/-) mice using flow cytometry and fluorescent microscopy, and we examined the role of cytokines in regulating uPARAP expression and collagen internalization. We show that uPARAP is highly expressed in the lung, and that uPARAP(-/-) mice have increased lung elastance at baseline and after injury. uPARAP(-/-) mice are protected from changes in lung permeability after acute lung injury and have increased collagen content after bleomycin injury. uPARAP is the primary pathway for internalization of collagens in MLFs. Furthermore, collagen internalization through uPARAP does not require matrix metalloproteinase digestion and is independent of integrins. Mediators of lung injury, including transforming growth factor-ß, TNF-α, and IL-1, down-regulate both uPARAP expression and collagen internalization. uPARAP is highly expressed in the murine lung, and loss of uPARAP leads to differences in lung mechanics, lung permeability, and collagen content after injury. uPARAP is required for collagen internalization by MLFs. Thus, uPARAP is a novel pathway that regulates matrix remodeling in the lung after injury.