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. [Display omitted] •Mucosal lymphoid tissues drive organ-specific response during SARS-CoV-2 infection•Injury signature is enriched in the lymphoid tissues of the lung relative to the gut•Lung lymphoid tissues harbor increased inflammatory macrophages during infection•Absence of activated dendritic cells in those tissues suggests immune dysfunction Ng et al. investigate the role of mucosal lymphoid tissues in SARS-CoV-2 infection, uncovering distinct immune responses in the lung versus the gut. Lung lymphoid tissues exhibit elevated inflammatory macrophages, diminished activated dendritic cells, and amplified injury signatures, underscoring their pivotal role in organ-specific infection response.