Mast cell-driven remodeling of pulmonary immune and stromal landscapes in COVID-19.

The role of mast cells (MCs) in the pathogenesis of COVID-19 remains poorly understood. In the present study, we profiled the spatial phenotype of MC interaction with the pulmonary immune and stromal landscapes. The study included lung tissue samples from 12 COVID-19 patients and 12 patients with undifferentiated community-acquired pneumonia (CAP). Histochemical, monoplex, and multiplex immunohistochemical staining with spatial phenotyping, profiling, and mapping of MCs, as well as interactions with the immune and stromal landscape of the lungs, including elastic and collagen fibers, were used. Compared with other respiratory infections, SARS-CoV-2-associated pneumonia caused an increase in the pool of MCs in the lungs simultaneously with the activation of targeted secretion of tryptase and the formation of significant differences in the spatial phenotype of colocalization of MCs with immunocompetent cells and fibers. The intensity of juxtacrine and paracrine interactions of MC with cytotoxic lymphocytes and monocytes increased, initiating the polarization of macrophages into type 2. In this case, MCs and type 2 macrophages formed extended multicellular chains in the form of a functional syncytium, creating profibrotic niches of the local tissue microenvironment. Under COVID-19 conditions, an unexpected increase in MC interaction with elastic extracellular matrix (ECM) fibers and localized tryptase release revealed new insights into tissue tensometry and ECM remodeling. New spatial patterns of interaction between MCs and the immune and stromal landscape may have beneficial effects in developing therapeutic solutions for fibrotic change prevention.