Spatiotemporal analysis of SARS-CoV-2 infection reveals an expansive wave of monocyte-derived macrophages associated with vascular damage and virus clearance in hamster lungs

Abstract

Lung immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for the ability to deal with infection. Using light sheet fluorescence microscopy of hamster lung slices in combination with virological, immunohistochemical, and RNA sequencing analyses, we show a wave of monocyte-derived macrophage (MDM) infiltration and the antiviral response which follows the spread of SARS-CoV-2 through the lungs and lead to virus elimination. These innate immune processes are related to the onset of necrotizing inflammatory and remodeling responses, which manifest as extensive cell death, vascular damage, and cell proliferation. We show that MDM appear in parallel with virus clearance and endothelial injury. Prothrombotic factor upregulation, tissue repair, and alveolar cell proliferation result in tissue remodeling, which is followed by fibrosis despite a decrease in inflammatory and antiviral activities. Although the lung tissue integrity is repaired, longer-term alterations of the lung arise as an outcome of concurrent tissue damage and regeneration processes. IMPORTANCE We present the first study of the 3D kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the early host response in a large lung volume using a combination of tissue imaging and transcriptomics. This approach allowed us to make a number of important findings: Spatially restricted antiviral response is shown, including the formation of monocytic macrophage clusters and upregulation of the major histocompatibility complex II in infected epithelial cells. The monocyte-derived macrophages are linked to SARS-CoV-2 clearance, and the appearance of these cells is associated with post-infection endothelial damage; thus, we shed light on the role of these cells in infected tissue. An early onset of tissue repair occurring simultaneously with inflammatory and necrotizing processes provides the basis for longer-term alterations in the lungs.

SARS-CoV-2 Seropositivity in Urban Population of Wild Fallow Deer, Dublin, Ireland, 2020–2022

“…Infected cells were observed in tracheal epithelium from 1 of 2 animals inoculated with ancestral SARS-CoV-2 but not Omicron. The reasons for differences in tissue distribution are unclear, and further studies will be needed to determine tissue distribution at different timepoints after infection ( 33 , 34 ).…”

Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models

“…SARS-CoV-2 infection in ferrets also results in significant alterations in the composition of macrophage subsets in bronchoalveolar lavage fluid (BALF), with monocyte-derived M1 and M2 macrophages playing pivotal roles in both early viral clearance and late-phase excessive inflammation (Lee et al, 2021). Furthermore, SARS-CoV-2 infection in Syrian hamsters induces rapid and extensive infiltration of monocyte-derived macrophages (MDM) in the lungs, which are involved in tissue remodeling and fibrosis via the up-regulation of prothrombotic factors, tissue repair, and alveolar cell proliferation (Bagato et al, 2024). Neutrophils are the most abundant white blood cells that infiltrate the infected lungs first after virus infection.…”