Spatiotemporal analysis of SARS-CoV-2 infection in hamster lungs reveals an expansive wave of monocyte-derived macrophages associated with vascular damage and virus clearance
Characteristics of the innate immune response to SARS-CoV-2 in the lungs are pivotal for the ability of the organism to deal with infection. Excessive infiltration of macrophages is associated with poor disease outcome. Using 3D spatiotemporal analysis of optically clear hamster lung tissues in combination with virological, immunohistochemical and RNA sequence analyses we show the spread of SARS-CoV-2 through the lungs and rapid anti-viral response in infected lung epithelial cells, followed by a synchronized wave of CD68+ monocyte-derived macrophage (MDM) infiltration leading to virus elimination from the tissue. The SARS-CoV-2 induced innate immune processes are closely related with the onset of necrotic and lung remodelling responses in the lungs, which is manifested in extensive apoptosis, vascular damage, thrombosis, and an early initiation of cell proliferation. Here we show that MDM are directly linked to the virus clearance, and these cells appear in connection with tissue injury and blood vessel rupture. Rapid initiation of prothrombotic factor upregulation, tissue repair and alveolar cell proliferation results in tissue remodelling, which is followed by lung fibrosis development despite decrease in the inflammatory and anti-viral activities. Thus, although the animals are able to resolve the infection and repair lung tissue integrity, longer term structural changes in lungs indicate that the efficient balance between tissue damage and repair is critical for successful lung function restoration. Overall design: 21 hamsters were infected orotracheally as described earlier (Blaurock et al., 2022) with 10^5 TCID50 of the ancestral SARS-CoV-2 (isolate 2019_nCoV Muc-IMB-1) per animal. Tissues from infected animals killed at day 1-7 and day 14 as well as mock-infected hamsters killed at day 7 were included in the study (n=3 per day). The left lung lobe was carefully removed, immersion-fixed in 10% neutral-buffered formalin, paraffin-embedded, and 2–3-µm sections were stained with hematoxylin and eosin (HE) for light microscopical examination. In parallel RNA extraction and Illumina RNAseq was performed.