An In-Depth Analysis of the Pathogenicity of the SARS-CoV-2 Delta and Omicron Variants in Golden Syrian Hamsters
SARS-CoV-2 has continued to evolve throughout the COVID-19 pandemic, giving rise to multiple variants of concern (VOCs). These VOCs differ in transmissibility, immune evasion and virulence. Since its emergence in November 2021, BA.1 (Omicron), and its sub lineages, have rapidly overtaken the B.617.2 (Delta) lineage. Importantly, Omicron induces a milder disease, and this was attributed to preferential infection of the upper respiratory tract tissues.  Multiple studies have examined VOCs in experimentally infected rodent models. However, in most cases they have been limited to comparing virus replication, weight loss and basic histopathology in animals infected with different variants. Here, we aimed to (i) gain a better understanding of the complex immunopathology of SARS-CoV-2 variants infection, and (ii) develop quantitative methods that could be used to assess SARS-CoV-2 variants virulence in the hamster model. We used a variety of approaches including RNA in situ hybridization (ISH) and immunohistochemistry (followed by whole slide image analysis and quantification),  bulk RNAseq and qRT-PCR to quantify virus replication, the extent of pulmonary lesions, and host responses. We obtained data showing that Delta infects a higher number of cells than Omicron throughout the respiratory tract, with the possible exception of the nose epithelium. In line with previous studies, Omicron displayed a limited ability to invade the lung parenchyma. Upregulation of interferon stimulated genes (ISGs) was directly related to the presence of virus-infected cells. Importantly, the degree of pulmonary lesions, quantified by assessing type-II pneumocytes proliferation and macrophage infiltrates, was considerably higher in Delta- compared to Omicron-infected animals.    In summary, this study provides an experimental pipeline that can be used to both investigate the pathogenesis of SARS-CoV-2 variants in hamsters and quantitatively assess their virulence. The rapid assessment of the potential of newly emerging variants to cause severe disease will be invaluable as the pandemic progresses.