Abstract
BACKGROUND: The COVID-19 pandemic, caused by SARS-CoV-2, has led to the emergence of viral variants with distinct characteristics. Understanding the differential impacts of SARS-CoV-2 variants is crucial for effective public health response and treatment development. We investigated the differential effects of the original Wuhan strain and the emergent Omicron variant of SARS-CoV-2 using a K18-hACE2 transgenic mouse model. We compared the mortality rates, viral loads, and histopathological changes in lung and tracheal tissues, as well as alterations in the lung and intestinal microbiota following infection. RESULTS: Our findings revealed significant differences between the variants, with the Wuhan strain causing higher mortality rates, severe lung pathology, and elevated viral loads compared to the Omicron variant. Microbiome analyses uncovered novel and distinct shifts in the lung and intestinal microbiota associated with each variant, providing evidence for variant-specific microbiome alterations. These changes suggest microbiome-related mechanisms that might modulate disease severity and host responses to SARS-CoV-2 infection. CONCLUSIONS: This study highlights critical differences between the Wuhan strain and Omicron variant in terms of mortality, lung pathology, and microbiota changes, emphasizing the role of the microbiome in influencing disease outcomes. Novel findings include the identification of variant-specific microbiota shifts, which underscore potential microbiome-related mechanisms underlying differences in disease severity. These insights pave the way for future research exploring microbiome-targeted interventions to mitigate the impacts of SARS-CoV-2 and other viral infections.