Since the start of the COVID-19 pandemic in 2019, the SARS-CoV-2 virus has produced a number of variants, including alpha, beta, delta and omicron, each with its own subvariants.
New research, published Sept. 22 in Science Advances, used engineered mice to compare SARS-COV-2 omicron subvariants, and found one of them, BA.5, was more virulent likely due to its ability to rapidly replicate early during infection.
The study addresses a challenge to studying and understanding rapidly evolving variants of concern due to a lack of animal models for running tests that could help explain why variants and subvariants each behave differently in people.
The genetically modified mice, called K18-hACE2 mice, used in the research express a human receptor that allowed SARS-COV-2 to enter otherwise inaccessible mouse cells.
“One of the things we found is that the strain that causes more pathology, BA.5, replicates much faster early on during infection,” said Avery August, deputy provost and professor of microbiology and immunology in the College of Veterinary Medicine (CVM). August and Hector Aguilar-Carreño, professor of virology, also in CVM, are co-corresponding authors of the study, “Age-Dependent Acquisition of Pathogenicity by SARS-CoV-2 Omicron BA.5.”
“By doing that, the virus generates a really strong immune response, which then leads to increased pathology and symptoms compared to subvariants that don’t replicate as fast,” August said.
“Prior to this study, there were no small animal models to study the new SARS-CoV-2 Omicron variants of concern, because no animals got sick with other variants,” Aguilar-Carreño said. “Our study allows us to use relatively older K18-hACE2 mice as a disease model to understand how the virus becomes pathogenic, and to test whether and how vaccines and antivirals work for the new Omicron sub-variants.”
Early omicron BA.1 and BA.2 subvariants also replicated and spread in the K-18 mice, but they caused minimal illness and death. On the other hand, BA.5-infected mice exhibited significant weight loss, high pathology in lungs, high levels of inflammatory cells and cytokines, signaling proteins that are associated with inflammation. While some 3-month old mice survived and all 5 to 8 month-old BA.5-infected mice died.