Age-dependent acquisition of pathogenicity by SARS-CoV-2 Omicron BA.5
Brian Imbiakha1, Shahrzad Ezzatpour2, David W Buchholz1
1Department of Microbiology and Immunology, Cornell University, College of Veterinary Medicine, Ithaca, NY, 14853, USA.
Abstract:
Pathology studies of SARS-CoV-2 Omicron variants of concern (VOC) are challenged by the lack of pathogenic animal models. While Omicron BA.1 and BA.2 replicate in K18-hACE2 transgenic mice, they cause minimal to negligible morbidity and mortality, and less is known about more recent Omicron VOC. Here, we show that in contrast to Omicron BA.1, BA.5-infected mice exhibited high levels of morbidity and mortality, correlating with higher early viral loads. Neither Omicron BA.1 nor BA.5 replicated in brains, unlike most prior VOC. Only Omicron BA.5-infected mice exhibited substantial weight loss, high pathology scores in lungs, and high levels of inflammatory cells and cytokines in bronchoalveolar lavage fluid, and 5- to 8-month-old mice exhibited 100% fatality. These results identify a rodent model for pathogenesis or antiviral countermeasure studies for circulating SARS-CoV-2 Omicron BA.5. Further, differences in morbidity and mortality between Omicron BA.1 and BA.5 provide a model for understanding viral determinants of pathogenicity.
Insights
The Omicron BA.5 variant of SARS-CoV-2 causes severe disease and mortality in mice, unlike BA.1. This study identifies a new mouse model for studying Omicron BA.5 pathogenesis and developing countermeasures.
Area of Science:
- Virology
- Immunology
- Pathology
Background:
- Pathology studies of SARS-CoV-2 variants of concern (VOC) are limited by the absence of suitable animal models.
- Previous Omicron variants (BA.1, BA.2) showed minimal pathogenicity in K18-hACE2 transgenic mice.
Purpose of the Study:
- To establish a rodent model for SARS-CoV-2 Omicron BA.5 pathogenesis.
- To investigate the pathogenicity differences between Omicron BA.1 and BA.5.
Main Methods:
- Infection of K18-hACE2 transgenic mice with SARS-CoV-2 Omicron BA.1 and BA.5.
- Assessment of morbidity, mortality, viral loads, and lung pathology.
- Analysis of inflammatory markers in bronchoalveolar lavage fluid.
Main Results:
- Omicron BA.5 caused significant morbidity, mortality (100% in 5-8 month old mice), weight loss, and lung pathology, unlike Omicron BA.1.
- Higher early viral loads correlated with increased BA.5 pathogenicity.
- Neither BA.1 nor BA.5 replicated in the brain, differing from prior SARS-CoV-2 variants.
Conclusions:
- SARS-CoV-2 Omicron BA.5 establishes a pathogenic phenotype in K18-hACE2 mice, providing a valuable model for pathogenesis and antiviral studies.
- Comparative analysis of BA.1 and BA.5 pathogenicity elucidates viral determinants of disease severity.
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