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Omicron XBB.1.5 subvariant causes severe pulmonary disease in K18-hACE-2 mice
Amany Elsharkawy1,2, Shannon Stone1, Anchala Guglani1
1Department of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA, United States.
Abstract:
Owing to their continuous evolution, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) display disparate pathogenicity in mouse models. Omicron and its sublineages have been dominant worldwide. Compared to pre-Omicron VOCs, early Omicron subvariants reportedly cause attenuated disease in human ACE-2-expressing mice (K18-hACE-2). In late 2022, the frequency of Omicron subvariant XBB.1.5 rapidly increased and it progressively replaced other circulating strains. The emergence of new strains requires current SARS-CoV-2 clinical animal model re-evaluation. In this study, we aim to characterize XBB.1.5 pathogenesis in K18-hACE-2. Herein, we demonstrated that XBB.1.5 infection is associated with significant weight loss, severe lung pathology, and substantial mortality. Intranasal XBB.1.5 infection resulted in 100% mortality in K18-hACE2 mice. High virus titers were detected in the lungs on days 3 and 5 after infection. Moreover, XBB.1.5 productively infected the cells within the nasal turbinate, olfactory bulb, intestines, and kidneys. In addition, in a subset of infected mice, we detected high virus titers in the brain. Consistently, we detected high viral antigen expression in the lungs. Furthermore, we observed severe lung injury hallmarks (e.g., immune cell infiltration, perivascular cuffing, and alveolar consolidation). Using immunofluorescence labeling and cytometric analysis, we revealed that XBB.1.5 infection leads to CD45+ cell influx into the lung parenchyma. We further demonstrated that most immune infiltrates are CD11b+ CD11c+ dendritic cells. Additionally, we detected significant induction of proinflammatory cytokines and chemokines in infected lungs. Taken together, our data show that Omicron subvariant XBB.1.5 is highly pathogenic in K18-hACE2 mice.
Insights
The Omicron XBB.1.5 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant causes severe disease and 100% mortality in K18-hACE-2 mice, highlighting its high pathogenicity.
Area of Science:
- Virology
- Immunology
- Pathology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continuously evolves, leading to variants of concern (VOCs) with differing pathogenicity.
- Omicron sublineages, including XBB.1.5, have become globally dominant, necessitating re-evaluation of existing animal models.
- Previous studies indicated attenuated disease in K18-hACE-2 mice for early Omicron subvariants compared to pre-Omicron VOCs.
Purpose of the Study:
- To characterize the pathogenesis of the Omicron XBB.1.5 subvariant in K18-hACE-2 mice.
- To assess the severity of lung pathology, mortality rates, and viral dissemination associated with XBB.1.5 infection.
- To investigate the immune response and cellular infiltration in the lungs following XBB.1.5 infection.
Main Methods:
- Intranasal inoculation of K18-hACE-2 mice with Omicron XBB.1.5.
- Monitoring of weight loss, mortality, and clinical signs.
- Quantification of virus titers in various organs (lungs, brain, kidneys, etc.).
- Histopathological examination of lung tissues.
- Immunofluorescence labeling and cytometric analysis for immune cell identification (CD45+, CD11b+, CD11c+).
- Measurement of proinflammatory cytokines and chemokines in lung homogenates.
Main Results:
- Intranasal XBB.1.5 infection led to 100% mortality in K18-hACE-2 mice.
- Significant weight loss, severe lung pathology, and high virus titers in the lungs were observed.
- XBB.1.5 productively infected nasal turbinates, olfactory bulbs, intestines, kidneys, and in a subset of mice, the brain.
- Histopathology revealed severe lung injury, including immune cell infiltration (predominantly CD11b+ CD11c+ dendritic cells), perivascular cuffing, and alveolar consolidation.
- Proinflammatory cytokines and chemokines were significantly induced in infected lungs.
Conclusions:
- Omicron subvariant XBB.1.5 exhibits high pathogenicity in K18-hACE-2 mice, causing severe disease and mortality.
- XBB.1.5 demonstrates extensive viral dissemination to multiple organs, including potential neuroinvasion.
- The findings underscore the need for updated SARS-CoV-2 animal models to reflect the virulence of emerging variants like XBB.1.5.
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