A C57BL/6 Mouse model of SARS-CoV-2 infection recapitulates age- and sex-based differences in human COVID-19 disease and recovery

Davis, Michael A.; Voss, Kathleen; Turnbull, Julie; Gustin, Andrew T.; Knoll, Megan; Muruato, Antonio E.; Hsiang, Tien-Ying; Dinnon, III Kenneth H.; Leist, Sarah R.; Nickel, Katie; Baric, Ralph S.; Ladiges, Warren; Akilesh, Shreeram; Smith, Kelly D.; Gale, Michael

doi:10.21203/rs.3.rs-2194450/v1

Cited by 3 publications

(1 citation statement)

References 38 publications

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“…This led to viral replication in the lung and mild respiratory disease (Dinnon et al, 2020;Leist et al, 2020). 12-month-old mice were used to recapitulate the more pronounced neuroinflammation observed in middle-and advanced-age COVID-19 patients (Amruta et al, 2022;Davis et al, 2022). At 5 days-post-infection (DPI) mice were euthanized and Cav-1 expression in brain microvessels was assessed by immunostaining (Figure 1A-C).…”

Section: Resultsmentioning

confidence: 99%

Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

Trevino,

Fogel,

Minshall

et al. 2023

Preprint

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Leukocyte infiltration of the CNS can contribute to neuroinflammation and cognitive impairment. Brain endothelial cells regulate adhesion, activation, and diapedesis of T cells across the blood-brain barrier (BBB) in inflammatory diseases. The integral membrane protein Caveolin-1 (Cav-1) critically regulates BBB permeability, but its influence on T cell CNS infiltration in respiratory viral infections is unknown. In this study, we sought to determine the role of Cav-1 at the BBB in neuroinflammation in a COVID-19 mouse model. We used mice genetically deficient in Cav-1 to test the role of this protein in T cell infiltration and cognitive impairment. We found that SARS-CoV-2 infection upregulated brain endothelial Cav-1. Moreover, SARS-CoV-2 infection increased brain endothelial cell vascular cell adhesion molecule-1 (VCAM-1) and CD3+ T cell infiltration of the hippocampus, a region important for short term learning and memory. Concordantly, we observed learning and memory deficits. Importantly, genetic deficiency in Cav-1 attenuated brain endothelial VCAM-1 expression and T cell infiltration in the hippocampus of mice with SARS-CoV-2 infection. Moreover, Cav-1 KO mice were protected from the learning and memory deficits caused by SARS-CoV-2 infection. These results indicate the importance of BBB permeability in COVID-19 neuroinflammation and suggest potential therapeutic value of targeting Cav-1 to improve disease outcomes.

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Section: Resultsmentioning

confidence: 99%

Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

Trevino,

Fogel,

Minshall

et al. 2023

Preprint

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A self-adjuvanted VLPs-based Covid-19 vaccine proven versatile, safe, and highly protective

Vuitika,

Côrtes,

Malaquias

et al. 2024

Sci Rep

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Vaccination has played a critical role in mitigating COVID-19. Despite the availability of licensed vaccines, there remains a pressing need for improved vaccine platforms that provide high protection, safety, and versatility, while also reducing vaccine costs. In response to these challenges, our aim is to create a self-adjuvanted vaccine against SARS-CoV-2, utilizing Virus-Like Particles (VLPs) as the foundation. To achieve this, we produced bacteriophage (Qβ) VLPs in a prokaryotic system and purified them using a rapid and cost-effective strategy involving organic solvents. This method aims to solubilize lipids and components of the cell membrane to eliminate endotoxins present in bacterial samples. For vaccine formulation, Receptor Binding Domain (RBD) antigens were conjugated using chemical crosslinkers, a process compatible with Good Manufacturing Practice (GMP) standards. Transmission Electron Microscopy (TEM) confirmed the expected folding and spatial configuration of the QβVLPs vaccine. Additionally, vaccine formulation assessment involved SDS-PAGE stained with Coomassie Brilliant Blue, Western blotting, and stereomicroscopic experiments. In vitro and in vivo evaluations of the vaccine formulation were conducted to assess its capacity to induce a protective immune response without causing side effects. Vaccine doses of 20 µg and 50 µg stimulated the production of neutralizing antibodies. In in vivo testing, the group of animals vaccinated with 50 µg of vaccine formulation provided complete protection against virus infection, maintaining stable body weight without showing signs of disease. In conclusion, the QβVLPs-RBD vaccine has proven to be effective and safe, eliminating the necessity for supplementary adjuvants and offering a financially feasible approach. Moreover, this vaccine platform demonstrates flexibility in targeting Variants of Concern (VOCs) via established conjugation protocols with VLPs. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-76163-w.

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Pathogenesis of Rift Valley Fever Virus in a BALB/c Mouse Model Is Affected by Virus Culture Conditions and Sex of the Animals

Graham,

Easterbrook,

Kennedy

et al. 2023

Viruses

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Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen causing disease in livestock and humans. Whilst initially restricted to the African continent, recent spread to the Arabian Peninsula has highlighted the likelihood of entry into new regions. Due to the absence of a regulatory-approved human vaccine, work is ongoing to develop and assess countermeasures. As such, small animal models play a pivotal role in providing information on disease pathogenesis and elucidating which intervention strategies confer protection. To develop and establish the BALB/c mouse model, we challenged mice with RVFV grown from two separate cell lines: one derived from mosquitoes (C6/36) and the other mammalian derived (Vero E6). Following infection, we assessed the clinical course of disease progression at days 1 and 3 post-challenge and evaluated viral tropism and immune analytes. The results demonstrated that RVFV infection was affected by the cell line used to propagate the challenge virus, with those grown in insect cells resulting in a more rapid disease progression. The lowest dose that caused uniform severe disease remained the same across both virus preparations. In addition, to demonstrate reproducibility, the lowest dose was used for a subsequent infection study using male and female animals. The results further demonstrated that male mice succumbed to infection more rapidly than their female counterparts. Our results establish an RVFV mouse model and key parameters that affect the course of disease progression in BALB/c mice.

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A C57BL/6 Mouse model of SARS-CoV-2 infection recapitulates age- and sex-based differences in human COVID-19 disease and recovery

Cited by 3 publications

References 38 publications

Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

A self-adjuvanted VLPs-based Covid-19 vaccine proven versatile, safe, and highly protective

Pathogenesis of Rift Valley Fever Virus in a BALB/c Mouse Model Is Affected by Virus Culture Conditions and Sex of the Animals

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