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. 2024 Oct 24;14(1):25147.
doi: 10.1038/s41598-024-77087-1.

Characterization of Collaborative Cross mouse founder strain CAST/EiJ as a novel model for lethal COVID-19

Candice N Baker #  1 , Debra Duso #  2 , Nagarama Kothapalli  2 , Tricia Hart  2 , Sean Casey  2 , Tres Cookenham  2 , Larry Kummer  2 , Janine Hvizdos  2 , Kathleen Lanzer  2 , Purva Vats  3 , Priya Shanbhag  3 , Isaac Bell  3 , Mike Tighe  2 , Kelsey Travis  2 , Frank Szaba  2 , Jeffrey M Harder  1 , Olivia Bedard  1 , Natalie Oberding  2 , Jerrold M Ward  2 , Mark D Adams  3 , Cathleen Lutz  1 , Shelton S Bradrick  2 , William W Reiley  4 , Nadia A Rosenthal  5   6
Affiliations

Characterization of Collaborative Cross mouse founder strain CAST/EiJ as a novel model for lethal COVID-19

Candice N Baker et al. Sci Rep. .

Abstract

Mutations in SARS-CoV-2 variants of concern (VOCs) have expanded the viral host range beyond primates, and a few other mammals, to mice, affording the opportunity to exploit genetically diverse mouse panels to model the broad spectrum of responses to infection in patient populations. Here we surveyed responses to VOC infection in genetically diverse Collaborative Cross (CC) founder strains. Infection of wild-derived CC founder strains produced a broad range of viral burden, disease susceptibility and survival, whereas most other strains were resistant to disease despite measurable lung viral titers. In particular, CAST/EiJ, a wild-derived strain, developed high lung viral burdens, more severe lung pathology than seen in other CC strains, and a dysregulated cytokine profile resulting in morbidity and mortality. These inbred mouse strains may serve as a valuable platform to evaluate therapeutic countermeasures against severe COVID-19 and other coronavirus pandemics in the future.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Evaluation of genetically diverse mouse strains for susceptibility to SARS-CoV-2 Beta variant infection in comparison to transgenic K18-hACE2 mice. (a) Experimental schematic showing nine unique mice strains were infected with 1 × 105 PFU SARS-CoV-2 Beta VOC and assayed at 3 days post-infection (dpi) and 7 dpi for lung viral titer (n = 8/strain per time point, 4 males, 4 female) as well as survival (n = 20/strain, 10 males, 10 females). (b) Phylogenetic tree showing diverse mouse strains is shown, adapted from Morgan et al. (c,d) Female and male body weights were monitored daily for 14.5 days post-infection. Data are graphed as mean percent of initial body weight ± SEM. Strains with n = 1 mouse surviving were excluded from further analysis. (e,f) Probability of survival is shown for each strain. (g) Lung viral titers at 3- and 7 days post-infection graphed as mean titer ± SD.
Fig. 2
Fig. 2
Cytokine and flow cytometric analysis from SARS-CoV-2 infected lung tissue show cytokine storm in CAST and K18-hACE2 mice. Mice were infected with 1 × 105 PFU SARS-CoV-2 Beta VOC. (a) Heatmap of cytokine and chemokine responses from naïve, 1-, 3-, and 5 days post-infection. (b–g) IL-6, Groα, MCP-5, IL-1β, MCP-1, MCP-3 levels in CAST/EiJ (green), C57BL/6J (grey) and K18-hACE2 (black) mice. (h–p) Total number of indicated cell types in lung samples at the indicated timepoint. The data are representative of two experiments of similar design, wherein 5 mice were used per group.
Fig. 3
Fig. 3
Histological and immunohistochemical analysis of SARS-CoV-2 infected lung tissues. (a) NP antibody staining of lung sections was performed to identify infected cells (in red) in the lungs of each mouse strain at day 3 post-infection. Black arrows point to low frequency infected macrophages found in C57BL/6J mice. Blue arrows point to infected bronchiolar club cells. Green arrows point to infected AT1 cells and orange arrows point to infected probable AT2 cells. (b) Hemotoxin and eosin-stained lung sections from each infected mouse strain are shown. (c) ACE2 was also targeted for immunohistochemistry using a specific antibody. Blue, green, and orange arrows point to club, AT1, and probable AT2 cells, respectively, expressing ACE2. (d) Pathology scores for bronchiolar necrosis, interstitial lesions and SARS-CoV-2 staining. Scoring scale used was 0, 1, 2, 3, 4 (none, minimal, mild, moderate, severe). The data are representative of three experiments of similar design, where in 4 mice (2 male and 2 female) were used per time point.
Fig. 4
Fig. 4
Therapeutic treatment of K18-hACE2 and CAST/EiJ mice infected with SARS-CoV-2 Beta VOC. (a) Mean weights ± SEM for each group over the course of 14.5 days. (b) Survival curves for the indicated groups with or without treatment with PF-07321332 at 500 mg/kg/day P.O. The data are representative of two experiments of similar design, where in 5 mice were used per group.
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