Comparison of the Pathogenicity of SARS-CoV-2 Delta and Omicron Variants by Analyzing the Expression Patterns of Immune Response Genes in K18-hACE2 Transgenic Mice

Kuruppu Arachchillage Praboda Priyangi Kuruppuarachchi^1,2,†, Yunyueng Jang^1,2,†, Sang Heui Seo^1,2,*

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¹ Laboratory of Influenza Research, College of Veterinary Medicine, Chungnam National University, 34134 Daejeon, Republic of Korea

² Institute of Influenza Virus, Chungnam National University, 34134 Daejeon, Republic of Korea

^*Correspondence: seos@cnu.ac.kr (Sang Heui Seo)
^†These authors contributed equally.
Academic Editor: Vijay Kumar

Front. Biosci. (Landmark Ed) 2022, 27(11), 316; https://doi.org/10.31083/j.fbl2711316

Submitted: 3 September 2022 | Revised: 8 November 2022 | Accepted: 9 November 2022 | Published: 30 November 2022

(This article belongs to the Special Issue Vaccine and anti-viral drug development for SARS-CoV2)

This is an open access article under the CC BY 4.0 license.

Abstract

Background: The recently emerged variants of the severe acute respiratory coronavirus 2 (SARS-CoV-2) pose a threat to public health. Understanding the pathogenicity of these variants is a salient factor in the development of effective SARS-CoV-2 therapeutics. This study aimed to compare the expression patterns of genes involved in immune responses in K18-hACE2 mice infected with the wild-type, Delta, and Omicron SARS-CoV-2 variants. Methods: K18-hACE2 mice were intranasally infected with either wild-type (B.1), Delta (B.1.617.2), or Omicron (B.1.1.529) variants. On day 6 post-infection, lung, brain, and kidney tissues were collected from each variant-infected group. The mRNA expression levels of 39 immune response genes in all three groups were compared by RT-qPCR. Viral titers were measured using the median tissue culture infectious dose (TCID ${}_{50}$ ) assay and expressed as Log10 TCID ${}_{50}$ /0.1 g. The statistical significance of the differences in gene expression was determined by one-way analysis of variance (ANOVA) (alpha = 0.05). Results: The expression of toll-like receptors (TLRs) was upregulated in the lung and brain tissues of the wild-type- and Delta-infected groups but not in those of the Omicron-infected group. The highest expression of cytokines, including interleukin (IL)-1 $\alpha{}$ , IL-1 $\beta{}$ , IL-17 $\alpha{}$ , interferon, and tumor necrosis factors, was observed in the lungs of mice infected with the wild-type variant. Additionally, CCL4, CCL11, CXCL9, and CXCL10 were upregulated ( $>$ 3-fold) in wild-type-infected mice, with markedly higher expressions in the brain than in the lungs. Most of the apoptotic factors were mainly expressed in the brain tissues of Omicron-infected mice (caspase 8, caspase 9, p53, Bax, Bak, BCL-2, and Bcl-XL), whereas neither the lung nor kidney showed more than 3-fold upregulation of these apoptotic factors. Conclusions: Collectively, our findings revealed that the wild-type SARS-CoV-2 variant exhibited the highest pathogenicity, followed by the Delta variant, then the Omicron variant.

Keywords

apoptosis

cytokines

Delta

Omicron

SARS-CoV-2

viral pathogenicity

Funding

2019R1A2C2002166812/National Research Foundation of Korea (NRF)

Figures

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Fig. 1.

The surviving rate, body weight changes, and viral titers of K18-hACE2 transgenic mice infected with the SARS-CoV-2 variants (n = 10 per group). (A) Survival rate of mice infected with wild-type, Delta, and Omicron SARS-CoV-2 and uninfected mice. (B) Body weight changes after infection with wild-type, Delta, Omicron, and PBS. (C) Viral titers in tissues of mice infected with wild-type, Delta, or Omicron determine by Log10 TCID ${}_{50}$ /0.1 g. * p $<$ 0.05, ** p $<$ 0.01.

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