Insights into the pathogenesis of the previous and circulating SARS-CoV-2 variants in mice

A recent article posted to the bioRxiv* preprint server presented the diverse pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) in a humanized mouse model.

Study: Differential pathogenesis of SARS-CoV-2 variants of concern in human ACE2-expressing mice. Image Credit: Fit Ztudio/Shutterstock
Study: Differential pathogenesis of SARS-CoV-2 variants of concern in human ACE2-expressing mice. Image Credit: Fit Ztudio/Shutterstock

Background

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has been responsible for over six million human deaths worldwide since 2019. The recurrent emergence of heavily mutated SARS-CoV-2 VOCs, such as Alpha, Beta, Gamma, Delta, and Omicron, resulted in the subsequent global waves of the COVID-19 pandemic.

The SARS-CoV-2 VOCs exhibit improved adaptability, immune evasion, disease severity, and transmission capacities than the original viral strain. However, the comparative severity of COVID-19 caused by the prior and presently circulating SARS-CoV-2 variants is not yet understood.

About the study

In the present study, the investigators explored the multiplication and pathological processes of SARS-CoV-2 variants in transgenic human angiotensin-converting enzyme 2 (hACE2)-expressing (K18-hACE2) mice.

The K18-hACE2 mouse model is a well-established model for COVID-19 investigations as it promotes SARS-CoV-2 replication in the central nervous and respiratory systems, leading to high cytokine and chemokine levels and extensive tissue pathologies.

A sample virus of the original SARS-CoV-2 B.1 Wuhan sequence or the SARS-CoV-2 B.1.1.529 (Omicron), B.1.617.2 (Delta), B.1.351 (Beta), or B.1.1.7 (Alpha) VOCs were inoculated intranasally in K18-hACE2 mice aged eight weeks. A batch of mice was also infected with the mouse-adapted SARS-CoV-2 (MA10). The in vivo mouse investigations with infectious SARS-CoV-2 were conducted at an Animal Biosafety Level 3 laboratory and maintained careful adherence to established standard operating procedures. 

K18-hACE2 mice's weight, activity, appetite, neurological signs, and breathing were evaluated twice daily. In independent analyses, mice were inoculated with phosphate-buffered saline (PBS) as mock or SARS-CoV-2 via nasal routes. On three and five to seven days following infection, mice were anesthetized with isoflurane, and cold PBS was perfused. Subsequently, their brains and lungs were obtained and flash-frozen in 2-methyl butane for further investigations like plaque assays.  

The authors measured the gene expression of chemokine C-C motif ligand 2 (CCL-2) and interleukin 6 (IL-6) in the lungs of the SARS-CoV-2- and mock-infected K18-hACE2 mice on day 3 following infection. The alterations in gene expression between the mock- and SARS-CoV-2-infected animals were assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR).

Results and discussions

The study results illustrated that the mock group of PBS-injected K18-hACE2 mice were healthy over the research period. On the contrary, at the 104 plaque-forming units (PFU) infectious dose, SARS-CoV-2 B.1 led to 75% deaths, whereas the Delta, Beta, and Alpha strains resulted in 100% mortality in mice. Statistically, mouse survival for the SARS-CoV-2 Delta, Beta, and Alpha variants was significantly lower than for the B.1 virus. COVID-19 severity and disease progression were more rapid in the MA10-infected K18-hACE2 mice than in all SARS-CoV-2 clinical isolates evaluated. 

Interestingly, Omicron infection led to 50% deaths and a longer survival time in mice. A significant variation in survival was observed between the mice challenged with the same dose of Omicron and other SARS-CoV-2 VOCs assessed. 

Mice infected with the Alpha and Beta variants demonstrated signs of infection and weight loss as early as three days following SARS-CoV-2 infection. By day 6, all Beta and Alpha-infected mice died following the loss of 20% of body weight and suffering severe COVID-19 symptoms.

Delta-infected mice demonstrated significant weight loss, and all of them died within seven days of infection. Statistically, bodyweight loss for the SARS-CoV-2 B.1-infected mice was lower than for mice infected by the Delta, Beta, and Alpha strains. Notably, bodyweight loss for Omicron-infected mice was substantially milder with onset time at an advanced phase during the infection versus other SARS-CoV-2 VOCs.

On days 3 and 5 to 7 following infection, the infectious viral titers in the brain and lungs of mice infected by the Delta, Beta, and Alpha VOCs were drastically higher than those for mice infected by the SARS-CoV-2 B.1 strain. By contrast, the infectious viral titers for Omicron-infected mice were significantly decreased than for those infected by the Delta, Alpha, and Beta VOCs on days 3 and 5 to 7. Similar observations were found in the case of viral replication for the Omicron and Alpha, Delta, and Beta VOCs. 

Omicron-challenged mice exhibited lower messenger ribonucleic acid (mRNA) CCL-2 and IL-6 levels in the lungs than in the Alpha-infected animals. This data indicates that Omicron infection causes minimal lung inflammation relative to the Alpha VOC.

Conclusions

The study findings showed that the SARS-CoV-2 Beta, Alpha, and Delta viruses were substantially more fatal than the SARS-CoV-2 original B.1 sequence in K18-hACE2 mice.

Alpha, Beta, and Delta infections led to drastically higher virus concentrations in the brain and lungs of infected-mice relative to the B.1 strain. Surprisingly, mice infected with the SARS-CoV-2 Omicron VOC demonstrated a higher survival rate and less severe clinical symptoms. Additionally, Omicron replication was substantially lower in the brain and lungs of infected mice than by other SARS-CoV-2 VOCs. Moreover, transcription levels of chemokines and cytokines in the lungs of the Omicron-infected mice were dramatically low relative to the Alpha-challenged mice. 

In summary, the present work imparts deep insights into the pathogenesis of the earlier and currently circulating SARS-CoV-2 VOCs in mice. The authors state that the pathogenicity of SARS-CoV-2 was dependent on the VOC and was the greatest for the Delta, Beta, and Alpha variants and lowest for Omicron. Thus, the present study would be beneficial for learning about the pathogenesis of emerging SARS-coV-2 variants.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Shanet Susan Alex

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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