Omicron BA.5 variant demonstrates increased neuroinvasiveness and pathogenicity in mice

In a recent study under review at Nature Portfolio and currently posted to the Research Square* preprint server, researchers assessed the extent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern (VOC) BA.5 sub-VOC infection-associated brain infection and death, compared to that by Omicron BA.1 sub-VOC.

This comparative analysis used a K18-human angiotensin-converting enzyme 2 (hACE2) murine model.

Study: Increased neurovirulence of omicron BA.5 over BA.1 in human brain organoids and K18-hACE2 mice. Image Credit: Gorodenkoff/Shutterstock,com

Study: Increased neurovirulence of omicron BA.5 over BA.1 in human brain organoids and K18-hACE2 mice. Image Credit: Gorodenkoff/Shutterstock.com

*Important notice: Research Square publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

The continual evolution of Omicron has given rise to increasingly transmissible, virulent, and immune-evasive Omicron sub-VOCs, threatening the efficacy of coronavirus disease 2019 (COVID-19) vaccines and therapeutics such as monoclonal antibodies and antiviral drugs.

Moreover, COVID-19 symptoms may persist or develop in the post-acute phase of COVID-19, referred to as long COVID, presenting with a wide spectrum of clinical manifestations, including neurological.  

Data on Omicron BA.5 pathogenicity and virulence, compared to previously emerged VOCs and infection-associated brain damage, are limited, investigating which could aid in developing next-generation, universal, updated, and effective vaccines with a wide neutralization breadth.

About the study

In the present study, researchers evaluated the neurovirulence and neuroinvasiveness of BA.5 compared to previous SARS-CoV-2 VOCs and sub-VOCs.

K18-hACE2 murine animals were infected with an ancestral isolate (SARS-CoV-2QLD02), BA.1 isolate (SARS-CoV-2QIMR01), and BA.5 isolate (SARS-CoV-2QIMR03), following which, their body weight was monitored and immunohistochemistry (IHC) analysis was performed.

To verify BA.5 infection in neurons, the cortex of infected K18-hACE2 murine animals was co-stained with an anti-S protein monoclonal antibody and neural nuclear antigen marker, anti-NeuN.

Ribonucleic acid sequencing (RNAseq) analysis was performed, and the RNAseq dataset was used for assessing the abundance of different types of cells.

Differential gene expression (DEG) analysis and gene set enrichment analyses (GSEAs) were performed, and DEGs were analyzed by ingenuity pathway analysis (IPA).

Human-induced pluripotent cells (hiPSCs), obtained from adult human dermal fibroblast cells (HDFa), were utilized for generating spherical and 2.0 mm to 3.0 mm diameter-sized ‘mini-brains.’

Brain organoids were infected with the SARS-CoV-2 isolates for in vitro assessment of BA.5 neurovirulence.

Omicron sub-VOCs were isolated from nasopharyngeal swab samples of SARS-CoV-2-positive individuals. Vero E6 cells were used for the cell culture experiments, and polymerase chain reaction (PCR) was performed for genotyping.

Results

SARS-CoV-2QIMR03 showed significantly greater pathogenicity in the K18-hACE2 murine animals than SARS-CoV-2QIMR01, indicating greater neuroinvasiveness of BA.5 than Omicron BA.1. In turn,  leading to infection in the brain and associated death, in an extent comparable to that by SARS-CoV-2QLD02.

Additionally, BA.5 sub-VOC-infected organoids of the human brain cortex to a greater extent than Omicron BA.1 and the ancestral strains.

Neurons were the prime targets in the murine brain for SARS-CoV-2 infection, and in the human cortical organoids, immature neurons and neuronal progenitor cells were primarily infected. SARS-CoV-2QLD02 infection resulted in >20.0% weight loss by 4.0 to 5.0 days post-infection (dpi).

SARS-CoV-2QIMR01 showed much lower virulence, with 20.0% of the mice losing >20% of weight, needing to be euthanized by 9.0 or 10.0 dpi. SARS-CoV-2QIMR03 infection led to severe weight loss, needing all mice to be euthanized by 4.0 to 6.0 dpi.

In addition, BA.5-positive murine animals exhibited more overt COVID-19 symptoms than Omicron BA.1-positive mice. Omicron BA.5-associated mortality was delayed significantly compared to that associated with the ancestral SARS-CoV-2 isolate; however, the average delay period was 0.9 days.

At 4.0 dpi, SARS-CoV-2 titers were significantly greater for Omicron BA.5 than for Omicron BA.1. A day later, the ancestral SARS-CoV-2 isolate had 2.0 logs greater pulmonary titers and 4.0 logs greater nasal titers than Omicron BA.5.

The quantity of SARS-CoV-2 RNA was 25-fold greater for BA.5-infected organoids than their ancestral SARS-CoV-2 isolate-infected counterparts.

BA.5-infected organoids, versus uninfected organoids, identified 2,390 DEGs, and 575 were upregulated. For the ancestral isolate, 252 DEGs were identified, of which 132 were upregulated.

In addition, SARS-CoV-2 titers in the brain were 4.0 logs greater for the ancestral isolate than for the Omicron BA.5 sub-VOC. In the K18-hACE2 murine brains infected with BA.5, the team observed extensive infection in the cortical, hippocampal, and hypothalamic cells, and the SARS-CoV-2 antigen was evident clearly in the axons and dendrites (probably neural).

BA.5-infected K18-hACE2 murine brains showed several lesions previously documented among SARS-CoV-2-positive individuals and primate models, including neuronal vacuolation or hydropic degeneration.

SARS-CoV-2 presence in the cortical cells was related to cellular apoptosis, vacuolation, and a lack of immunological cell infiltrates.

Lesions were observed among BA.5-infected K18-hACE2 murine brains, previously documented in post-mortem reports of SARS-CoV-02-positive patients, include perivascular edema, microglial nodules, and small hemorrhagic lesions.

The findings indicated a cytokine storm and the topmost upstream regulators (USRs), including interferons (IFN) of type I (IFN-α2, -β1, -λ1), tumor necrosis factor (TNF), interleukins (IL)-1,6, and type II.

Lung and brain infection USRs were highly concordant for the SARS-CoV-2 isolates. DEG analysis yielded similar results.

The olfactory neuroepithelial genes were significantly and negatively enriched, indicating olfactory cell loss in the brain of BA.5-infected mice.

The inflammatory responses in BA.5-infected K18- hACE2 murine brains were mainly innate, at 4.0 to 6.0 dpi, and denoted acute COVID-19. DEG findings for Omicron BA.5 showed the ’coronavirus pathogenesis pathway’ as a top canonical pathway.

Conclusion

Overall, the study findings showed that Omicron BA.5 is more likely to cause neuronal infections among  K18-hACE2 murine brain tissues and cortical organoids of the human brain than Omicron BA.1, indicative of the greater neuro-invasiveness and neurovirulence of BA.5, compared to BA.1.

*Important notice: Research Square 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:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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