Preclinical study finds sex differences in neurological response to SARS-CoV-2 infection

Neurological problems during and after coronavirus disease 2019 (COVID-19) are persistent and frequent. However, research is still ongoing as to why certain people exhibit specific symptoms. Research led by Yi-Ping Hsueh from the Institute of Molecular Biology in Taiwan suggests SARS-CoV-2 infection in the brain could be sex-dependent.

In a preclinical model, the researchers found female mice were less susceptible to SARS-CoV-2-induced weight loss and more likely to survive than males at low doses.

Study: Sex-biased response to and brain cell infection by SARS-CoV-2 in a highly susceptible human ACE2 transgenic model. Image Credit: Alexander Limbach / Shutterstock

Based on the results, the researchers suggest their transgenic mice model could help with further study sex differences in COVID-19 infection, which could help develop future treatments.

The study authors write:

Our transgenic mice provide an appropriate model for investigating the impact of SARS-CoV-2 infection on various organs and tissues, as well as the neuropsychiatric symptoms observed in COVID-19 patients.”

The study “Sex-biased response to and brain cell infection by SARS-CoV-2 in a highly susceptible human ACE2 transgenic model” is available as a preprint on the bioRxiv* server, while the article undergoes peer review.

Transgenic mouse model is highly receptive to viral infection

The research team created a human ACE2 transgenic mouse line using the (HS4)2-pCAG-hACE2-HA-(HS4)2 transgene cassette, which expresses HA-tagged human ACE2 controlled by the ubiquitous CAG promotor and flanking two copies of the HS4 insulators to limit transgene silencing. The end result was an elevated expression in specific body areas, including the lungs, brain, and kidneys. At lower levels, ACE2 expression was also present in the duodenum, heart, and liver.

The transgenic line was proven to be highly susceptible to SARS-CoV-2 infection.

A low intranasal dose of the virus prompted weight loss from all transgenic mice after the third or fourth day. Mice started to die by day 5 with an overall 96% mortality rate. Only one female mouse survived after the ninth day and fully recovered from infection. The female mouse also had increased body weight and appeared healthy two weeks after infection.

This difference is unlikely due to differential expression levels of hACE2 proteins in male and female mice because immunoblotting revealed comparable hACE2 protein levels among male and female mice for various organs.”

Male mice died quicker than female mice, with survival rates of 56% at day 5, 44% at day 6, and 12% at day 7. All male mice died. Conversely, only one female mouse died by day 6, and 83% of mice died on day 7.

There was less weight loss in female mice at lower viral titers than male mice, indicating a sex difference to the SARs-CoV-2 virus.

Sex differences observed in changes in neuronal activity

The researchers used cell cultures to look at how SARS-CoV-2 affects brain cells. Using dual immunostaining techniques, they confirmed human ACE2 expression in both neurons and astrocytes. Astrocytes had higher expression levels of human ACE2 proteins.

When the cells were given a pseudovirus SARS-CoV-2 infection, electrophysiology results showed increases in amplitude, suggesting the spike protein affected neuronal synaptic responses.

These results indicate that expression of SARS-CoV-2 Spike protein influences the synaptic activity of neurons, which is likely relevant to the neurological symptoms displayed by COVID-19 patients,” concluded the research team.

*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.

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.