Now that the emergency phase of the COVID-19 pandemic has officially ended, we are left to face its long-term consequences. About 40% of patients who had COVID-19 in the past three years have experienced symptoms months after the infection when they are no longer contagious. This condition was initially defined as long-COVID by the patients – the first to raise attention to their long-lasting symptoms using social media – and is now known as post-COVID-19 condition (PCC).
What are the symptoms of long-COVID?
The most common symptoms of long-COVID are fatigue, shortness of breath, pain, increased heart rate, altered sense of taste and smell, headache, and a long list of neurological and psychological impairments. Patients often describe their difficulty with concentration and short-term memory using the powerful expression “brain fog”; sleep disorders, anxiety, and depression are also common complaints. These symptoms can either persist after the acute infection (with negative COVID-19 tests at this point) or develop weeks after the end of the disease, even if it was mild.
Who is most at risk of long-COVID?
Given the hundreds of thousands of individuals who have been infected by SARS-CoV-2 so far, the number of people at risk of suffering long-term consequences is very high. PCC represents both a healthcare burden and a societal problem, since it severely impacts the quality of life, reducing the ability to work and engage in social activities. Interestingly, PCC is more frequent in females, while the chances of having severe acute COVID-19 are higher in males.
Why does long-COVID happen?
The causes and mechanisms of PCC are yet to be characterised at the molecular level, leaving patients suffering from this condition without proper treatment. The study of animal models, extremely helpful in understanding acute COVID-19 and in testing vaccines and treatments, is helping to unveil some of the aspects of long-COVID. To date, no animal model fully reproduces this disease as it occurs in humans, but several studies conducted on different species have yielded interesting results.
Animals to understand how long-COVID affects the brain
Hamsters and mice have been employed to study COVID-19.
Hamsters infected with SARS-CoV-2 had a modified expression of specific genes in the brain one month after infection when the virus was no longer detectable. These animals, compared to those that were never infected, over-express genes involved in inflammation. Another study has found inflammation and accumulation of altered forms of two proteins called tau and alpha-synuclein in the brain of hamsters two weeks after infection with SARS-CoV-2. This is particularly interesting because the accumulation in the brain of these modified proteins is a feature of neurodegenerative diseases (like Parkinson’s and Alzheimer’s), suggesting similar mechanisms between these three conditions. Moreover, behavioural studies have shown that infected hamsters have reduced spontaneous activities and increased sensitivity to pain, resembling some of the neurological symptoms reported by patients, probably due to a continuous inflammation of the nervous system.
Similarly, long-term inflammation of the brain after infection with SARS-CoV-2 has been found in mice, even when the respiratory disease was mild, and the virus was not detectable in the brain. Once again, inflammation was accompanied by altered gene expression suggestive of cognitive impairment like in ageing and Alzheimer’s disease.
Does vaccination protect from Long-COVID?
Importantly, most of the studies published so far involve non-vaccinated animals infected with the original strain of SARS-CoV-2, but since the beginning of the pandemic several variants have emerged, and a growing number of people have been vaccinated worldwide, improving our ability to fight the infection.
This brings up two important questions:
- Do the differences between variants influence the risk of having long-COVID and the intensity of the symptoms?
- Since long-COVID can still occur when infected after vaccination, is it different from the disease developed by non-vaccinated individuals?
What kind of studies about long-COVID will be needed?
To really understand how to tackle the long-COVID problem, more than one animal model will be necessary, with different combinations of variants, vaccination status, and genetic backgrounds. This is not an easy task: with so many factors to consider and such a wide range of possible outcomes, complex experiments will be needed.
Our research group, together with the other members of the EU-funded EPIVINF project, is working to understand a specific aspect of PCC: the impact of SARS-CoV-2 on the regulation of the host gene expression and how it can affect neurological health in the long term.
Bibliography:
Animal models to study the neurological manifestations of the post-COVID-19 condition, Usai C et al., Lab Animal 2023, https://doi.org/10.1038/s41684-023-01231-z
Website of the EPIVINF project: https://www.epivinf.eu/
Virus&Co. 