Researchers have shown that even mild SARS-CoV-2 infection can cause lingering neurological symptoms. These findings might shed light on the infamous “long COVID” [1].
Mild doesn’t mean harmless
COVID survivors sometimes experience cognitive symptoms, such as “brain fog”, that can linger for months. Those symptoms can be debilitating, affecting work performance and learning, and they are not limited to severe cases of COVID. This was especially relevant in the early days of the pandemic before vaccines and anti-COVID medicines were introduced and before less destructive (though more contagious) variants took over.
The cognitive symptoms of COVID resemble those of cancer-therapy-related cognitive impairment (CRCI), also known as “chemo fog” [2]. Scientists know that chemo fog’s foremost culprit is neuroinflammation, which is caused by the overactivation of microglia, the resident macrophages of the brain. Reactive microglia produce pro-inflammatory cytokines that impair generation of neurons and oligodendrocytes, the cells that produce the myelin sheaths that neurons need for insulation.
Could the same be happening during COVID, including in mild cases? In this study, published in the journal Cell, the researchers used a mouse model of mild SARS-CoV-2 and examined brain tissue. Infection in such mice is limited to the respiratory system and largely subsides in one week. To imitate COVID, human ACE-2 receptors, which are targeted by SARS-CoV-2, were introduced via adenoviral vectors.
Although the model produced mild, mostly asymptomatic COVID that did not directly affect the nervous system, the researchers found that pro-inflammatory cytokines and chemokines, such as IFN-γ, IL6, TNF-α, and CCL-11, were substantially elevated compared to healthy controls both in blood serum and in cerebrospinal fluid (CSF) seven days after infection. Most notably, CSF levels of CCL-11, a chemokine associated with age-related cognitive impairment [3], continued to increase. After seven weeks, CCL-11 was much higher than it was seven days after infection.
Just as the researchers suspected, microglia reactivity in subcortical white matter, but not in cortical grey matter, was also elevated seven days after infection and persisted at least until the end of the follow-up period.
Confirmed in human brains
The researchers were able to analyze several white matter samples from humans who died from various causes while having COVID. Lack of indication that those people had severe COVID symptoms (for instance, they were not admitted to ICU) suggested that their COVID was probably mild at the time of death. In most cases, this was also confirmed by lung examination. The researchers found that just like in the mouse model, microglial reactivity in the samples was considerably elevated compared to healthy controls.
In line with previous research showing that microglial overactivation can inhibit neurogenesis [4], the researchers detected a stark decrease in the production of new neurons in the hippocampus, which was inversely correlated with the actual load of reactive microglia.
The peculiar case of CCL-11
The unusual behavior of CCL-11 demanded further investigation in humans. The researchers examined circulating CCL-11 levels in 48 human subjects suffering from long COVID, some with and some without cognitive symptoms. CCL-11 levels were considerably elevated in patients with “brain fog” compared to patients who had not reported cognitive symptoms.
Two variables seemed to affect the severity of cognitive symptoms: sex and history of autoimmune disease. People with autoimmune disease had higher levels of CCL-11, and men had higher levels than women even though female COVID survivors report lingering cognitive symptoms more frequently. Other factors, such as body mass index (BMI) and the duration of long COVID, could not account for the variability in CCL-11 levels.
To further elucidate the role of CCL-11, the researchers injected four doses of it over ten days it into healthy mice. The treatment resulted in increased microglial reactivity specifically in hippocampal white matter, and hippocampal neurogenesis was decreased.
While the spotlight here on COVID, other respiratory viral infections such as the flu can also cause cognitive and other neurological symptoms [5]. The researchers looked at a mouse model of H1N1, better known as the swine flu. The behavior of pro-inflammatory cytokines and chemokines bore striking resemblance to their behavior in COVID. Just like in COVID, of all chemokines, only CCL-11 levels remained high beyond the seven-day mark.
Microglial reactivity shot up following the infection, but it was normalized in subcortical white matter, though not in the hippocampus during the follow-up period. This differentiates H1N1 from COVID, which affected those two brain regions equally.
Conclusion
This study shows that even mild infection with SARS-CoV-2 can lead to a long-term increase in neuroinflammation, which correlates with the experience of “brain fog” in long COVID. While it is possible that neuroinflammation levels go back to normal in the long run, its consequences might linger. COVID probably still holds some unpleasant surprises and should be avoided at all reasonable costs.
Literature
[1] Fernández-Castañeda, A., Lu, P., Geraghty, A. C., Song, E., Lee, M. H., Wood, J., … & Monje, M. (2022). Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell.
[2] Janelsins, M. C., Kesler, S. R., Ahles, T. A., & Morrow, G. R. (2014). Prevalence, mechanisms, and management of cancer-related cognitive impairment. International review of psychiatry, 26(1), 102-113.
[3] Butcher, L., Peres, K., André, P., Morris, R. H., Walter, S., Dartigues, J. F., … & Erusalimsky, J. D. (2018). Association between plasma CCL11 (eotaxin-1) and cognitive status in older adults: Differences between rural and urban dwellers. Experimental Gerontology, 113, 173-179.
[4] Monje, M. L., Toda, H., & Palmer, T. D. (2003). Inflammatory blockade restores adult hippocampal neurogenesis. Science, 302(5651), 1760-1765.
[5] Jurgens, H. A., Amancherla, K., & Johnson, R. W. (2012). Influenza infection induces neuroinflammation, alters hippocampal neuron morphology, and impairs cognition in adult mice. Journal of Neuroscience, 32(12), 3958-3968.
