This is the current component of a series on cognitive disorders and inflammation. For more information on inflammation and Covid-19, visit my website: www. williamhaseltine. com
Although inflammation is not an unusual feature of many infections, viral and otherwise, SARS-CoV-2 elicits a particularly intense inflammatory response. The exact explanation remains uncertain. However, what is becoming increasingly clear is that much of the damage related to Covid-19 can be attributed to this hyperinflammation. This is true both in the short term, during an acute infection, and in the long term, during a long Covid. infection or post-acute sequelae of SARS CoV-2 infection (PASC). Cognitive impairments such as “brain fog”, difficulty concentrating, and poor short-term memory are some of the most worrying symptoms of Long Covid. Often, those are severe enough to interfere with daily tasks, with a significant effect on quality of life.
In a collaborative study, researchers from Yale University and Stanford University discovered a credible cause: inflammation. A higher state of Covid-19 inflammation can cause excessive activation of microglial cells, the main immune cells of the central nerve formula, resulting in the dysregulation of cells necessary for healthy cognitive function, adding oligodendrocytes and neurons. Surprisingly, Fernández-Castañeda et al. found that even mild cases of COVID-19 caused enough inflammation to produce cognitive and brain health problems.
Here I give a review of the first component of their findings, microglial reactivity, and in a follow-up article, I talk about how this affects brain health.
Microglial cells are a type of macrophage found in the brain and spinal cord, where they make up 10 to 15% of all cells. As macrophages, their function is to actively consume and destroy all invading microbes. In addition, they produce a variety of signaling proteins, called cytokines and chemokines, to help stimulate the inflammatory reaction and direct other immune cells to places that need protection. Although they exist to protect us, the reactivity of microglial cells has also been linked to cognitive problems; Inflammation is to help us eliminate infections, but in excess it can have devastating consequences, especially in an environment as delicate as the brain.
Cognitive impairment similar to the cancer remedy is one example, with microglial reactivity in the hippocampus leading to neuronal dysfunction. The overlap of symptoms with Long Covid, adding the presence of a continuous “chemotherapy fog,” has made Fernández-Castañeda and her colleagues suspect that a similar mechanism may be at play.
To verify this theory, the experts turned to mouse models. They exposed an organization of mice using human angiotensin-converting enzyme 2 (ACE2), the main gateway to SARS-CoV-2, to a mild SARS-CoV-2 infection that lasted nothing. more than a week. The mice showed no observable symptoms or weight loss.
Importantly, the mice were designed to bring only ACE2 receptors into their airways, strictly restricting infection to the nose, throat, and lungs. This meant that the virus did not have a direct formula in the central nervous system of the mice, meaning that any cognitive disorder had to be the result of domino effects instead.
Despite the mild, necessarily asymptomatic infection, all mice had elevated levels of pro-inflammatory cytokines and chemokines, both in the blood and in the cerebrospinal fluid. These included: IFN-γ, IL6, TNF-α, CXCL10, CCL7, CCL2, CCL11, GMCSF and BAFF. Some cytokines remained elevated for up to seven weeks after the initial respiratory infection.
As discussed in a previous article, IL-6 has been implicated in cognitive impairment after cranial radiation therapy. The chemokine CCL11, in turn, has been implicated in the cognitive decline that accompanies aging. It should be noted that the levels of CCL11 in the blood had normalized seven weeks after the initial infection, in the cerebrospinal fluid were higher seven weeks after infection than seven days after infection.
Next, the scientists tried to test whether prolonged buildup of cytokine levels in the cerebrospinal fluid correlated with noticeable changes in the brain.
Compared to control mice, which also carried human ACE2 in the respiratory tract but were inflamed with a fake virus, those that had been exposed to SARS-CoV-2 had greater microglial reactivity in subcortical white matter. White matter is the deepest tissues of the brain and serves to unite, and enable communication between, other parts of the central nervous system formula, especially the spinal cord and the gray matter regions that form the surface of the brain. Think of it as a kind of superwalk. White matter is very important for healthy cognitive function, and adjustments in white matter can have an effect on the power and speed with which “messages” can be sent around the central nervous system formula: a bumpy path can only accommodate a limited volume. of traffic
Although the total amount of microglia remained the same in the Covid-19 mice and in the mice, the amount of activated microglia was particularly higher in the sick group. As with cytokine levels, reactive microglial cells persisted for up to seven weeks after infection.
Fernández-Castañeda and her colleagues also had the rare opportunity to examine the reactivity of microglial cells in human samples. The researchers analyzed the subcortical white matter of nine other people who tested positive for SARS-CoV-2 at the time of their death, as shown through nasal PCR tests. Although those aren’t necessarily mild cases, as the other nine people died of infection-like headaches, none of them died in hospitalization and only two had to be admitted to intensive care. moderate symptoms of damage. However, reflecting what was observed in the mouse models, all nine patients had higher degrees of microglial activation compared to a control cohort (Figure 1).
To gain a more accurate understanding of the state of microglial cells after Covid-19, the scientists performed single cell RNA sequencing. This is an incredibly fine strategy that allows you to see the full diversity of genes expressed in a single cell. When analyzing knowledge from about 6000 individual microglial cells, Fernández-Castañeda et al. noted an upregulation of genes related to inflammation, adding cytokine production and cytotoxicity. they use synapses and maintain important synapses. Essentially, the genes that help maintain balance and cognitive health.
After an outbreak with Covid-19, the genetic profile of reactive microglial cells ends up closely resembling that of microglial cells related to Alzheimer’s disease, as well as those similar to aging, which go hand in hand with cognitive decline.
Therefore, a mild Covid-19 can cause an inflammatory reaction that enters the brain and activates microglial cells. These cells then stimulate more pro-inflammatory molecules and a general cytotoxicity that can persist up to seven weeks after infection.
The next article in this series focuses on the consequences of such sustained microglial reactivity in the white matter regions of the brain.