Neurological Effects of COVID-19 Linked to 3 Cytokines
Targeting IL2, IL12, and IL13 in the brain may be key to treating "COVID brain."
Posted October 15, 2022 | Reviewed by Vanessa Lancaster
- COVID-19 prompts a storm of inflammatory cytokines that penetrate the blood-brain barrier (BBB) and directly affect the brain.
- Neurological symptoms from COVID-19 appear to be due to peripheral IL6 crossing the BBB and inducing brain cells to produce IL12 and IL13.
- The inability to cross the BBB hampers promising drug candidates from treating neurological symptoms of COVID-19.
COVID-19 patients can develop a number of neurological symptoms during the acute phase of the disease. These include loss of smell, cognitive problems, headaches, dizziness, and even delirium, which is characterized by severe cognitive disturbances such as altered consciousness, altered attention, and confusion.
In fact, 20–30 percent of COVID-19 patients develop mental status changes or delirium, and the rate jumps to 60–70 percent in patients with severe cases of COVID-19.
Medical professionals suspected that a hyper-activated immune system underlies the development of neurological symptoms in COVID-19 patients. A “cytokine storm” is sparked, in which myriad inflammatory cytokines and chemokines are produced in the periphery. These peripheral inflammatory cytokines are then thought to penetrate the blood-brain barrier and directly affect the brain. But precisely which cytokines may be mediating these effects has been unknown.
IL2, IL12, and IL13 Linked to COVID-19 Neurological Symptoms
In a research paper published on October 5, investigators from King's College London reported evidence implicating three particular cytokines in the development of neurological symptoms from COVID-19: interleukin-2 (IL2), interleukin-12 (IL12), and interleukin-13 (IL13).
Researchers collected serum samples from COVID-19 patients with and without symptoms of delirium. They then used a well-established in vitro model involving immortalized human brain cells to examine the effect of direct exposure to the serum samples on brain cell activity.
Their results showed that serum taken from COVID-19 patients with delirium increased cell death and decreased the generation of new brain cells. "We have found that there is a profound reduction in the generation of new brain cells and an increase in cell death, and these are likely mechanisms behind delirium, and possibly other neurological symptoms, in COVID-19 patients," said Alessandra Borsini, first author and NIHR Maudsley BRC Senior Research Fellow at the Institute of Psychiatry, Psychology & Neuroscience, King's College London.
When researchers analyzed serum samples, they found that samples from COVID-19 patients with delirium had a six-fold higher level of IL6. Furthermore, treating the brain cells with the delirium serum samples caused the brain cells to produce IL12 and IL13. These two cytokines may form a cascade generated by brain cells in response to inflammation in the body created by IL6.
Professor Carmine Pariante, co-author and Professor of Biological Psychiatry at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), said
We have shown that it is likely that the initial production of cytokine proteins as part of the inflammatory response in COVID-19 infection triggers a cascade of other cytokines which reduce generation of new brain cells and increase cell death, leading to brain symptoms such as delirium.
These neurological symptoms are very concerning for patients and their families, and the hope is that our research can help identify which treatments would be most appropriate to lessen or prevent these symptoms.
Treatments Limited by the Availability of Agents Able to Cross the Blood Brain Barrier
These findings have immediate application in developing pharmacological approaches to treat neurological symptoms brought on by COVID-19. And drugs already exist that target IL6, IL12, and IL13:
- IL6: IL6 inhibitors such as tocilizumab and sarilumab have been used to treat COVID-19 patients and have reduced mortality rates.
- IL12: IL12 inhibitors such as ustekinumab and briakinumab have been used to treat inflammatory bowel disease.
- IL13: The IL13 selective inhibitor lebrikizumab has been tested in a phase 2b trial for metastatic cancer.
Unfortunately, the inhibitors described above are not good candidates to treat neurological disorders involving the central nervous system. That is because they all have high molecular weights and do not cross the blood-brain barrier. A significant amount of work would be required to develop a drug delivery strategy that can overcome the blood-brain barrier obstacle.
Janus kinase (JAK) inhibitors, such as baricitinib, ruxolitinib, and tofacitinib, are promising candidate therapeutics. JAK inhibitors have already been very effective treatments for COVID-19. However, since JAK inhibitors have low molecular weights and have also been shown to prevent the deleterious effects of IL12 and IL13 on brain cells, their wider use in the context of neurological impairment from COVID-19 should be explored.
Borsini, A., Merrick, B., Edgeworth, J. et al. (2022). Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurological symptoms. Mol. Psychiatry: https://doi.org/10.1038/s41380-022-01741-1.