Infection from SARs-CoV-2 often results in numerous neurological impacts, resulting in staple symptomology for COVID-19 like loss of smell (anosmia) and migraines. To uncover more about this virus’ mechanisms within the central nervous system, researchers have investigated how COVID-19 impacts brain cells.
The Brazilian team has been investigating COVID-19’s role in the brain since 2020, when they released groundbreaking findings revealing that the virus causing COVID-19 infects brain cells, particularly astrocytes. “Two previous studies detected the presence of the novel coronavirus in the brain, but no one knew for sure if it was in the bloodstream, endothelial cells [lining the blood vessels] or nerve cells. We showed for the first time that it does indeed infect and replicate in astrocytes, and that this can reduce neuron viability,” says senior author Daniel Martins-de-Souza, researcher and professor at UNICAMP’s Biology Institute.
Astrocytes play an essential role within the brain by providing biochemical support and nutrients for neurons. Additionally, they help regulate neurotransmitter levels and maintain the blood-brain barrier, a crucial support system to protect the brain from pathogens and foreign bodies. Brain tissue from 26 patients who died of COVID-19 revealed astrocyte infection, and COVID-19’s diverse symptomology suggests far-reaching neurological impacts.
The researchers utilized immunohistochemistry, a staining process where antibodies act as markers of viral antigens or other tissue components to be analyzed. “For example, we can insert one antibody into the sample to turn the astrocytes red on binding to them, another to mark the SARS-CoV-2 spike protein by making it green, and a third to highlight the virus’s double-stranded RNA, which only appears during replication, by turning it magenta,” says Martins-de-Souza. “When the images produced during the experiment were overlaid, all three colors appeared simultaneously only in astrocytes.”
Their findings not only revealed that the virus was present in five of the 26 analyzed samples but that possibly even more damage was occurring to the central nervous system. “We observed signs of necrosis and inflammation, such as edema [swelling caused by a buildup of fluid], neuronal lesions and inflammatory cell infiltrates,” says Thiago Cunha, professor in FMRP-USP and member of the Center for Research on Inflammatory Diseases.
Adriano Sebolella and his team at FMRP-USP used the method of brain-derived slice cultures, where human brain tissue is obtained during surgery, cultured in vitro, and infected with the virus. This technique allowed the researchers to confirm that SARS-CoV-2 can infect brain tissue, specifically with a preference for astrocytes.
In another part of their research, 81 volunteers who recovered from mild COVID-19 underwent MRI scans, on average, 60 days post-diagnostic testing. One-third of the participants still had neurological or neuropsychiatric symptoms at the time, with the primary symptom being headache (40%) and fatigue (40%), followed by memory alterations (30%), anxiety (28%), loss of smell (28%), and daytime drowsiness (25%). The MRI scans also revealed that some volunteers had decreased cortical thickness in some brain regions compared to the controls’ average.
“We posted a link for people interested in participating in the trial to register, and were surprised to get more than 200 volunteers in only a few days. Many were polysymptomatic, with widely varying complaints. In addition to the neuroimaging exam, they’re being evaluated neurologically and taking standardized tests to measure performance in cognitive functions such as memory, attention and mental flexibility. In the article we present the initial results,” says Clarissa Yasuda, professor and member of the Brazilian Research Institute for Neuroscience and Neurotechnology.
Another discovery revealed by the PNAS article suggests that the SARs-CoV-2 virus doesn’t use the ACE-2 protein to invade the CNS as it does in the lungs. “Astrocytes don’t have the protein in their membranes. Research by Flávio Veras and his group shows that SARS-CoV-2 binds to the protein neuropilin in this case, illustrating its versatility in infecting different tissues,” explains Martins-de-Souza.
Taken together, these findings all reveal a great deal about COVID-19’s mechanisms within the brain. Marcelo Mori, professor IB-UNICAMP and a member of the Obesity and Comorbidities Research Center, the study was only possible thanks to the collaboration of researchers with varied and complementary backgrounds and expertise. “It demonstrates that first-class competitive science is always interdisciplinary,” he says. “It’s hard to compete internationally if you stay inside your own lab, confining yourself to the techniques with which you’re familiar and the equipment to which you have access.”