Exploring the Effects of SAR-CoV-2 Infections on the Brain

A team of researchers explored the neuro-immune pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The findings have been published in the Immunity journal.

SARS-CoV-2 affinity for the central nervous system

Previously published case reports reported the presence of SARS-CoV-2 ribonucleic acid (RNA) within the central nervous system (CNS) including the cerebrospinal fluid (CSF). However, case series’ published have not reported the viral RNA detection or elevated leukocyte counts in CSF among patients with acute SARS-CoV-2 infections. Further, overt SARS-CoV-2 particles have not been identified in the brain by electron microscopy (EM).

Receptors of cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1α,1β, and 6 are reported to be present on the blood-brain barrier (BBB). SARS-CoV-2 RNA could be present within the CNS due to contamination from blood after altered BBB permeability subsequent to the cytokine storm and widespread systemic inflammation. The resultant toxicity in the brain (due to elevated cytokine expression) could cause cognitive decay.

Elevated intrathecal expression of macrophage inflammatory protein- 1 beta (MIP-1β) and IL-6, 8, 15 expressions have been reported in cases of BBB disruption. According to the Trojan horse theory, immunological cells could also migrate from peripheral blood after opsonizing SARS-CoV-2. Furthermore, autoantibodies against neuronal and glial antigens and signs of activation of extrafollicular B cells have been detected in critically ill COVID-19 patients who experienced pronounced neurocognitive symptoms.

Histopathological investigations of deceased COVID-19 patients have demonstrated very few cytotoxic (CD8+) T cells within the CNS parenchyma. However, increased T cell counts inside the perivascular niche and near microglial nodules have been reported. Additionally, a study reported damaged neurons and astrocytes in patients with severe COVID-19. However, this study lacked control groups and similar findings have also been associated with hypoxia, septic shock, and simultaneous use of multiple medications, metabolic alterations, and invasive treatments.

Astrocyte and microglial activation (mechanism of innate immunity) did not show positive correlations with the levels of SARS-CoV-2 RNA in the brain of deceased COVID-19 patients, and such activation could also be observed among patients with dementia and sepsis.

The link between the neuroimmune axis and sickness behavior

Sickness is associated with retarded cognitive functions and decreased sensitivity to external stimuli. Sickness behavior affects motivation, drive, and moods, leading to social isolation and therefore contributing to saving of energy for battling SARS-CoV-2 infections. In accordance, while similar viral loads have been detected among persons with symptomatic and asymptomatic SARS-CoV-2 infections, asymptomatic cases demonstrated faster SARS-CoV-2 clearance.

Sickness behavior is not virus-specific and can be observed in patients with chronic inflammatory disorders and systemic autoimmune conditions, e.g., Systemic Lupus Erythematosus (SLE), inflammatory changes such as increased expression of type I interferons (IFNs). IFN responses to viruses with single-stranded RNA (like SARS-CoV-2) or double-stranded RNA ligands of the endothelial and epithelial cells of the brain have been reported to mediate depression-like sickness behavior.

Administering IFN-β has been related to lower recall of memory and lesser spatial learning. This is mediated by chemokines such as chemokine receptor 3 (CXCR3) and C-X-C motif chemokine ligand10 (CXCL10) which are produced by the endothelial and epithelial cells of the brain. In vitro studies have reported induction of cytokine receptors in the CNS after administering lipopolysaccharides (LPS) or IL-1 in rodents causing sickness behavior. This can be reversed by giving IL-10 and insulin-like growth factor I.

Lymphocytic choriomeningitis virus (LCMV) infection-induced IFN-I signaling in mice negatively impacted tissue repair mechanisms and recovery of neurological functions after cerebrovascular injuries. LCMV infections are also associated with persistently increased BBB permeability, mediated by melanoma differentiation-associated protein 5 (MDA5) and IFN-α/β receptor (IFNAR). Socially isolated mice demonstrated low IFN-γ expression in the experiments.

The link between the neuroimmune axis and critical illnesses

Symptoms of acute infections such as fatigue, pain, and neurocognitive impairments (concentration difficulties, loss of memory, and decreased motivation and drive) could last several weeks, months, or even years after the resolution of the acute phase of viral infections. This is referred to as the post-viral syndrome.

The authors suggest that long COVID is similar to other post-viral syndromes. CNS symptoms in long COVID patients could be due to the continued production of or persistent exposure to pro-inflammatory cytokines of CNS cells even after the acute inflammation clears out.

Medications (analgesics, antibiotics, sedatives), fever, immobility, comorbidities, organ dysfunctions, artificial nutrition, and social isolation affect the CNS, especially among severe COVID-19 patients. SARS-CoV-2-associated pneumonia, acute respiratory distress syndrome (ARDS), and dysregulations in the homeostasis of ion channels of brain cells induced by cytokines pose further challenges in neuronal functioning. However, disorders associated with encephalopathy and sepsis are also associated with cognitive impairments in the long term.

To conclude, the substantial inflammation within the CNS with lacking evidence for active SARS-CoV-2 replication suggests that neurological symptoms in acute or post-acute COVID-19 most probably occur due to indirect neuroimmune effects instead of direct effects of SARS-CoV-2 neurotropism.


Aschman, T., Mothes, R., Heppner, F.L., Radbruch, H., What SARS-CoV-2 does to our brains, Immunity (2022), doi:


Pooja Toshniwal Paharia

Dr. Pooja Toshniwal Paharia is a Consultant Oral and Maxillofacial Physician and Radiologist, M.DS (Oral Medicine and Radiology) from Mumbai. She strongly believes in evidence-based radiodiagnosis and therapeutic regimens for benign, potentially malignant, or malignant lesions and conditions either arising from the oral and maxillofacial structures or manifesting in the associated regions.

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