Mild Respiratory COVID-19 Can Cause Neural Cell and Myelin Dysregulation

Using a mouse model, researchers tested the potential effects of mild respiratory COVID-19 on the brains of survivors.

Similar neuropathophysiology has been observed following cancer therapy and respiratory SARS-CoV-2 infection, which may contribute to the cognitive impairment reported among patients following even mild cases of COVID-19, according to study findings published in the journal Cell.

Recognizing that the syndrome of cognitive symptoms often experienced by survivors of COVID-19 resembles the syndrome of cancer therapy–related cognitive impairment —commonly referred to as “chemo-fog” — the researchers sought to explore the possibility of shared pathophysiologic mechanisms between the 2 scenarios. In fact, in the neurologic syndrome frequently observed among patients receiving treatment for cancer, white-matter microglial reactivity and consequent neural dysregulation are key.

In the current study, researchers sought to test the effects of mild COVID-19 by using a mouse model of mild SARS-CoV-2 infection limited to the respiratory system and that clears within 1 week. SARS-CoV-2 infection requires expression of its viral entry receptor — human angiotensin-converting enzyme 2 (ACE2) — which was thus delivered via adeno-associated virus (AAV) receptor to the trachea and the lungs of the mouse. At 2 weeks after intratracheal ACE2-AAV delivery, SARS-CoV2 was delivered intranasally. Control mice received intratracheal AAV-expressing human ACE2, but only mock infection intranasally.

As anticipated, SARS-CoV-2 was present in the lungs of the infected mice, with histopathology of the lung revealing minimal interstitial infiltrates with no evidence of alveolar damage. In this respiratory infection model, however, although a lack of evident signs/symptoms of illness existed, prominently elevated cytokine profiles were detected in serum and cerebrospinal fluid (CSF) at both 7-day and 7-week timepoints following respiratory infection. At 7 days’ postinfection, elevated CSF cytokines and chemokines included interferon (IFN)-γ, interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-X-C motif chemokine ligand 1 (CXCL10), C-C motif chemokine ligand 2 (CCL2), CCL7, CCL11, granulocyte macrophage colony-stimulating factor (GM-CSF), and B cell activating factor (BAFF). Of these chemokines, CXCL10, CCL2, CCL7, CCL11, and GM-CSF remained elevated, whereas IL-10 and CCL5 became elevated in CSF at 7 weeks postinfection.

Of note, CSF levels of CCL11 — a chemokine that is linked to cognitive impairment in aging — were further increased at 7 weeks’ postinfection compared with 7 days’ postinfection. In the same mice, however, serum CCL11 levels were elevated at 7 days’ postinfection and normalized by 7 weeks’ postinfection. Along with elevated CSF cytokines/chemokines, including CCL11, decreased oligodendrocytes and myelin loss were evident as well, thus demonstrating that isolated respiratory infection with

SARS-CoV-2 can be associated with profound, prolonged changes in cytokines within the central nervous system.

The researchers continued with their analysis by examining microglial/macrophage reactivity in a mild COVID-19 mouse model compared with control mice. As theorized, they found increased microglial/macrophage reactivity in subcortical white matter, as evaluated by ionized calcium-binding adapter molecule 1 (IBA1) and cluster of differentiation 68 (CD68) co-positivity.

Compared with SARS-CoV-2 infection, mild respiratory influenza induced in mice caused similar patterns of white-matter selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 levels at early timepoints; however, after influenza, only elevated CCL11 and hippocampal pathology persisted.

Study limitations included the fact that the incidence and severity of cognitive impairment following COVID-19 caused by newer variants such as Omicron, or as a result of breakthrough infection in vaccinated individuals, remain to be fully elucidated. As noted by the researchers, “Emerging data indicate that the risk of cognitive impairment may be decreased in breakthrough infections of fully vaccinated individuals.” Additionally, the neurobiological effects of respiratory COVID-19 in children and in elderly individuals warrant dedicated study.

The researchers concluded that “Future work, incorporating cognitive testing in mice following respiratory COVID-19, will be needed to test possible therapeutic interventions aimed at restoring neural homeostasis and plasticity and mitigating the neurobiological sequelae of COVID-19.”

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Fernández-Castañeda A, Lu P, Geraghty AC, et al. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell.  Published online June 13, 2022. doi:10.1016.j.cell.2022.06.008