COVID-19's neurological effects linked to immune response, not direct viral attack

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A recent Nature Neuroscience study assesses the impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, on the manifestations of neurological symptoms. This evaluation has been based on transcriptomic and proteomic profiling of the brainstem tissue of affected patients.

Study: Proteomic and transcriptomic profiling of brainstem, cerebellum and olfactory tissues in early- and late-phase COVID-19. Image Credit: Rattiya Thongdumhyu / Shutterstock.com

Background

Neurological symptoms like brain fog and fatigue that result from COVID-19 can arise at different stages of the disease and persist, even after recovery from the acute infection. Theoretically, neurological symptoms can develop due to neurocognitive disturbances or central nervous system (CNS) responses to inflammation.

Molecular and histopathological studies have indicated that SARS-CoV-2 infection leads to activation of the immune system and disturbance of the CNS-specific cells. Likewise, during severe COVID-19, a higher concentration of macrophages and T-cells, as well as microglial activation, have been observed in autopsy studies.

Single-cell ribonucleic acid (RNA) sequencing, flow cytometry, and transcriptional profiling of human lung tissues and blood cells of COVID-19 patients with severe infection have also indicated the presence of dysregulated natural killer and myeloid cells, as well as higher numbers of dedifferentiated monocytes, in blood samples. Furthermore, blood and cerebrospinal fluid (CSF) samples exhibited a higher concentration of the antiviral interferon (IFN) type I signature.

Although these studies provide important insights into the pathophysiology responsible for the neurological sequelae of COVID-19, additional studies are needed.

About the study

The current study performed proteomic and single-cell profiles of the medulla oblongata, olfactory bulb, olfactory mucosa, and cerebellum of the infection site during acute and advanced stages of COVID-19. Spatial transcriptomics was also performed during and after acute SARS-CoV-2 infection to assess the cell type topography of the IFN response in the brainstem.

For the control group, tissues from patients admitted to the intensive care unit (ICU) with comparable multiorgan failure and bacterial superinfections were assessed.

Study findings

During acute SARS-CoV-2 infection, a high level of local CNS reactions occurred in response to systemic infection that persisted to a lesser degree, even after infection recovery. The proteomic profile of different COVID-19 stages indicated an upregulation of type I IFN-related signaling.

Interestingly, single nuclear RNA-seq (snRNA-seq) detected the presence of systemic inflammation within the brainstem endothelial cells, reactive microglia, and glutamatergic neurons, even in the absence of active SARS-CoV-2 replication. This observation was further supported by the lack of viral and IFN transcripts in the analytical samples. 

Changes in glutamatergic neurons were observed within the ambiguous nucleus and dorsal nucleus of the vagal nerve. Alterations in oligodendrocytes, astrocytes, and microglia transcriptional states were also observed during acute COVID-19.

Importantly, many inflammatory changes that occurred in the CNS during COVID-19 were not SARS-CoV-2 specific. For example, similar alterations in CNS have also been observed during cancer therapy-related cognitive impairment.

In contrast to previous studies, the immunohistochemistry and snRNA-seq findings indicated that viral particles were not persistent or replicating after recovery from infection. However, the presence of viral RNA was detected in some brainstem samples.

The proteomic profile of CNS was impacted by disease duration rather than viral load. Thus, significant peripheral inflammatory changes likely occur during the acute phase of COVID-19.

The study findings highlight that systemic SARS-CoV-2 infection resulted in considerable upregulation of IFN-stimulated genes and proteins. Significant downregulation of genes linked to synaptic organization and myelination was also observed.

SARS-CoV-2 infection also resulted in a significant reduction in OPALIN+ oligodendrocytes, which has also been observed in patients with multiple sclerosis. The oligodendroglial alterations could be due to multifactorial transcriptional reprogramming, which was associated with acute systemic inflammatory responses of severe SARS-CoV-2 infection.

Changes in synaptic processes at the transcriptome and protein levels were also observed without any signs of neuronal infection. Histological studies documented neurovascular damage that was not observed in brainstem samples.

Conclusions

The manifestations of neurocognitive symptoms in the acute and late stages of COVID-19 were found to be associated with a local CNS reaction to systemic infection rather than due to SARS-CoV-2 infection of the brain. The impacts of neuroimmunology, pathomechanisms, and genetic interferonopathies on the CNS due to SARS-CoV-2 infection were also reported. 

In the future, additional research is needed to better understand the association between viral-induced systemic inflammation and its impact on synapse organization, myelination, and neurodegeneration. This data could be further assessed by correlating it with clinically observed neurological symptoms due to SARS-CoV-2 and other viruses.

Journal reference:
  • Radke, J., Meinhardt, J., Aschman, T., et al. (2024) Proteomic and transcriptomic profiling of brainstem, cerebellum and olfactory tissues in early- and late-phase COVID-19. Nature Neuroscience; 1-12. doi:10.1038/s41593-024-01573-y
Dr. Priyom Bose

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Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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