key: cord-1030846-46domrsx
authors: Mao, Xiao-Yuan; Jin, Wei-Lin
title: Cell perturbation in choroid plexus and cortex aiding COVID-19 neurological symptoms
date: 2021-08-28
journal: Sci Bull (Beijing)
DOI: 10.1016/j.scib.2021.08.017
sha: 74e139e35a22b118dd7dd43adca6e4260c0a9be7
doc_id: 1030846
cord_uid: 46domrsx

nan

Patients with COVID-19 often succumb to neurological manifestations such as loss of smell, headache, disturbed consciousness, seizure and stroke. In a recent paper published in Nature, Yang et al. [1] reported substantial cellular perturbations in the choroid plexus and cortex, notably an infiltration of peripheral T cells into the parenchyma and microglial activation and astrogliosis with distinct transcriptional profiles. These findings provide a complex view of the cellular and molecular processes underlying COVID-19-related neurological abnormalities.

In addition to the development of respiratory insufficiency, the nervous system of hospitalized COVID-19 patients is also frequently affected [2] . Direct evidence from recent work shows that nearly 36.4% (78/214) of SARS-CoV-2-infected patients suffer from neurologic symptoms [3] . In addition, further analysis of postmortem brain tissue samples of a COVID-19 patient revealed that SARS-CoV-2 is present in neural and capillary endothelial cells. There is a succinct summary of nervous system involvement in COVID-19 [4] . Our previous work has also provided an overview of brain infection in patients with COVID-19 in the ongoing pandemic [5] . Currently, neurological complications are considered a critical cause of morbidity and mortality in the threat of COVID-19. It is important to determine how cellular and molecular processes may contribute to neurological changes in COVID-19 patients.

Recently, Yang et al. [1] profiled single-nucleus transcriptomes (snRNA-seq) of frontal cortex and choroid plexus samples from the COVID-19 brain to provide a comprehensive assessment across diverse cell types. A very convenient interactive data browser (https://twc-stanford.shinyapps.io/scRNA_Brain_COVID19) has been created to dissect the molecular mechanisms of the effects of SARS-CoV-2 on the brain. Across cell populations from the medial frontal cortex, Yang et al. [1] reported six broad cell subtypes with 786 unique differentially expressed genes (DEGs), notably in astrocytes, microglia, and layer 2/3 excitatory neurons of the cortex. In contrast, snRNA-seq analysis of choroid plexus samples across seven major epithelial, mesenchymal, immune, ependymal, and glial cell types showed robust expression of several genes relevant to SARS-CoV-2 infection, such as interferon (IFITM3 and STAT3) and complement (C1S and C3), and these findings were confirmed with immunohistochemistry (IHC) and real-time quantitative polymerase chain reaction (RT-qPCR) assays. The choroid plexus is a natural brain barrier that protects against the inflammatory response [6] . Macrophage migration and infiltration occur in the choroid plexus-brain barrier [6] . When the choroid plexus is inflamed it can send inflammatory signals such as the C-C chemokine ligand (CCL) and chemokine legend (CXCL) family of chemokines into the brain, thereby triggering COVID-19 neurological symptoms. To corroborate this notion, cell-cell communication analysis was performed by Yang and his coworkers. It is noteworthy that there was an enhanced choroid-to-cortex network across several critical inflammatory pathways, such as the CCL and CXCL family of chemokines from the choroid plexus epithelium to various glial cell types (including astrocytes, oligodendrocytes and microglia) and layer 2/3 and layer 4 excitatory neurons of the cortex. Additionally, there was a strong increase in complement pathway signaling from the choroid plexus to brain microglia in COVID-19 patients. Microglia are resident brain cells mediating the immune defense system of the central nervous system (CNS) [7] , which is integral to the subsequent inflammatory response. It has been well established that neuroinflammation is induced by microglial activation. Indeed, Yang et al. uncovered a COVID-19 disease-related microglial subpopulation marked by genes implicated in neuroinflammation, such as RIPK1. It has been previously shown that aberrant T cell infiltration can also contribute to neuroinflammation and impair neurogenesis. In this work, Yang et al. revealed that brain T cells are observed in all but one COVID-19 patient across distinct transcriptional profiles. In the nervous system, reactive astrocytes (or astrogliosis) are also a contributing factor to neuroinflammation. It has been demonstrated that reactive astrocytes express damage-associated molecular patterns (DAMPs) and pathogen-associated molecular pattern (PAMP) receptors, which are important components of innate immunity [8] . Yang and his colleagues revealed a COVID-19-associated astrocyte cluster marked by increased expression of inflammatory factor (IFITM3) and astrogliosis gene (GFAP). Astrocytic impairments can affect neurotransmission [9] . In this work Yang et al. together, these results indicated that peripheral SARS-CoV-2 attacks the choroid plexus, which then builds a neuroinflammatory environment into the brain parenchyma. This network is an important route that likely supports the notion that SARS-CoV-2 directly causes brain infection, as summarized in Fig. 1 . It is worth mentioning that the study of Yang et al. [1] showed that there is an absence or a low level of viral RNA detected in some brain samples of COVID-19, and the possibility of contamination has been raised as previously described [10] . COVID-19-related neurological symptoms have now been widely described. To the best of our knowledge, there are two possible aspects for triggering brain infection, namely, direct brain infection and indirect brain effects. On the one hand, the choroid plexus-cortex network, as mentioned above, the olfactory route and blood-brain barrier (BBB) are potential routes for the entry of SARS-CoV-2 into the brain. Direct evidence supporting infection of the olfactory system arises from the loss of smell, a common neurological manifestation in COVID-19 [11] . It is likely that the neurological signs are triggered by the activation of TMPRSS2 on the spike protein within SARS-CoV-2 or binding of the ACE2 receptor to the virus in the nasal mucosa [12] . The BBB is also a prevalent route of viral entry into the brain. Patients with severe COVID-19 often experience a serious cytokine storm, with increased circulating levels of IL-6, IL-17, TNF-α, and IL-1β. TNF-α can directly enter the brain through a compromised BBB [4] , activating microglia and astrocytes and inducing the immune response. On the other hand, several other factors, such as respiratory failure, neutrophil recruitment and systemic metabolic changes, possibly result in indirect brain effects. SARS-CoV-2-induced respiratory failure leads to severe hypoxia and subsequently affects organs most vulnerable to hypoxia, including the brain [13] . Thrombosis is also a feature of patients with COVID-19. This pathological trait may start in the lung and other human organs with neutrophil recruitment [14] . Ultimately, neutrophils release extracellular traps (NETs), which further facilitate intravascular thrombosis in organs, including the brain. In addition, systemic metabolic alterations, including water and electrolyte imbalance and cumulative toxic metabolites, have also been shown to trigger some nonspecific neurologic signs, such as agitation and headache. Collectively, both major routes that we propose are elaborated in Fig. 1 .

Inflammation or immune dysregulation is a key feature of COVID-19, which is associated with a cytokine storm. In severe COVID-19 patients, cytokine release syndrome often occurs, which is accompanied by increasing circulating levels of inflammatory factors such as IL-6, IL-1β, and TNF-α, as well as IL-2, IL-8, and IL-17 In conclusion, the studies of Yang et al. [1] have revealed the dysregulation of diverse cell populations in the choroid plexus and cortex, which may provide comprehensive molecular traces for the emergence of COVID-19 neurological symptoms; however, further investigation is warranted to understand how these molecular processes contribute to COVID-19 neurologic deficits.

The authors declare that they have no conflict of interest. 

Dysregulation of brain and choroid plexus cell types in severe COVID-19

Neurologic Features in severe SARS-CoV-2 infection

Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China

Effects of COVID-19 on the nervous system

The COVID-19 pandemic: consideration for brain infection

A cellular and spatial map of the choroid plexus across brain ventricles and ages

Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs

Astrocyte Reactivity: Subtypes, states, and functions in CNS innate immunity

Selective induction of astrocytic gliosis generates deficits in neuronal inhibition

Neuropathological features of COVID-19

Anosmia and loss of smell in the era of COVID-19

Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

Neuropathologic features of four autopsied COVID-19 patients

Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome

Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19)

he joined the Department of Clinical Pharmacology, Xiangya Hospital of Central South University. His lab takes great interest in probing the molecular mechanisms underlying brain homeostasis and therapeutic intervention, especially the aspect of metabolic control, neuroinflammation, extracellular matrix remodeling

he joined the Institute of Neurosciences, Shanghai Jiao Tong University as an associated professor

This work was supported by the National Natural Science Foundation of China (81671293 and 81974502) and Natural Science Foundation of Hunan Province (2020JJ3061). We thank Ms. Qi-Wen Guan from Xiao-Yuan Mao laboratory for assisting in drawing the graphic.