Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

Andrews, Madeline G.; Mukhtar, Tanzila; Eze, Ugomma C.; Simoneau, Camille R.; Perez, Yonatan; Mostajo-Radji, Mohammed A.; Wang, Shaohui; Velmeshev, Dmitry; Jahan, Sultana; Kumar, G. Renuka; Pollen, Alex A.; Crouch, Elizabeth E.; Ott, Mélanie; Kriegstein, Arnold R.

doi:10.1101/2021.01.17.427024

Cited by 45 publications

(45 citation statements)

References 45 publications

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“…Here we show that astrocytes are the main locus of infection -and possibly replication -of SARS-CoV-2 in COVID-19 patients' brains, as evidenced by the detection of the viral genome, the SARS-CoV-2 spike protein and dsRNA in both postmortem brain tissues and in vitro astrocytes. These findings are in line with recently published evidence showing that astrocytes from primary human cortical tissue and stem cellderived cortical organoids are susceptible to SARS-CoV-2 infection (Andrews et al, 2021).…”

Section: Discussionsupporting

confidence: 92%

Morphological, cellular and molecular basis of brain infection in COVID-19 patients

Crunfli

Carregari

Veras

et al. 2020

Preprint

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COVID-19 patients may exhibit neuropsychiatric and/or neurological symptoms. We found that anxiety and cognitive impairment are manifested by 28-56% of SARS-CoV-2-infected individuals with mild or no respiratory symptoms and are associated with altered cerebral cortical thickness. Using an independent cohort, we found histopathological signs of brain damage in 19% of individuals who died of COVID-19. All of the affected brain tissues exhibited foci of SARS-CoV-2 infection, particularly in astrocytes. Infection of neural stem cell-derived astrocytes changed energy metabolism, altered key proteins and metabolites used to fuel neurons and for biogenesis of neurotransmitters, and elicited a secretory phenotype that reduces neuronal viability. Our data support the model where SARS-CoV-2 reaches the brain, infects astrocytes and triggers neuropathological changes that contribute to the structural and functional alterations in the brain of COVID-19 patients.

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Section: Discussionsupporting

confidence: 92%

Morphological, cellular and molecular basis of brain infection in COVID-19 patients

Crunfli

Carregari

Veras

et al. 2020

Preprint

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“…Reports suggest tropism of SARS-CoV-2 to NPCs with viral proteins colocalizing with SOX2-positive neural rosettes ( Song et al, 2020 ) and NPC marker Nestin ( Mesci et al, 2020 ; Zhang et al, 2020 ). However, other reports do not support this observation ( Andrews et al, 2021 ; Ramani et al, 2020 ). This discrepancy cannot be readily attributed to the protocol for organoid differentiation, their age, incubation time with the virus and the viral dose ( Table 1 ) highlighting the need for further corroboration by independent studies with larger numbers of replications (see also Brain Organoid Models Have Started to Reveal Cellular and Molecular Mechanisms of Environmental Insults and Technological Advances Drive Progress in Brain Organoid Research and Increase Interpretability Across Studies ).…”

Section: Viral Infections With Vertical Transmission From Mother To Fetusmentioning

confidence: 70%

“…If ChP is permissive to SARS-CoV-2 brain entry, the question is which cell types within the brain may be affected by the virus. Several brain organoid studies show infection of NSCs ( Mesci et al, 2020 ; Song et al, 2020 ; Zhang et al, 2020 ), neurons ( Jacob et al, 2020 ; Mesci et al, 2020 ; Ramani et al, 2020 ; Song et al, 2020 ; Zhang et al, 2020 ; Andrews et al, 2021 ), and even astrocytes ( Jacob et al, 2020 ; Mesci et al, 2020 ; Andrews et al, 2021 ) by the novel coronavirus. Considering neurogenesis, the next focus will be on the potential infection of NSCs and newborn neurons.…”

Section: Viral Infections With Vertical Transmission From Mother To Fetusmentioning

confidence: 99%

The Effects of Environmental Adversities on Human Neocortical Neurogenesis Modeled in Brain Organoids

Sarieva

Mayer

2021

Front. Mol. Biosci.

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Over the past decades, a growing body of evidence has demonstrated the impact of prenatal environmental adversity on the development of the human embryonic and fetal brain. Prenatal environmental adversity includes infectious agents, medication, and substances of use as well as inherently maternal factors, such as diabetes and stress. These adversities may cause long-lasting effects if occurring in sensitive time windows and, therefore, have high clinical relevance. However, our knowledge of their influence on specific cellular and molecular processes of in utero brain development remains scarce. This gap of knowledge can be partially explained by the restricted experimental access to the human embryonic and fetal brain and limited recapitulation of human-specific neurodevelopmental events in model organisms. In the past years, novel 3D human stem cell-based in vitro modeling systems, so-called brain organoids, have proven their applicability for modeling early events of human brain development in health and disease. Since their emergence, brain organoids have been successfully employed to study molecular mechanisms of Zika and Herpes simplex virus-associated microcephaly, as well as more subtle events happening upon maternal alcohol and nicotine consumption. These studies converge on pathological mechanisms targeting neural stem cells. In this review, we discuss how brain organoids have recently revealed commonalities and differences in the effects of environmental adversities on human neurogenesis. We highlight both the breakthroughs in understanding the molecular consequences of environmental exposures achieved using organoids as well as the on-going challenges in the field related to variability in protocols and a lack of benchmarking, which make cross-study comparisons difficult.

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“…417 The same has been suggested for the CNS where direct invasion of viruses into the astroglial compartment has been shown. 418,419 It has also been shown that entry into the nervous system space may happen through capillary pericyte infection by SARS-CoV-2. 420 The fact however that SARS-CoV-2 infection is not consistently found in COVID-19 patients with neurological symptoms may suggest a transient nature of CNS infection.…”

Section: Covid-19 To the Rescuementioning

confidence: 99%

Broken Connections: The Evidence for Neuroglial Failure in ME/CFS

Renz‐Polster¹

2021

Preprint

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In spite of decades of research, the pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is still poorly understood. Several pathomechanisms have been identified, yet, it remains unclear how they are related and which of them may be upstream or downstream.. In this paper, we present a theoretical strategy that may help clarify the causal chain of pathophysiological events in ME/CFS. We propose to focus on the common final histological pathway of ME/CFS and suggest to ask: Which cellular compartment may explain the pathological processes and clinical manifestations observed in ME/CFS? Any functional unit consistently identified through this search may then be a plausible candidate for further exploration.For this "histological" approach we have compiled a list of 22 undisputed clinical and pathophysiological features of ME/CFS that need to be plausibly and most directly explained by the dysfunctional cellular unit in question. For each feature we have searched the literature for pathophysiological explanations and analyzed if they may point to the same functional cellular unit.Through this search we have identified the CNS neuroglia - microglia and astroglia - as the one functional unit in the human body which may best explain all and any of the clinical and pathological features, dysfunctions and observations described for ME/CFS. While this points to neuroinflammation as the central hub in ME/CFS, it also points to a novel understanding of the neuroimmune basis of ME/CFS. After all, the neuroglial cells are now understood as the functional matrix of the human brain connectome which operates beyond and above specific brain centers, receptor units or neurotransmitter systems and integrates innate immune functions with CNS regulatory functions pertaining to autonomous regulation, cellular metabolism and the stress response.

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Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

Cited by 45 publications

References 45 publications

Morphological, cellular and molecular basis of brain infection in COVID-19 patients

Morphological, cellular and molecular basis of brain infection in COVID-19 patients

The Effects of Environmental Adversities on Human Neocortical Neurogenesis Modeled in Brain Organoids

Broken Connections: The Evidence for Neuroglial Failure in ME/CFS

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