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1.
Signal Transduct Target Ther ; 6(1): 169, 2021 04 24.
Article in English | MEDLINE | ID: covidwho-1199270

ABSTRACT

Neurological manifestations are frequently reported in the COVID-19 patients. Neuromechanism of SARS-CoV-2 remains to be elucidated. In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.


Subject(s)
Brain Diseases/metabolism , Brain/metabolism , COVID-19/metabolism , Olfactory Bulb/metabolism , SARS-CoV-2/metabolism , Animals , Astrocytes/metabolism , Astrocytes/pathology , Astrocytes/virology , Brain/pathology , Brain/virology , Brain Diseases/pathology , Brain Diseases/virology , COVID-19/pathology , Disease Models, Animal , Humans , Macaca mulatta , Microglia/metabolism , Microglia/pathology , Microglia/virology , Neurons/metabolism , Neurons/pathology , Neurons/virology , Olfactory Bulb/pathology , Olfactory Bulb/virology
2.
Pharmacol Res ; 168: 105581, 2021 06.
Article in English | MEDLINE | ID: covidwho-1157664

ABSTRACT

In-depth characterization of heart-brain communication in critically ill patients with severe acute respiratory failure is attracting significant interest in the COronaVIrus Disease 19 (COVID-19) pandemic era during intensive care unit (ICU) stay and after ICU or hospital discharge. Emerging research has provided new insights into pathogenic role of the deregulation of the heart-brain axis (HBA), a bidirectional flow of information, in leading to severe multiorgan disease syndrome (MODS) in patients with confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Noteworthy, HBA dysfunction may worsen the outcome of the COVID-19 patients. In this review, we discuss the critical role HBA plays in both promoting and limiting MODS in COVID-19. We also highlight the role of HBA as new target for novel therapeutic strategies in COVID-19 in order to open new translational frontiers of care. This is a translational perspective from the Italian Society of Cardiovascular Researches.


Subject(s)
Brain Diseases/therapy , Brain/drug effects , COVID-19/therapy , Heart Diseases/therapy , Heart/drug effects , Adrenal Cortex Hormones/administration & dosage , Anti-Inflammatory Agents/administration & dosage , Antiviral Agents/administration & dosage , Brain/immunology , Brain/metabolism , Brain Diseases/immunology , Brain Diseases/metabolism , COVID-19/immunology , COVID-19/metabolism , Critical Care/methods , Critical Illness/therapy , Dietary Supplements , Functional Food , Heart Diseases/immunology , Heart Diseases/metabolism , Humans , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Microvessels/drug effects , Microvessels/immunology , Microvessels/metabolism , Multiple Organ Failure/immunology , Multiple Organ Failure/metabolism , Multiple Organ Failure/therapy , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/metabolism
4.
Mol Neurobiol ; 58(7): 3347-3361, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1120777

ABSTRACT

The severity of COVID-19 infection is surging day by day. With the cases increasing daily, it is becoming more and more essential to understand the pathogenic mechanisms underlying the severity of the disease. It is now well known that the infection manifests itself primarily as respiratory, but the involvement of the other organ systems has now been documented in many studies. SARS-CoV-2 can invade the nervous system by a multitude of proposed mechanisms that have been discussed in this review. NF-κB and Nrf2 are transcription factors that regulate genes responsible for inflammatory and anti-oxidant response respectively. Specific focus in this review has been given to NF-κB and Nrf2 pathways that are involved in the cytokine storm and oxidative stress that are the hallmarks of COVID-19. As the immune injury is an important mechanism of neuro-invasion and neuroinflammation, there is the possible involvement of these two pathways in the neurological complications. The crosstalk mechanisms of these signaling pathways have also been discussed. Immuno-modulators both synthetic and natural are promising candidates in catering to the pathologies targeted in the aforementioned pathways.


Subject(s)
Brain Diseases/virology , Brain/metabolism , COVID-19/complications , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Oxidative Stress/physiology , Brain Diseases/metabolism , COVID-19/metabolism , Humans , Signal Transduction/physiology
5.
ACS Chem Neurosci ; 12(4): 573-580, 2021 02 17.
Article in English | MEDLINE | ID: covidwho-1065791

ABSTRACT

Long-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.


Subject(s)
Brain Diseases/physiopathology , Brain Stem/physiopathology , COVID-19/complications , Inflammation/physiopathology , Thrombosis/physiopathology , Angiotensin-Converting Enzyme 2/metabolism , Brain Diseases/metabolism , Brain Diseases/virology , Brain Stem/blood supply , Brain Stem/metabolism , Brain Stem/virology , COVID-19/metabolism , COVID-19/physiopathology , Humans , Inflammation/metabolism , Inflammation/virology , Neuropilin-1/metabolism , RNA, Viral/isolation & purification , RNA, Viral/metabolism , Receptors, Coronavirus/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Thrombosis/metabolism , Thrombosis/virology , Viral Tropism
6.
Mol Psychiatry ; 26(4): 1044-1059, 2021 04.
Article in English | MEDLINE | ID: covidwho-983662

ABSTRACT

Scientists and health professionals are exhaustively trying to contain the coronavirus disease 2019 (COVID-19) pandemic by elucidating viral invasion mechanisms, possible drugs to prevent viral infection/replication, and health cares to minimize individual exposure. Although neurological symptoms are being reported worldwide, neural acute and long-term consequences of SARS-CoV-2 are still unknown. COVID-19 complications are associated with exacerbated immunoinflammatory responses to SARS-CoV-2 invasion. In this scenario, pro-inflammatory factors are intensely released into the bloodstream, causing the so-called "cytokine storm". Both pro-inflammatory factors and viruses may cross the blood-brain barrier and enter the central nervous system, activating neuroinflammatory responses accompanied by hemorrhagic lesions and neuronal impairment, which are largely described processes in psychiatric disorders and neurodegenerative diseases. Therefore, SARS-CoV-2 infection could trigger and/or worse brain diseases. Moreover, patients with central nervous system disorders associated to neuroimmune activation (e.g. depression, Parkinson's and Alzheimer's disease) may present increased susceptibility to SARS-CoV-2 infection and/or achieve severe conditions. Elevated levels of extracellular ATP induced by SARS-CoV-2 infection may trigger hyperactivation of P2X7 receptors leading to NLRP3 inflammasome stimulation as a key mediator of neuroinvasion and consequent neuroinflammatory processes, as observed in psychiatric disorders and neurodegenerative diseases. In this context, P2X7 receptor antagonism could be a promising strategy to prevent or treat neurological complications in COVID-19 patients.


Subject(s)
Brain Diseases/complications , Brain Diseases/pathology , COVID-19/complications , COVID-19/pathology , Neuroimmunomodulation , Receptors, Purinergic P2X7/metabolism , SARS-CoV-2/pathogenicity , Brain Diseases/drug therapy , Brain Diseases/metabolism , COVID-19/immunology , COVID-19/metabolism , Humans , Inflammasomes/immunology , Inflammasomes/metabolism , Pandemics , SARS-CoV-2/immunology
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