Current perspective of COVID-19 on neurology: A mechanistic insight

2021 ◽  
Vol 24 ◽  
Author(s):  
Rajesh Kumar ◽  
Seetha Harilal ◽  
Sabitha M ◽  
Leena K Pappachan ◽  
P R Roshni ◽  
...  
Keyword(s):  
Cell Types ◽  
Systemic Circulation ◽  
Multiple Organ ◽  
Coagulation Cascade ◽  
Neurological Involvement ◽  
Causative Organism ◽  
Depth Study ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease ◽  
The Brain

: SARS-CoV-2, the novel coronavirus and the causative organism of Covid-19 pandemic wreaked havoc worldwide producing asymptomatic to symptomatic cases leading to significant morbidity and mortality even after infection. Most of the countries reported a mortality rate of 2-3 % majorly due to cardiorespiratory failures. Recent studies highlighted the neurological involvement playing a key role in cardiorespiratory failures and other symptoms such as headache, anosmia, and ageusia observed in Covid-19 patients. Studies suggests SARS-CoV-2 entry via olfactory epithelium (OE) and the expression of type 2 transmembrane serine protease (TMPRSS2) in addition to angiotensin converting enzyme 2 (ACE2) can facilitate SARS-CoV-2 neurotropism. The virus can either travel via peripheral blood vessel causing endothelial dysfunction, triggering coagulation cascade and multiple organ dysfunction or reach the systemic circulation and take a different route to the blood brain barrier (BBB), disrupting the BBB causing neuroinflammation or neuronal excitotoxicity resulting in the development of encephalitis, encephalopathy, seizures, and strokes. SARS-CoV-2 invasion on brain stem is believed to be responsible for the cardiorespiratory failures observed in Covid-19 patients. Apart from viral invasion via hematogenous route, SARS-CoV-2 neural invasion via PNS nerve terminal, resulting in viral replication and retrograde transportation to soma leading to invasion of the CNS including the brain producing neurological manifestations of the disease either in the initial stages or during the course of the disease and even in a long period post infection in many cases. The ACE2 receptors are expressed in the brain and glial cells and SARS-CoV-2 acts via neuronal as well as non-neuronal pathway. But the exact cell types involved and how they can trigger inflammatory pathways need further in-depth study for the development of targeted therapy.

scholarly journals Dysautonomia and Implications for Anosmia in Long COVID-19 Disease

2021 ◽  
Vol 10 (23) ◽  
pp. 5514
Author(s):  
Alexandre Vallée
Keyword(s):  
Blood Brain Barrier ◽  
Olfactory Epithelium ◽  
Systemic Circulation ◽  
Multiple Organ ◽  
Brain Barrier ◽  
Coagulation Cascade ◽  
Multiple Organ Dysfunction ◽  
Neurologic Symptom ◽  
Blood Brain ◽  
The Brain

Long COVID-19 patients often reported anosmia as one of the predominant persisting symptoms. Recent findings have shown that anosmia is associated with neurological dysregulations. However, the involvement of the autonomic nervous system (ANS), which can aggregate all the long COVID-19 neurological symptoms, including anosmia, has not received much attention in the literature. Dysautonomia is characterized by the failure of the activities of components in the ANS. Long COVID-19 anosmia fatigue could result from damage to olfactory sensory neurons, leading to an augmentation in the resistance to cerebrospinal fluid outflow by the cribriform plate, and further causing congestion of the glymphatic system with subsequent toxic build-up in the brain. Studies have shown that anosmia was an important neurologic symptom described in long COVID-19 in association with potential COVID-19 neurotropism. SARS-CoV-2 can either travel via peripheral blood vessels causing endothelial dysfunction, triggering coagulation cascade and multiple organ dysfunction, or reach the systemic circulation and take a different route to the blood–brain barrier, damaging the blood–brain barrier and leading to neuroinflammation and neuronal excitotoxicity. SARS-CoV-2 entry via the olfactory epithelium and the increase in the expression of TMPRSS2 with ACE2 facilitates SARS-CoV-2 neurotropism and then dysautonomia in long COVID-19 patients. Due to this effect, patients with anosmia persisting 3 months after COVID-19 diagnosis showed extensive destruction of the olfactory epithelium. Persistent anosmia observed among long COVID-19 patients may be involved by a cascade of effects generated by dysautonomia leading to ACE2 antibodies enhancing a persistent immune activation.

scholarly journals SARS-CoV-2 Is Not Detected in the Cerebrospinal Fluid of Encephalopathic COVID-19 Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Dimitris G. Placantonakis ◽  
Maria Aguero-Rosenfeld ◽  
Abdallah Flaifel ◽  
John Colavito ◽  
Kenneth Inglima ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Viral Entry ◽  
Cell Types ◽  
Host Cells ◽  
Nasopharyngeal Swab ◽  
Rt Pcr ◽  
Neurologic Sequelae ◽  
Show Evidence ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease

Neurologic manifestations of the novel coronavirus SARS-CoV-2 infection have received wide attention, but the mechanisms remain uncertain. Here, we describe computational data from public domain RNA-seq datasets and cerebrospinal fluid data from adult patients with severe COVID-19 pneumonia that suggest that SARS-CoV-2 infection of the central nervous system is unlikely. We found that the mRNAs encoding the ACE2 receptor and the TMPRSS2 transmembrane serine protease, both of which are required for viral entry into host cells, are minimally expressed in the major cell types of the brain. In addition, CSF samples from 13 adult encephalopathic COVID-19 patients diagnosed with the viral infection via nasopharyngeal swab RT-PCR did not show evidence for the virus. This particular finding is robust for two reasons. First, the RT-PCR diagnostic was validated for CSF studies using stringent criteria; and second, 61% of these patients had CSF testing within 1 week of a positive nasopharyngeal diagnostic test. We propose that neurologic sequelae of COVID-19 are not due to SARS-CoV-2 meningoencephalitis and that other etiologies are more likely mechanisms.

scholarly journals Pathogenesis of Multiple Organ Injury in COVID-19 and Potential Therapeutic Strategies

2021 ◽  
Vol 12 ◽  
Author(s):  
Miquéias Lopes-Pacheco ◽  
Pedro Leme Silva ◽  
Fernanda Ferreira Cruz ◽  
Denise Battaglini ◽  
Chiara Robba ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Biological Activities ◽  
Case Fatality ◽  
Cell Types ◽  
Multiple Organ ◽  
Organ Injury ◽  
Downstream Effects ◽  
Threatening Condition ◽  
Life Threatening ◽  
Novel Coronavirus

Severe acute respiratory disease coronavirus 2 (SARS-CoV-2, formerly 2019-nCoV) is a novel coronavirus that has rapidly disseminated worldwide, causing the coronavirus disease 2019 (COVID-19) pandemic. As of January 6th, 2021, there were over 86 million global confirmed cases, and the disease has claimed over 1.87 million lives (a ∼2.2% case fatality rate). SARS-CoV-2 is able to infect human cells by binding its spike (S) protein to angiotensin-conversing enzyme 2 (ACE2), which is expressed abundantly in several cell types and tissues. ACE2 has extensive biological activities as a component of the renin-angiotensin-aldosterone system (RAAS) and plays a pivotal role as counter-regulator of angiotensin II (Ang II) activity by converting the latter to Ang (1-7). Virion binding to ACE2 for host cell entry leads to internalization of both via endocytosis, as well as activation of ADAM17/TACE, resulting in downregulation of ACE2 and loss of its protective actions in the lungs and other organs. Although COVID-19 was initially described as a purely respiratory disease, it is now known that infected individuals can rapidly progress to a multiple organ dysfunction syndrome. In fact, all human structures that express ACE2 are susceptible to SARS-CoV-2 infection and/or to the downstream effects of reduced ACE2 levels, namely systemic inflammation and injury. In this review, we aim to summarize the major features of SARS-CoV-2 biology and the current understanding of COVID-19 pathogenesis, as well as its clinical repercussions in the lung, heart, kidney, bowel, liver, and brain. We also highlight potential therapeutic targets and current global efforts to identify safe and effective therapies against this life-threatening condition.

scholarly journals Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes

2020 ◽  
Author(s):  
Joshua D. Breidenbach ◽  
Prabhatchandra Dube ◽  
Subhanwita Ghosh ◽  
Nikolai N. Modyanov ◽  
Deepak Malhotra ◽  
...  
Keyword(s):  
Viral Entry ◽  
Serine Proteases ◽  
Cell Types ◽  
Multiple Organ ◽  
Healthy Individuals ◽  
Host Cell Membrane ◽  
Disease States ◽  
Organ Systems ◽  
Vulnerable Patient ◽  
Transmembrane Serine Protease

AbstractViral entry mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an important aspect of virulence. Proposed mechanisms involve host cell membrane-bound angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine proteases (TTSPs), such as transmembrane serine protease isoform 2 (TMPRSS2). The distribution of expression of these genes across cell types representing multiple organ systems in healthy individuals has been recently demonstrated. However, comorbidities such as diabetes and cardiovascular disease are highly prevalent in patients with Coronavirus Disease 2019 (COVID-19) and associated with worse outcomes. Whether these conditions contribute directly to SARS-CoV-2 virulence remain unclear. Here we show that the expression levels of ACE2, TMPRSS2 and other viral entry-related genes are modulated in target organs of select disease states. In tissues such as heart, which normally express ACE2 but minimal TMPRSS2, we found that TMPRSS2 as well as other TTSPs are elevated in individuals with comorbidities vs healthy individuals. Additionally, we found increased expression of viral entry-related genes in the settings of hypertension, cancer or smoking across target organ systems. Our results demonstrate that common comorbidities may contribute directly to SARS-CoV-2 virulence and suggest new therapeutic targets to improve outcomes in vulnerable patient populations.

scholarly journals Rapid Glucocorticoid Signaling via Membrane-Associated Receptors

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5549-5556 ◽  
Author(s):  
Jeffrey G. Tasker ◽  
Shi Di ◽  
Renato Malcher-Lopes
Keyword(s):  
Systemic Circulation ◽  
Multiple Organ ◽  
G Protein Coupled Receptors ◽  
Signaling Cascades ◽  
Downstream Signaling ◽  
Glucocorticoid Signaling ◽  
Organ Systems ◽  
Genomic Regulation ◽  
G Protein Coupled ◽  
The Brain

Glucocorticoids are secreted into the systemic circulation from the adrenal cortex and initiate a broad range of actions throughout the organism that regulate the function of multiple organ systems, including the liver, muscle, the immune system, the pancreas, fat tissue, and the brain. Delayed glucocorticoid effects are mediated by classical steroid mechanisms involving transcriptional regulation. Relatively rapid effects of glucocorticoids also occur that are incompatible with genomic regulation and invoke a noncanonical mode of steroid action. Studies conducted in several labs and on different species suggest that the rapid effects of glucocorticoids are mediated by the activation of one or more membrane-associated receptors. Here, we provide a brief review focused on multiple lines of evidence suggesting that rapid glucocorticoid actions are triggered by, or at least dependent on, membrane-associated G protein-coupled receptors and activation of downstream signaling cascades. We also discuss the possibility that membrane-initiated actions of glucocorticoids may provide an additional mechanism for the regulation of gene transcription.

scholarly journals Molecular Mechanisms of Neuroimmune Crosstalk in the Pathogenesis of Stroke

2021 ◽  
Vol 22 (17) ◽  
pp. 9486
Author(s):  
Yun Hwa Choi ◽  
Collin Laaker ◽  
Martin Hsu ◽  
Peter Cismaru ◽  
Matyas Sandor ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Lymphatic Vessels ◽  
Immunological Response ◽  
Cell Types ◽  
Multiple Organ ◽  
Post Stroke ◽  
Organ Systems ◽  
The Brain

Stroke disrupts the homeostatic balance within the brain and is associated with a significant accumulation of necrotic cellular debris, fluid, and peripheral immune cells in the central nervous system (CNS). Additionally, cells, antigens, and other factors exit the brain into the periphery via damaged blood–brain barrier cells, glymphatic transport mechanisms, and lymphatic vessels, which dramatically influence the systemic immune response and lead to complex neuroimmune communication. As a result, the immunological response after stroke is a highly dynamic event that involves communication between multiple organ systems and cell types, with significant consequences on not only the initial stroke tissue injury but long-term recovery in the CNS. In this review, we discuss the complex immunological and physiological interactions that occur after stroke with a focus on how the peripheral immune system and CNS communicate to regulate post-stroke brain homeostasis. First, we discuss the post-stroke immune cascade across different contexts as well as homeostatic regulation within the brain. Then, we focus on the lymphatic vessels surrounding the brain and their ability to coordinate both immune response and fluid homeostasis within the brain after stroke. Finally, we discuss how therapeutic manipulation of peripheral systems may provide new mechanisms to treat stroke injury.

scholarly journals Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes

2020 ◽  
Vol 10 (4) ◽  
pp. 146 ◽  
Author(s):  
Joshua Breidenbach ◽  
Prabhatchandra Dube ◽  
Subhanwita Ghosh ◽  
Belal Abdullah ◽  
Nikolai Modyanov ◽  
...  
Keyword(s):  
Viral Entry ◽  
Serine Proteases ◽  
Cathepsin L ◽  
Cell Types ◽  
Multiple Organ ◽  
Healthy Individuals ◽  
Host Cell Membrane ◽  
Organ Systems ◽  
Membrane Bound ◽  
Transmembrane Serine Protease

Viral entry mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an important aspect of virulence. Proposed mechanisms involve host cell membrane-bound angiotensin-converting enzyme 2 (ACE2), type II transmembrane serine proteases (TTSPs), such as transmembrane serine protease isoform 2 (TMPRSS2), lysosomal endopeptidase Cathepsin L (CTSL), subtilisin-like proprotein peptidase furin (FURIN), and even potentially membrane bound heparan sulfate proteoglycans. The distribution and expression of many of these genes across cell types representing multiple organ systems in healthy individuals has recently been demonstrated. However, comorbidities such as diabetes and cardiovascular disease are highly prevalent in patients with Coronavirus Disease 2019 (COVID-19) and are associated with worse outcomes. Whether these conditions contribute directly to SARS-CoV-2 virulence remains unclear. Here, we show that the expression levels of ACE2, TMPRSS2 and other viral entry-related genes, as well as potential downstream effector genes such as bradykinin receptors, are modulated in the target organs of select disease states. In tissues, such as the heart, which normally express ACE2 but minimal TMPRSS2, we found that TMPRSS2 as well as other TTSPs are elevated in individuals with comorbidities compared to healthy individuals. Additionally, we found the increased expression of viral entry-related genes in the settings of hypertension, cancer, or smoking across target organ systems. Our results demonstrate that common comorbidities may contribute directly to SARS-CoV-2 virulence and we suggest new therapeutic targets to improve outcomes in vulnerable patient populations.

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