Establishment of Human Pluripotent Stem Cell-Derived Skin Organoids Enabled Pathophysiological Model of SARS-CoV-2 Infection.

Coronavirus disease 2019 (COVID-19) patients with impact on skin and hair loss are reported. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is detected in the skin of some patients; however, the detailed pathological features of skin tissues from patients infected with SARS-CoV-2 at a molecular level are limited. Especially, the ability of SARS-CoV-2 to infect skin cells and impact their function is not well understood. A proteome map of COVID-19 skin is established here and the susceptibility of human-induced pluripotent stem cell (hiPSC)-derived skin organoids with hair follicles and nervous system is investigated, to SARS-CoV-2 infection. It is shown that KRT17+ hair follicles can be infected by SARS-CoV-2 and are associated with the impaired development of hair follicles and epidermis. Different types of nervous system cells are also found to be infected, which can lead to neuron death. Findings from the present work provide evidence for the association between COVID-19 and hair loss. hiPSC-derived skin organoids are also presented as an experimental model which can be used to investigate the susceptibility of skin cells to SARS-CoV-2 infection and can help identify various pathological mechanisms and drug screening strategies.

A Review on SARS-CoV-2-Induced Neuroinflammation, Neurodevelopmental Complications, and Recent Updates on the Vaccine Development.

Coronavirus disease 2019 (COVID-19) is a devastating viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The incidence and mortality of COVID-19 patients have been increasing at an alarming rate. The mortality is much higher in older individuals, especially the ones suffering from respiratory distress, cardiac abnormalities, renal diseases, diabetes, and hypertension. Existing evidence demonstrated that SARS-CoV-2 makes its entry into human cells through angiotensin-converting enzyme 2 (ACE-2) followed by the uptake of virions through cathepsin L or transmembrane protease serine 2 (TMPRSS2). SARS-CoV-2-mediated abnormalities in particular cardiovascular and neurological ones and the damaged coagulation systems require extensive research to develop better therapeutic modalities. As SARS-CoV-2 uses its S-protein to enter into the host cells of several organs, the S-protein of the virus is considered as the ideal target to develop a potential vaccine. In this review, we have attempted to highlight the landmark discoveries that lead to the development of various vaccines that are currently under different stages of clinical progression. Besides, a brief account of various drug candidates that are being tested to mitigate the burden of COVID-19 was also covered. Further, in a dedicated section, the impact of SARS-CoV-2 infection on neuronal inflammation and neuronal disorders was discussed. In summary, it is expected that the content covered in this article help to understand the pathophysiology of COVID-19 and the impact on neuronal complications induced by SARS-CoV-2 infection while providing an update on the vaccine development.

Infection Mechanism of SARS-COV-2 and Its Implication on the Nervous System.

In late December 2019, multiple atypical pneumonia cases resulted in severe acute respiratory syndrome caused by a pathogen identified as a novel coronavirus SARS-CoV-2. The most common coronavirus disease 2019 (COVID-19) symptoms are pneumonia, fever, dry cough, and fatigue. However, some neurological complications following SARS-CoV-2 infection include confusion, cerebrovascular diseases, ataxia, hypogeusia, hyposmia, neuralgia, and seizures. Indeed, a growing literature demonstrates that neurotropism is a common feature of coronaviruses; therefore, the infection mechanisms already described in other coronaviruses may also be applicable for SARS-CoV-2. Understanding the underlying pathogenetic mechanisms in the nervous system infection and the neurological involvement is essential to assess possible long-term neurological alteration of COVID-19. Here, we provide an overview of associated literature regarding possible routes of COVID-19 neuroinvasion, such as the trans-synapse-connected route in the olfactory pathway and peripheral nerve terminals and its neurological implications in the central nervous system.

Does COVID-19 contribute to development of neurological disease?

BACKGROUND: Although coronavirus disease 2019 (COVID-19) has been associated primarily with pneumonia, recent data show that the causative agent of COVID-19, the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect a large number of vital organs beyond the lungs, such as the heart, kidneys, and the brain. Thus, there is evidence showing possible retrograde transmission of the virus from the olfactory epithelium to regions of the brain stem. METHODS: This is a literature review article. The research design method is an evidence-based rapid review. The present discourse aim is first to scrutinize and assess the available literature on COVID-19 repercussion on the central nervous system (CNS). Standard literature and database searches were implemented, gathered relevant material, and extracted information was then assessed. RESULTS: The angiotensin-converting enzyme 2 (ACE2) receptors being the receptor for the virus, the threat to the central nervous system is expected. Neurons and glial cells express ACE2 receptors in the CNS, and recent studies suggest that activated glial cells contribute to neuroinflammation and the devastating effects of SARS-CoV-2 infection on the CNS. The SARS-CoV-2-induced immune-mediated demyelinating disease, cerebrovascular damage, neurodegeneration, and depression are some of the neurological complications discussed here. CONCLUSION: This review correlates present clinical manifestations of COVID-19 patients with possible neurological consequences in the future, thus preparing healthcare providers for possible future consequences of COVID-19.

Evidence of Coronavirus (CoV) Pathogenesis and Emerging Pathogen SARS-CoV-2 in the Nervous System: A Review on Neurological Impairments and Manifestations.

The coronavirus disease 2019 (COVID-19) pandemic is an issue of global significance that has taken the lives of many across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for its pathogenesis. The pulmonary manifestations of COVID-19 have been well described in the literature. Initially, it was thought to be limited to the respiratory system; however, we now recognize that COVID-19 also affects several other organs, including the nervous system. Two similar human coronaviruses (CoV) that cause severe acute respiratory syndrome (SARS-CoV-1) and Middle East respiratory syndrome (MERS-CoV) are also known to cause disease in the nervous system. The neurological manifestations of SARS-CoV-2 infection are growing rapidly, as evidenced by several reports. There are several mechanisms responsible for such manifestations in the nervous system. For instance, post-infectious immune-mediated processes, direct virus infection of the central nervous system (CNS), and virus-induced hyperinflammatory and hypercoagulable states are commonly involved. Guillain-Barré syndrome (GBS) and its variants, dysfunction of taste and smell, and muscle injury are numerous examples of COVID-19 PNS (peripheral nervous system) disease. Likewise, hemorrhagic and ischemic stroke, encephalitis, meningitis, encephalopathy acute disseminated encephalomyelitis, endothelialitis, and venous sinus thrombosis are some instances of COVID-19 CNS disease. Due to multifactorial and complicated pathogenic mechanisms, COVID-19 poses a large-scale threat to the whole nervous system. A complete understanding of SARS-CoV-2 neurological impairments is still lacking, but our knowledge base is rapidly expanding. Therefore, we anticipate that this comprehensive review will provide valuable insights and facilitate the work of neuroscientists in unfolding different neurological dimensions of COVID-19 and other CoV associated abnormalities.

The nervous system-A new territory being explored of SARS-CoV-2.

In December 2019, COVID-19 outbroke in Wuhan, then sweeping the mainland of China and the whole world rapidly. On March 4, Beijing Ditan Hospital confirmed the existence of SARS-CoV-2 in the cerebrospinal fluid by gene sequencing, indicating the neurotropic involvement of SARS-CoV-2. Meanwhile, neurological manifestations in the central nervous system, peripheral nervous system and skeletal muscular were also observed, indicating the potential neuroinvasion of SARS-CoV-2. In particular, we focused on its neurological manifestations and specific pathogenesis, as well as its comparison with other viral respiratory infections. Finally, we further summarized the significance of the neuroinvasion and the follow-up issues that need to be paid attention to by scientists, so as to help neurologists understand the influence of SARS-CoV-2 on nervous system better and promote the accurate diagnosis and efficient treatment of COVID-19.

Immune response and blood-brain barrier dysfunction during viral neuroinvasion.

The blood-brain barrier (BBB), which protects the CNS from pathogens, is composed of specialized brain microvascular endothelial cells (BMECs) joined by tight junctions and ensheathed by pericytes and astrocyte endfeet. The stability of the BBB structure and function is of great significance for the maintenance of brain homeostasis. When a neurotropic virus invades the CNS via a hematogenous or non-hematogenous route, it may cause structural and functional disorders of the BBB, and also activate the BBB anti-inflammatory or pro-inflammatory innate immune response. This article focuses on the structural and functional changes that occur in the three main components of the BBB (endothelial cells, astrocytes, and pericytes) in response to infection with neurotropic viruses transmitted by hematogenous routes, and also briefly describes the supportive effect of three cells on the BBB under normal physiological conditions. For example, all three types of cells express several PRRs, which can quickly sense the virus and make corresponding immune responses. The pro-inflammatory immune response will exacerbate the destruction of the BBB, while the anti-inflammatory immune response, based on type I IFN, consolidates the stability of the BBB. Exploring the details of the interaction between the host and the pathogen at the BBB during neurotropic virus infection will help to propose new treatments for viral encephalitis. Enhancing the defense function of the BBB, maintaining the integrity of the BBB, and suppressing the pro-inflammatory immune response of the BBB provide more ideas for limiting the neuroinvasion of neurotropic viruses. In the future, these new treatments are expected to cooperate with traditional antiviral methods to improve the therapeutic effect of viral encephalitis.

Systemic Complications of COVID-19.

Coronavirus disease-2019 (COVID-19) creates severe respiratory distress and often a cascade of other systemic complications impacting several organ systems. The immune response includes a cytokine storm that creates many life-threatening problems including coagulopathies, arrhythmias, and secondary infections. This article discusses the multisystem responses to the physical insults created by this corona virus.

Unpuzzling COVID-19: tissue-related signaling pathways associated with SARS-CoV-2 infection and transmission.

The highly infective coronavirus disease 19 (COVID-19) is caused by a novel strain of coronaviruses - the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - discovered in December 2019 in the city of Wuhan (Hubei Province, China). Remarkably, COVID-19 has rapidly spread across all continents and turned into a public health emergency, which was ultimately declared as a pandemic by the World Health Organization (WHO) in early 2020. SARS-CoV-2 presents similar aspects to other members of the coronavirus family, mainly regarding its genome, protein structure and intracellular mechanisms, that may translate into mild (or even asymptomatic) to severe infectious conditions. Although the mechanistic features underlying the COVID-19 progression have not been fully clarified, current evidence have suggested that SARS-CoV-2 may primarily behave as other ß-coronavirus members. To better understand the development and transmission of COVID-19, unveiling the signaling pathways that may be impacted by SARS-CoV-2 infection, at the molecular and cellular levels, is of crucial importance. In this review, we present the main aspects related to the origin, classification, etiology and clinical impact of SARS-CoV-2. Specifically, here we describe the potential mechanisms of cellular interaction and signaling pathways, elicited by functional receptors, in major targeted tissues/organs from the respiratory, gastrointestinal (GI), cardiovascular, renal, and nervous systems. Furthermore, the potential involvement of these signaling pathways in evoking the onset and progression of COVID-19 symptoms in these organ systems are presently discussed. A brief description of future perspectives related to potential COVID-19 treatments is also highlighted.

[Neurological damage linked to coronaviruses : SARS-CoV-2 and other human coronaviruses]. / Les atteintes neurologiques liées au SARS-CoV-2 et autres coronavirus humains.

The recent emergence of a new coronavirus, SARS-CoV-2, responsible for COVID-19, is a new warning of the risk to public health represented by viral zoonoses and in particular by coronaviruses. Mainly described as being able to infect the upper and lower respiratory tract, coronaviruses can also infect the central and peripheral nervous systems as many other respiratory viruses, such as influenza or respiratory syncytial virus. Viral infections of the nervous system are a major public health concern as they can cause devastating illnesses up to death, especially when they occur in the elderly, who are more susceptible to these infections. Knowledge concerning the pathophysiology of recently emerging coronaviruses (MERS-CoV, SARS-CoV and SARS-CoV-2) and how they reach the central nervous system are very sketchy and the work in progress aims in particular to better understand their biology and the mechanisms associated with neurological damage. In this review we will discuss the current state of knowledge on the neurotropism of human coronaviruses and the associated mechanisms by developing in particular the latest data concerning SARS-CoV-2.

TITLE: Les atteintes neurologiques liées au SARS-CoV-2 et autres coronavirus humains. ABSTRACT: L'émergence récente d'un nouveau coronavirus, le SARS-CoV-2, responsable de la maladie appelée COVID-19, est un nouvel avertissement du risque pour la santé publique représenté par les zoonoses virales et notamment par les coronavirus. Principalement connus pour leur capacité à infecter les voies respiratoires supérieures et inférieures, les coronavirus peuvent également affecter le système nerveux central et périphérique, comme c'est le cas pour de nombreux virus respiratoires, tels que les virus influenza ou le virus respiratoire syncytial. Les infections du système nerveux sont un problème important de santé publique car elles peuvent provoquer des atteintes dévastatrices allant jusqu'au décès du patient, en particulier lorsqu'elles surviennent chez les personnes fragilisées ou âgées plus sensibles à ce type d'infection. Les connaissances de la physiopathologie des infections par les coronavirus émergents (MERS-CoV, SARS-CoV et SARS-CoV-2) et leurs moyens d'accéder au système nerveux central sont, pour l'heure, très sommaires. Les travaux en cours visent notamment à mieux appréhender les mécanismes associés aux atteintes neurologiques observées. Dans cette revue nous aborderons l'état des connaissances actuelles sur le neurotropisme des coronavirus humains et les mécanismes associés en développant tout particulièrement les dernières données concernant le SARS-CoV-2.

Organ-specific manifestations of COVID-19 infection.

Although COVID-19 presents primarily as a lower respiratory tract infection transmitted via air droplets, increasing data suggest multiorgan involvement in patients that are infected. This systemic involvement is postulated to be mainly related to the SARS-CoV-2 virus binding on angiotensin-converting enzyme 2 (ACE2) receptors located on several different human cells. Lung involvement is the most common serious manifestation of the disease, ranging from asymptomatic disease or mild pneumonia, to severe disease associated with hypoxia, critical disease associated with shock, respiratory failure and multiorgan failure or death. Among patients with COVID-19, underlying cardiovascular comorbidities including hypertension, diabetes and especially cardiovascular disease, has been associated with adverse outcomes, whereas the emergence of cardiovascular complications, including myocardial injury, heart failure and arrhythmias, has been associated with poor survival. Gastrointestinal symptoms are also frequently encountered and may persist for several days. Haematological complications are frequent as well and have been associated with poor prognosis. Furthermore, recent studies have reported that over a third of infected patients develop a broad spectrum of neurological symptoms affecting the central nervous system, peripheral nervous system and skeletal muscles, including anosmia and ageusia. The skin, the kidneys, the liver, the endocrine organs and the eyes are also affected by the systemic COVID-19 disease. Herein, we provide a comprehensive overview of the organ-specific systemic manifestations of COVID-19.

Neuropathogenic human coronaviruses: A review.

Human Coronaviruses (HCoVs) have long been known as respiratory viruses. However, there are reports of neurological findings in HCoV infections, particularly in patients infected with the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) amid Coronavirus disease 2019 (COVID-19) pandemic. Therefore, it is essential to interpret the interaction of HCoVs and the nervous system and apply this understanding to the COVID-19 pandemic. This review of the literature analyses how HCoVs, in general, and SARS-CoV-2, in particular, affect the nervous system, highlights the various underlying mechanisms, addresses the associated neurological and psychiatric manifestations, and identifies the neurological risk factors involved. This review of literature shows the magnitude of neurological conditions associated with HCoV infections, including SARS-CoV-2. This review emphasises, that, during HCoV outbreaks, such as COVID-19, a focus on early detection of neurotropism, alertness for the resulting neurological complications, and the recognition of neurological risk factors are crucial to reduce the workload on hospitals, particularly intensive-care units and neurological departments.

[Neurological aspects of the COVID-19 pandemic caused by the SARS-CoV-2 coronavirus]. / A SARS-CoV-2 koronavírus által okozott COVID-19-járvány neurológiai vonatkozásai.

By the spring of 2020 the COVID-19 outbreak caused by the new SARS-CoV-2 coronavirus has become a pandemic, requiring fast and efficient reaction from societies and health care systems all over the world. Fever, coughing and dyspnea are considered the major signs of COVID-19. In addition to the involvement of the respiratory system, the infection may result in other symptoms and signs as well. Based on reports to date, neurological signs or symptoms appear in 30-50% of hospitalized COVID-19 patients, with higher incidence in those with more severe disease. Classical acute neurological syndromes have also been reported to associate with COVID-19. A drop in the volume of services for other acute diseases has been described in countries with healthcare systems focusing on COVID-19. During the COVID-19 epidemic it is also important to provide appropriate continuous care for those with chronic neurological disorders. It will be the task of the future to estimate the collateral damage caused by the COVID-19 epidemic on the outcome of other neurological disorders, and to screen for the possible late neurological complications of the SARS-CoV-2 coronavirus infection.

COVID-19 and SARS-Cov-2 Infection: Pathophysiology and Clinical Effects on the Nervous System.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-Cov-2, resulting in severe acute respiratory syndrome, with high potential of spreading and infecting humans worldwide. Since December 2019, when the virus was identified in humans, the literature on COVID-19 has grown exponentially and extrarespiratory symptoms including neurologic symptoms are increasingly highlighted. METHODS: Given the high and increasing number of publications reporting neurologic involvements of SARS-Cov-2, we thought that providing an update for neurologic complications of COVID-19 would be useful for physicians and especially young trainees in neurology and neurosurgery. Indeed, in this review we discuss several neurologic aspects reported in the literature to date including the evidence and pathways of neuroinvasion in COVID-19 and the main neurologic disorders reported in the literature to date, as well as future perspectives and the potential long-term consequence of current neuroinfection in COVID-19 patients. RESULTS: Currently, there is convincing evidence that SARS-CoV-2, the etiologic agent of COVID-19, can affect the nervous system, with damage and neurologic alterations. These neurologic disorders are grouped into several categories, ranging from nonspecific and moderate symptoms such as headache, myalgia, and hyposmia to severe symptoms including cerebrovascular disease and intracranial infections. Severe neurologic symptoms such as acute cerebrovascular disease occur only in a minority of patients with usual risk factors and are associated with poor outcome. However, most COVID-19 patients exhibit only minor or mild neurologic symptoms. CONCLUSIONS: Management of COVID-19 patients should include early clinical, radiologic, and laboratory neurologic assessment, with a close follow-up, especially in severe forms. Future studies should assess late and long-term consequences of current COVID-19 patients with neurologic involvement.

COVID-19 and the nervous system.

A pandemic due to novel coronavirus arose in mid-December 2019 in Wuhan, China, and in 3 months' time swept the world. The disease has been referred to as COVID-19, and the causative agent has been labelled SARS-CoV-2 due to its genetic similarities to the virus (SARS-CoV-1) responsible for the severe acute respiratory syndrome (SARS) epidemic nearly 20 years earlier. The spike proteins of both viruses dictate tissue tropism using the angiotensin-converting enzyme type 2 (ACE-2) receptor to bind to cells. The ACE-2 receptor can be found in nervous system tissue and endothelial cells among the tissues of many other organs.Neurological complications have been observed with COVID-19. Myalgia and headache are relatively common, but serious neurological disease appears to be rare. No part of the neuraxis is spared. The neurological disorders occurring with COVID-19 may have many pathophysiological underpinnings. Some appear to be the consequence of direct viral invasion of the nervous system tissue, others arise as a postviral autoimmune process, and still others are the result of metabolic and systemic complications due to the associated critical illness. This review addresses the preliminary observations regarding the neurological disorders reported with COVID-19 to date and describes some of the disorders that are anticipated from prior experience with similar coronaviruses.

Neurotropic mechanisms in COVID-19 and their potential influence on neuropsychological outcomes in children.

Children have shown more physical resilience to COVID-19 than adults, but there is a cohort of vulnerable infants and young children who may experience disease burden, both in the acute phase and chronically. Children may have had early undocumented exposure to COVID-19. Even when the risk of exposure was known, developmental variables may have made the avoidance of physical proximity difficult for children. Preliminary hypotheses concerning neurotropic factors have been documented by researchers. Children with COVID-19 and comorbid physical or mental disorders may be vulnerable to exacerbations of neurotropic factors and comorbidities, the neural impact of which has been documented for other coronaviruses. Researchers are investigating COVID-19 symptom descriptions, neurotropic mechanisms at the genomic and transcriptomatic levels, neurological manifestations, and the impact of comorbid health complications. Neuropsychologists need information concerning the likely impact of COVID-19 on children. With a view toward that goal, this article provides recommendations for some initial updates in neuropsychology practice.

Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has caused a global pandemic in only 3 months. In addition to major respiratory distress, characteristic neurological manifestations are also described, indicating that SARS-CoV-2 may be an underestimated opportunistic pathogen of the brain. Based on previous studies of neuroinvasive human respiratory coronaviruses, it is proposed that after physical contact with the nasal mucosa, laryngopharynx, trachea, lower respiratory tract, alveoli epithelium, or gastrointestinal mucosa, SARS-CoV-2 can induce intrinsic and innate immune responses in the host involving increased cytokine release, tissue damage, and high neurosusceptibility to COVID-19, especially in the hypoxic conditions caused by lung injury. In some immune-compromised individuals, the virus may invade the brain through multiple routes, such as the vasculature and peripheral nerves. Therefore, in addition to drug treatments, such as pharmaceuticals and traditional Chinese medicine, non-pharmaceutical precautions, including facemasks and hand hygiene, are critically important.

Updates on What ACS Reported: Emerging Evidences of COVID-19 with Nervous System Involvement.

With the ongoing pandemic of coronavirus disease (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), our knowledge of the pathogenesis of COVID-19 is still in its infancy. Almost every aspect of the pathogen remains largely unknown, ranging from mechanisms involved in infection transmission, interplay with the human immune system, and covert mechanisms of end-organ damage. COVID-19 has manifested itself worldwide with a syndromic appearance that is dominated by respiratory dysregulations. While clinicians are focused on correcting respiratory homeostasis, echoing the original SARS, SARS-CoV-2 is also invading other end-organs, which may not exhibit overt clinical features. Nervous system involvement was not initially considered to play a significant role in patients with COVID-19. However, since this viewpoint was initially published, multiple studies have been released regarding the possible neurovirulence of SARS-CoV-2. In our previous viewpoint, we implored our colleagues to recognize the covert tactics of SARS-CoV-2 and emphasized that symptoms like anosmia, dysgeusia, ataxia, and altered mental status could be early signs of the neurotropic potential of this virus. The past few weeks, after the viewpoint surfaced, it was noticed that it has enabled clinicians and healthcare professionals to compute the neurovirulence associated with SARS-CoV-2 in COVID-19 patients, as evidenced by very recently reported studies.