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1.
J Gen Virol ; 102(10)2021 10.
Article in English | MEDLINE | ID: covidwho-1490495

ABSTRACT

The highly pathogenic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a severe respiratory virus. Recent reports indicate additional central nervous system (CNS) involvement. In this study, human DPP4 transgenic mice were infected with MERS-CoV, and viral antigens were first detected in the midbrain-hindbrain 4 days post-infection, suggesting the virus may enter the brainstem via peripheral nerves. Neurons and astrocytes throughout the brain were infected, followed by damage of the blood brain barrier (BBB), as well as microglial activation and inflammatory cell infiltration, which may be caused by complement activation based on the observation of deposition of complement activation product C3 and high expression of C3a receptor (C3aR) and C5a receptor (C5aR1) in neurons and glial cells. It may be concluded that these effects were mediated by complement activation in the brain, because of their reduction resulted from the treatment with mouse C5aR1-specific mAb. Such mAb significantly reduced nucleoprotein expression, suppressed microglial activation and decreased activation of caspase-3 in neurons and p38 phosphorylation in the brain. Collectively, these results suggest that MERS-CoV infection of CNS triggers complement activation, leading to inflammation-mediated damage of brain tissue, and regulating of complement activation could be a promising intervention and adjunctive treatment for CNS injury by MERS-CoV and other coronaviruses.


Subject(s)
Brain/pathology , Complement System Proteins/immunology , Coronavirus Infections/pathology , Dipeptidyl Peptidase 4/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/pathology , Brain/blood supply , Brain/immunology , Brain/virology , Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Models, Animal , Humans , Inflammation , Mice , Mice, Transgenic , Microglia/immunology , Microglia/pathology
2.
Neuropharmacology ; 201: 108841, 2021 12 15.
Article in English | MEDLINE | ID: covidwho-1466809

ABSTRACT

A strong association between perinatal viral infections and neurodevelopmental disorders has been established. Both the direct contact of the virus with the developing brain and the strong maternal immune response originated by viral infections can impair proper neurodevelopment. Coronavirus disease 2019 (COVID-19), caused by the highly-infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a large global outbreak and is a major public health issue. While initial studies focused on the viral impact on the respiratory system, increasing evidence suggest that SARS-CoV-2 infects other organs and tissues including the mature brain. While studies continue to determine the neuropathology associated to COVID-19, the consequences of SARS-CoV-2 infection to the developing brain remain largely unexplored. The present review discusses evidence suggesting that SARS-CoV-2 infection may have persistent effects on the course of pregnancy and on brain development. Studies have shown that several proinflammatory mediators which are increased in the SARS-CoV-2-associated cytokine storm, are also modified in other viral infections known to increase the risk of neurodevelopmental disorders. In this sense, further studies should assess the genuine effects of SARS-CoV-2 infection during pregnancy and delivery along with an extended follow-up of the offspring, including neurocognitive, neuroimaging, and electrophysiological examination. It also remains to be determined whether and by which mechanisms SARS-CoV-2 intrauterine and early life infection could lead to an increased risk of developing neuropsychiatric disorders, such as autism (ASD) and schizophrenia (SZ), in the offspring.


Subject(s)
Autism Spectrum Disorder/epidemiology , COVID-19/epidemiology , Cytokine Release Syndrome/epidemiology , Neurodevelopmental Disorders/epidemiology , Pregnancy Complications, Infectious/epidemiology , Prenatal Exposure Delayed Effects/epidemiology , Schizophrenia/epidemiology , Autism Spectrum Disorder/immunology , Brain/embryology , Brain/immunology , COVID-19/immunology , Cytokine Release Syndrome/immunology , Female , Humans , Infectious Disease Transmission, Vertical , Neurodevelopmental Disorders/immunology , Pregnancy , Pregnancy Complications, Infectious/immunology , Prenatal Exposure Delayed Effects/immunology , Risk Factors , SARS-CoV-2 , Schizophrenia/immunology
3.
J Neuroinflammation ; 18(1): 231, 2021 Oct 13.
Article in English | MEDLINE | ID: covidwho-1468067

ABSTRACT

It is well accepted that environmental stressors experienced over a one's life, from microbial infections to chemical toxicants to even psychological stressors, ultimately shape central nervous system (CNS) functioning but can also contribute to its eventual breakdown. The severity, timing and type of such environmental "hits", woven together with genetic factors, likely determine what CNS outcomes become apparent. This focused review assesses the current COVID-19 pandemic through the lens of a multi-hit framework and disuses how the SARS-COV-2 virus (causative agent) might impact the brain and potentially interact with other environmental insults. What the long-term consequences of SAR2 COV-2 upon neuronal processes is yet unclear, but emerging evidence is suggesting the possibility of microglial or other inflammatory factors as potentially contributing to neurodegenerative illnesses. Finally, it is critical to consider the impact of the virus in the context of the substantial psychosocial stress that has been associated with the global pandemic. Indeed, the loneliness, fear to the future and loss of social support alone has exerted a massive impact upon individuals, especially the vulnerable very young and the elderly. The substantial upswing in depression, anxiety and eating disorders is evidence of this and in the years to come, this might be matched by a similar spike in dementia, as well as motor and cognitive neurodegenerative diseases.


Subject(s)
COVID-19/immunology , Inflammation Mediators/immunology , Mental Disorders/immunology , Neurodegenerative Diseases/immunology , Neuroimmunomodulation/immunology , Animals , Brain/immunology , COVID-19/epidemiology , Humans , Immunotherapy/trends , Mental Disorders/epidemiology , Mental Disorders/therapy , Neurodegenerative Diseases/epidemiology , Neurodegenerative Diseases/therapy , Stress, Psychological/epidemiology , Stress, Psychological/immunology , Stress, Psychological/therapy
4.
Cells ; 10(7)2021 07 20.
Article in English | MEDLINE | ID: covidwho-1389305

ABSTRACT

Microglia are the resident immune cells of the central nervous system contributing substantially to health and disease. There is increasing evidence that inflammatory microglia may induce or accelerate brain aging, by interfering with physiological repair and remodeling processes. Many viral infections affect the brain and interfere with microglia functions, including human immune deficiency virus, flaviviruses, SARS-CoV-2, influenza, and human herpes viruses. Especially chronic viral infections causing low-grade neuroinflammation may contribute to brain aging. This review elucidates the potential role of various neurotropic viruses in microglia-driven neurocognitive deficiencies and possibly accelerated brain aging.


Subject(s)
Aging , Brain/physiopathology , Inflammation/physiopathology , Microglia/virology , Virus Diseases/physiopathology , Animals , Brain/immunology , Brain/virology , COVID-19/immunology , COVID-19/physiopathology , COVID-19/virology , Humans , Inflammation/immunology , Inflammation/virology , Microglia/immunology , Microglia/pathology , SARS-CoV-2/physiology , Virus Diseases/immunology , Virus Diseases/virology
5.
CNS Neurosci Ther ; 27(1): 36-47, 2021 01.
Article in English | MEDLINE | ID: covidwho-1388231

ABSTRACT

The blood-brain barrier (BBB) is an important physiological barrier that separates the central nervous system (CNS) from the peripheral circulation, which contains inflammatory mediators and immune cells. The BBB regulates cellular and molecular exchange between the blood vessels and brain parenchyma. Normal functioning of the BBB is crucial for the homeostasis and proper function of the brain. It has been demonstrated that peripheral inflammation can disrupt the BBB by various pathways, resulting in different CNS diseases. Recently, clinical research also showed CNS complications following SARS-CoV-2 infection and chimeric antigen receptor (CAR)-T cell therapy, which both lead to a cytokine storm in the circulation. Therefore, elucidation of the mechanisms underlying the BBB disruption induced by peripheral inflammation will provide an important basis for protecting the CNS in the context of exacerbated peripheral inflammatory diseases. In the present review, we first summarize the physiological properties of the BBB that makes the CNS an immune-privileged organ. We then discuss the relevance of peripheral inflammation-induced BBB disruption to various CNS diseases. Finally, we elaborate various factors and mechanisms of peripheral inflammation that disrupt the BBB.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , COVID-19/metabolism , Inflammation Mediators/metabolism , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/pathology , Brain/immunology , Brain/pathology , COVID-19/immunology , COVID-19/pathology , Endothelial Cells/immunology , Endothelial Cells/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Inflammation Mediators/immunology
6.
Front Immunol ; 12: 679425, 2021.
Article in English | MEDLINE | ID: covidwho-1344264

ABSTRACT

Gliomas are the most common primary brain tumors in adults. Despite the fact that they are relatively rare, they cause significant morbidity and mortality. High-grade gliomas or glioblastomas are rapidly progressing tumors with a very poor prognosis. The presence of an intrinsic immune system in the central nervous system is now more accepted. During the last decade, there has been no major progress in glioma therapy. The lack of effective treatment for gliomas can be explained by the strategies that cancer cells use to escape the immune system. This being said, immunotherapy, which involves blockade of immune checkpoint inhibitors, has improved patients' survival in different cancer types. This novel cancer therapy appears to be one of the most promising approaches. In the present study, we will start with a review of the general concept of immune response within the brain and glioma microenvironment. Then, we will try to decipher the role of various immune checkpoint inhibitors within the glioma microenvironment. Finally, we will discuss some promising therapeutic pathways, including immune checkpoint blockade and the body's effective anti-glioma immune response.


Subject(s)
Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Glioma/drug therapy , Glioma/pathology , Immune Checkpoint Inhibitors/therapeutic use , Tumor Microenvironment/drug effects , Biomarkers, Tumor , Brain/drug effects , Brain/immunology , Brain/metabolism , Brain/pathology , Brain Neoplasms/etiology , Brain Neoplasms/mortality , Disease Susceptibility , Glioma/etiology , Glioma/mortality , Humans , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Proteins/genetics , Immune Checkpoint Proteins/metabolism , Molecular Targeted Therapy , Prognosis , Treatment Outcome , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
7.
J Neuroimmunol ; 358: 577658, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1322224

ABSTRACT

Several neurological symptoms and complications have been described in association with COVID-19, such as anosmia, ageusia, encephalitis and Guillain-Barré syndrome. Here, we review the literature describing SARS-CoV-2-induced neurological manifestations and provide a comprehensive discussion of proposed mechanisms underlying the neurological pathophysiology. First, we analyse the neuroinvasiveness potential of the coronavirus family based on previous SARS-CoV-1 studies. Then, we describe the current evidence on COVID-19-induced nervous tissue damage, including processes behind brain vasculopathy and cytokine storm. We also discuss in detail anosmia and Guillain-Barré syndrome. Finally, we provide a summarised timeline of the main findings in the field. Future perspectives are presented, and suggestions of further investigations to clarify how SARS-COV-2 can affect the CNS.


Subject(s)
Brain/immunology , COVID-19/complications , COVID-19/immunology , Nervous System Diseases/etiology , Nervous System Diseases/immunology , SARS-CoV-2/immunology , Animals , Brain/pathology , COVID-19/diagnosis , Humans , Nervous System Diseases/diagnosis
8.
Inflammopharmacology ; 29(4): 1049-1059, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1303332

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can enter the central nervous system and cause several neurological manifestations. Data from cerebrospinal fluid analyses and postmortem samples have been shown that SARS-CoV-2 has neuroinvasive properties. Therefore, ongoing studies have focused on mechanisms involved in neurotropism and neural injuries of SARS-CoV-2. The inflammasome is a part of the innate immune system that is responsible for the secretion and activation of several pro-inflammatory cytokines, such as interleukin-1ß, interleukin-6, and interleukin-18. Since cytokine storm has been known as a major mechanism followed by SARS-CoV-2, inflammasome may trigger an inflammatory form of lytic programmed cell death (pyroptosis) following SARS-CoV-2 infection and contribute to associated neurological complications. We reviewed and discussed the possible role of inflammasome and its consequence pyroptosis following coronavirus infections as potential mechanisms of neurotropism by SARS-CoV-2. Further studies, particularly postmortem analysis of brain samples obtained from COVID-19 patients, can shed light on the possible role of the inflammasome in neurotropism of SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Central Nervous System/metabolism , Inflammasomes/metabolism , Pyroptosis/physiology , SARS-CoV-2/metabolism , Brain/immunology , Brain/metabolism , COVID-19/immunology , Central Nervous System/immunology , Humans , Inflammasomes/immunology , SARS-CoV-2/immunology
10.
Immunity ; 54(7): 1594-1610.e11, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1281436

ABSTRACT

COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear. Here, we interrogated the brain stems and olfactory bulbs in postmortem patients who had COVID-19 using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional, single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis, and control patients. We observed substantial immune activation in the central nervous system with pronounced neuropathology (astrocytosis, axonal damage, and blood-brain-barrier leakage) and detected viral antigen in ACE2-receptor-positive cells enriched in the vascular compartment. Microglial nodules and the perivascular compartment represented COVID-19-specific, microanatomic-immune niches with context-specific cellular interactions enriched for activated CD8+ T cells. Altered brain T-cell-microglial interactions were linked to clinical measures of systemic inflammation and disturbed hemostasis. This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.


Subject(s)
Brain/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Microglia/immunology , Blood-Brain Barrier/immunology , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Brain/metabolism , Brain/pathology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/pathology , Cell Communication , Central Nervous System/immunology , Central Nervous System/metabolism , Central Nervous System/pathology , Humans , Immune Checkpoint Proteins/metabolism , Inflammation , Lymphocyte Activation , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Olfactory Bulb/immunology , Olfactory Bulb/metabolism , Olfactory Bulb/pathology , Respiratory Insufficiency/immunology , Respiratory Insufficiency/pathology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
11.
Int J Mol Sci ; 22(9)2021 May 06.
Article in English | MEDLINE | ID: covidwho-1224026

ABSTRACT

In recent decades, researchers around the world have been studying intensively how micro-organisms that are present inside living organisms could affect the main processes of life, namely health and pathological conditions of mind or body. They discovered a relationship between the whole microbial colonization and the initiation and development of different medical disorders. Besides already known probiotics, novel products such as postbiotics and paraprobiotics have been developed in recent years to create new non-viable micro-organisms or bacterial-free extracts, which can provide benefits to the host with additional bioactivity to probiotics, but without the risk of side effects. The best alternatives in the use of probiotics and postbiotics to maintain the health of the intestinal microbiota and to prevent the attachment of pathogens to children and adults are highlighted and discussed as controversies and challenges. Updated knowledge of the molecular and cellular mechanisms involved in the balance between microbiota and immune system for the introspection on the gut-lung-brain axis could reveal the latest benefits and perspectives of applied photobiomics for health. Multiple interconditioning between photobiomodulation (PBM), probiotics, and the human microbiota, their effects on the human body, and their implications for the management of viral infectious diseases is essential. Coupled complex PBM and probiotic interventions can control the microbiome, improve the activity of the immune system, and save the lives of people with immune imbalances. There is an urgent need to seek and develop innovative treatments to successfully interact with the microbiota and the human immune system in the coronavirus crisis. In the near future, photobiomics and metabolomics should be applied innovatively in the SARS-CoV-2 crisis (to study and design new therapies for COVID-19 immediately), to discover how bacteria can help us through adequate energy biostimulation to combat this pandemic, so that we can find the key to the hidden code of communication between RNA viruses, bacteria, and our body.


Subject(s)
COVID-19/immunology , COVID-19/microbiology , Gastrointestinal Microbiome/immunology , Low-Level Light Therapy/methods , Probiotics/therapeutic use , SARS-CoV-2/immunology , Brain/immunology , Brain/radiation effects , COVID-19/radiotherapy , COVID-19/therapy , Cytokine Release Syndrome/microbiology , Cytokine Release Syndrome/radiotherapy , Gastrointestinal Microbiome/radiation effects , Humans , Lung/immunology , Lung/radiation effects , Metabolomics , Phototherapy/methods , SARS-CoV-2/radiation effects
12.
Inflammopharmacology ; 29(4): 939-963, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1169006

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) first discovered in Wuhan, Hubei province, China in December 2019. SARS-CoV-2 has infected several millions of people, resulting in a huge socioeconomic cost and over 2.5 million deaths worldwide. Though the pathogenesis of COVID-19 is not fully understood, data have consistently shown that SARS-CoV-2 mainly affects the respiratory and gastrointestinal tracts. Nevertheless, accumulating evidence has implicated the central nervous system in the pathogenesis of SARS-CoV-2 infection. Unfortunately, however, the mechanisms of SARS-CoV-2 induced impairment of the central nervous system are not completely known. Here, we review the literature on possible neuropathogenic mechanisms of SARS-CoV-2 induced cerebral damage. The results suggest that downregulation of angiotensin converting enzyme 2 (ACE2) with increased activity of the transmembrane protease serine 2 (TMPRSS2) and cathepsin L in SARS-CoV-2 neuroinvasion may result in upregulation of proinflammatory mediators and reactive species that trigger neuroinflammatory response and blood brain barrier disruption. Furthermore, dysregulation of hormone and neurotransmitter signalling may constitute a fundamental mechanism involved in the neuropathogenic sequelae of SARS-CoV-2 infection. The viral RNA or antigenic peptides also activate or interact with molecular signalling pathways mediated by pattern recognition receptors (e.g., toll-like receptors), nuclear factor kappa B, Janus kinase/signal transducer and activator of transcription, complement cascades, and cell suicide molecules. Potential molecular targets and therapeutics of SARS-CoV-2 induced neurologic damage are also discussed.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , COVID-19/metabolism , Inflammation Mediators/metabolism , SARS-CoV-2/metabolism , Blood-Brain Barrier/immunology , Blood-Brain Barrier/pathology , Brain/immunology , Brain/pathology , COVID-19/immunology , COVID-19/pathology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/pathology , Humans , Inflammation Mediators/immunology , SARS-CoV-2/immunology , Signal Transduction/physiology
14.
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
15.
Rev Med Virol ; 31(6): e2227, 2021 11.
Article in English | MEDLINE | ID: covidwho-1148855

ABSTRACT

Severe acute respiratory syndrome related coronavirus-2 (SARS-CoV-2) is the cause of Covid-19 which was classified as a global pandemic in March 2020. The increasing global health and economic burden of SARS-CoV-2 has necessitated urgent investigations into the pathogenesis of disease and development of therapeutic and vaccination regimens. Human trials of vaccine and antiviral candidates have been undertaken, but basic pathogenetic studies are still required to inform these trials. Gaps in understanding of cellular infection by, and immunity to, SARS-CoV-2 mean additional models are required to assist in improved design of these therapeutics. Human organoids are three-dimensional models that contain multiple cell types and mimic human organs in ex vivo culture conditions. The SARS-CoV-2 virus has been implicated in causing not only respiratory injury but also injury to other organs such as the brain, liver and kidneys. Consequently, a variety of different organoid models have been employed to investigate the pathogenic mechanisms of disease due to SARS-CoV-2. Data on these models have not been systematically assembled. In this review, we highlight key findings from studies that have utilised different human organoid types to investigate the expression of SARS-CoV-2 receptors, permissiveness, immune response, dysregulation of cellular functions, and potential antiviral therapeutics.


Subject(s)
Host-Pathogen Interactions/immunology , Models, Biological , Organoids/immunology , Receptors, Virus/antagonists & inhibitors , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Antiviral Agents/pharmacology , Brain/drug effects , Brain/immunology , Brain/virology , COVID-19/drug therapy , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cell Culture Techniques , Colon/drug effects , Colon/immunology , Colon/virology , Cytokines/genetics , Cytokines/immunology , Host-Pathogen Interactions/drug effects , Humans , Liver/drug effects , Liver/immunology , Liver/virology , Lung/drug effects , Lung/immunology , Lung/virology , Organoids/drug effects , Organoids/virology , Receptors, Virus/genetics , Receptors, Virus/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
16.
Transl Psychiatry ; 11(1): 179, 2021 03 19.
Article in English | MEDLINE | ID: covidwho-1142427

ABSTRACT

Microglia, the resident brain immune cells, play a critical role in normal brain development, and are impacted by the intrauterine environment, including maternal immune activation and inflammatory exposures. The COVID-19 pandemic presents a potential developmental immune challenge to the fetal brain, in the setting of maternal SARS-CoV-2 infection with its attendant potential for cytokine production and, in severe cases, cytokine storming. There is currently no biomarker or model for in utero microglial priming and function that might aid in identifying the neonates and children most vulnerable to neurodevelopmental morbidity, as microglia remain inaccessible in fetal life and after birth. This study aimed to generate patient-derived microglial-like cell models unique to each neonate from reprogrammed umbilical cord blood mononuclear cells, adapting and extending a novel methodology previously validated for adult peripheral blood mononuclear cells. We demonstrate that umbilical cord blood mononuclear cells can be used to create microglial-like cell models morphologically and functionally similar to microglia observed in vivo. We illustrate the application of this approach by generating microglia from cells exposed and unexposed to maternal SARS-CoV-2 infection. Our ability to create personalized neonatal models of fetal brain immune programming enables non-invasive insights into fetal brain development and potential childhood neurodevelopmental vulnerabilities for a range of maternal exposures, including COVID-19.


Subject(s)
Brain/growth & development , Brain/immunology , COVID-19/immunology , Cellular Reprogramming , Fetal Blood/immunology , Induced Pluripotent Stem Cells , Leukocytes, Mononuclear/immunology , Microglia/immunology , Pregnancy Complications, Infectious/immunology , Adult , Female , Humans , Infant, Newborn , Pregnancy
17.
Neuroimmunomodulation ; 28(1): 22-28, 2021.
Article in English | MEDLINE | ID: covidwho-1059821

ABSTRACT

COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) betacoronavirus, affects children in a different way than it does in adults, with milder symptoms. However, several cases of neurological symptoms with neuroinflammatory syndromes, such as the multisystem inflammatory syndrome (MIS-C), following mild cases, have been reported. As with other viral infections, such as rubella, influenza, and cytomegalovirus, SARS-CoV-2 induces a surge of proinflammatory cytokines that affect microglial function, which can be harmful to brain development. Along with the viral induction of neuroinflammation, other noninfectious conditions may interact to produce additional inflammation, such as the nutritional imbalance of fatty acids and polyunsaturated fatty acids and alcohol consumption during pregnancy. Additionally, transient thyrotoxicosis induced by SARS-CoV-2 with secondary autoimmune hypothyroidism has been reported, which could go undetected during pregnancy. Together, those factors may pose additional risk factors for SARS-CoV-2 infection impacting mechanisms of neural development such as synaptic pruning and neural circuitry formation. The present review discusses those conditions in the perspective of the understanding of risk factors that should be considered and the possible emergence of neurodevelopmental disorders in COVID-19-infected children.


Subject(s)
Brain/growth & development , COVID-19/immunology , Inflammation/immunology , Microglia/immunology , Neurodevelopmental Disorders/immunology , Brain/immunology , Brain/physiopathology , COVID-19/physiopathology , Diet , Dietary Fats, Unsaturated , Fatty Acids, Unsaturated , Fetal Alcohol Spectrum Disorders/immunology , Fetal Alcohol Spectrum Disorders/physiopathology , Humans , Inflammation/physiopathology , Neurodevelopmental Disorders/physiopathology , Neuronal Plasticity , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Systemic Inflammatory Response Syndrome
18.
Nature ; 590(7844): 29-31, 2021 02.
Article in English | MEDLINE | ID: covidwho-1038200
19.
CNS Neurosci Ther ; 27(1): 36-47, 2021 01.
Article in English | MEDLINE | ID: covidwho-1003961

ABSTRACT

The blood-brain barrier (BBB) is an important physiological barrier that separates the central nervous system (CNS) from the peripheral circulation, which contains inflammatory mediators and immune cells. The BBB regulates cellular and molecular exchange between the blood vessels and brain parenchyma. Normal functioning of the BBB is crucial for the homeostasis and proper function of the brain. It has been demonstrated that peripheral inflammation can disrupt the BBB by various pathways, resulting in different CNS diseases. Recently, clinical research also showed CNS complications following SARS-CoV-2 infection and chimeric antigen receptor (CAR)-T cell therapy, which both lead to a cytokine storm in the circulation. Therefore, elucidation of the mechanisms underlying the BBB disruption induced by peripheral inflammation will provide an important basis for protecting the CNS in the context of exacerbated peripheral inflammatory diseases. In the present review, we first summarize the physiological properties of the BBB that makes the CNS an immune-privileged organ. We then discuss the relevance of peripheral inflammation-induced BBB disruption to various CNS diseases. Finally, we elaborate various factors and mechanisms of peripheral inflammation that disrupt the BBB.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , COVID-19/metabolism , Inflammation Mediators/metabolism , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/pathology , Brain/immunology , Brain/pathology , COVID-19/immunology , COVID-19/pathology , Endothelial Cells/immunology , Endothelial Cells/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Inflammation Mediators/immunology
20.
Molecules ; 25(21)2020 Oct 22.
Article in English | MEDLINE | ID: covidwho-983191

ABSTRACT

Inflammation is a biological response to the activation of the immune system by various infectious or non-infectious agents, which may lead to tissue damage and various diseases. Gut commensal bacteria maintain a symbiotic relationship with the host and display a critical function in the homeostasis of the host immune system. Disturbance to the gut microbiota leads to immune dysfunction both locally and at distant sites, which causes inflammatory conditions not only in the intestine but also in the other organs such as lungs and brain, and may induce a disease state. Probiotics are well known to reinforce immunity and counteract inflammation by restoring symbiosis within the gut microbiota. As a result, probiotics protect against various diseases, including respiratory infections and neuroinflammatory disorders. A growing body of research supports the beneficial role of probiotics in lung and mental health through modulating the gut-lung and gut-brain axes. In the current paper, we discuss the potential role of probiotics in the treatment of viral respiratory infections, including the COVID-19 disease, as major public health crisis in 2020, and influenza virus infection, as well as treatment of neurological disorders like multiple sclerosis and other mental illnesses.


Subject(s)
Coronavirus Infections/therapy , Influenza, Human/therapy , Mental Disorders/therapy , Multiple Sclerosis/therapy , Pneumonia, Viral/therapy , Probiotics/therapeutic use , Respiratory Tract Infections/therapy , Betacoronavirus/drug effects , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , Brain/immunology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/microbiology , Coronavirus Infections/virology , Gastrointestinal Microbiome/immunology , Gastrointestinal Tract/immunology , Gastrointestinal Tract/microbiology , Humans , Immunomodulation , Influenza, Human/immunology , Influenza, Human/microbiology , Influenza, Human/virology , Lung/immunology , Mental Disorders/immunology , Mental Disorders/microbiology , Microbial Consortia/immunology , Multiple Sclerosis/immunology , Multiple Sclerosis/microbiology , Orthomyxoviridae/drug effects , Orthomyxoviridae/pathogenicity , Orthomyxoviridae/physiology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/microbiology , Pneumonia, Viral/virology , Respiratory Tract Infections/immunology , Respiratory Tract Infections/microbiology , SARS-CoV-2 , Symbiosis/immunology
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