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1.
J Virol ; 96(4): e0196921, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1702819

ABSTRACT

Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited antiviral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, ∼50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19) and cytokine (Ifn-λ and Tnf-α) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease. IMPORTANCE Understanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , COVID-19/immunology , Central Nervous System Viral Diseases/immunology , Microglia/immunology , SARS-CoV-2/physiology , Virus Replication/immunology , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , Central Nervous System/immunology , Central Nervous System/virology , Central Nervous System Viral Diseases/genetics , Central Nervous System Viral Diseases/virology , Chemokines/genetics , Chemokines/immunology , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Microglia/virology , Neurons/immunology , Neurons/virology , Virus Replication/genetics
2.
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
3.
J Neuroimmunol ; 361: 577728, 2021 12 15.
Article in English | MEDLINE | ID: covidwho-1440213

ABSTRACT

We herein report, by using confocal immunofluorescence, the colocalization of the SARS-CoV-2 nucleocapsid within neurons, astrocytes, oligodendrocytes and microglia in three deceased COVID-19 cases, of between 78 and 85 years of age at death. The viral nucleocapsid was detected together with its ACE2 cell entry receptor, as well as the NLRP3 inflammasome in cerebral cortical tissues. It is noteworthy that NLRP3 was colocalized with CD68 + macrophages in the brain and lung of the deceased, suggesting the critical role of this type of inflammasome in SARS-CoV-2 lesions of the nervous system/lungs and supporting its potential role as a therapeutic target.


Subject(s)
Brain/virology , COVID-19/virology , Inflammasomes/immunology , Microglia/virology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , SARS-CoV-2/pathogenicity , Aged , Aged, 80 and over , Astrocytes/virology , Autopsy , Brain/immunology , Brain/pathology , COVID-19/immunology , COVID-19/pathology , Female , Humans , Male , Microglia/immunology , Neurons/virology , Nucleocapsid , Oligodendroglia/virology
4.
Front Immunol ; 12: 730088, 2021.
Article in English | MEDLINE | ID: covidwho-1394763

ABSTRACT

In December 2019, a new viral disease emerged and quickly spread all around the world. In March 2020, the COVID-19 outbreak was classified as a global pandemic and by June 2021, the number of infected people grew to over 170 million. Along with the patients' mild-to-severe respiratory symptoms, reports on probable central nervous system (CNS) effects appeared shortly, raising concerns about the possible long-term detrimental effects on human cognition. It remains unresolved whether the neurological symptoms are caused directly by the SARS-CoV-2 infiltration in the brain, indirectly by secondary immune effects of a cytokine storm and antibody overproduction, or as a consequence of systemic hypoxia-mediated microglia activation. In severe COVID-19 cases with impaired lung capacity, hypoxia is an anticipated subsidiary event that can cause progressive and irreversible damage to neurons. To resolve this problem, intensive research is currently ongoing, which seeks to evaluate the SARS-CoV-2 virus' neuroinvasive potential and the examination of the antibody and autoantibody generation upon infection, as well as the effects of prolonged systemic hypoxia on the CNS. In this review, we summarize the current research on the possible interplay of the SARS-CoV-2 effects on the lung, especially on alveolar macrophages and direct and indirect effects on the brain, with special emphasis on microglia, as a possible culprit of neurological manifestation during COVID-19.


Subject(s)
COVID-19/complications , Central Nervous System Infections/complications , Central Nervous System Infections/virology , Lung/virology , SARS-CoV-2/pathogenicity , COVID-19/immunology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Humans , Lung/immunology , Microglia/immunology , Microglia/pathology , Microglia/virology , Nervous System Diseases/virology , SARS-CoV-2/immunology
5.
Front Immunol ; 11: 565521, 2020.
Article in English | MEDLINE | ID: covidwho-1389164

ABSTRACT

Neurological disorders caused by neuroviral infections are an obvious pathogenic manifestation. However, non-neurotropic viruses or peripheral viral infections pose a considerable challenge as their neuropathological manifestations do not emerge because of primary infection. Their secondary or bystander pathologies develop much later, like a syndrome, during and after the recovery of patients from the primary disease. Massive inflammation caused by peripheral viral infections can trigger multiple neurological anomalies. These neurological damages may range from a general cognitive and motor dysfunction up to a wide spectrum of CNS anomalies, such as Acute Necrotizing Hemorrhagic Encephalopathy, Guillain-Barré syndrome, Encephalitis, Meningitis, anxiety, and other audio-visual disabilities. Peripheral viruses like Measles virus, Enteroviruses, Influenza viruses (HIN1 series), SARS-CoV-1, MERS-CoV, and, recently, SARS-CoV-2 are reported to cause various neurological manifestations in patients and are proven to be neuropathogenic even in cellular and animal model systems. This review presents a comprehensive picture of CNS susceptibilities toward these peripheral viral infections and explains some common underlying themes of their neuropathology in the human brain.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/complications , Coronavirus Infections/immunology , Middle East Respiratory Syndrome Coronavirus/immunology , Neurogenic Inflammation/complications , Neurogenic Inflammation/immunology , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , SARS Virus/immunology , Severe Acute Respiratory Syndrome/complications , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/virology , COVID-19 , Coronavirus Infections/virology , Cytokines/blood , Disease Models, Animal , Humans , Microglia/immunology , Microglia/virology , Neurogenic Inflammation/virology , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology
6.
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
7.
Cell Chem Biol ; 29(2): 239-248.e4, 2022 02 17.
Article in English | MEDLINE | ID: covidwho-1347527

ABSTRACT

Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease-associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. Here, we report that TREM2 is a thyroid hormone-regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone and synthetic thyroid hormone agonists (thyromimetics). Our findings report the endocrine regulation of TREM2 by thyroid hormone, and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small-molecule therapeutic agents.


Subject(s)
Acetates/pharmacology , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Membrane Glycoproteins/genetics , Microglia/drug effects , Phenols/pharmacology , Receptors, Immunologic/genetics , Retinoid X Receptors/genetics , Thyroid Hormones/pharmacology , Acetates/chemical synthesis , Animals , Binding Sites , Brain/drug effects , Brain/immunology , Brain/pathology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Gene Expression Regulation , Humans , Immunity, Innate , Macrophages/drug effects , Macrophages/immunology , Macrophages/pathology , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/immunology , Mice , Mice, Inbred C57BL , Microglia/immunology , Microglia/pathology , Models, Molecular , Phenols/chemical synthesis , Phenoxyacetates/pharmacology , Promoter Regions, Genetic , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/genetics , RNA, Messenger/immunology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/immunology , Response Elements , Retinoid X Receptors/chemistry , Retinoid X Receptors/metabolism , Signal Transduction
8.
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
10.
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
11.
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
14.
Glia ; 68(11): 2345-2360, 2020 11.
Article in English | MEDLINE | ID: covidwho-361267

ABSTRACT

The present study examines functional contributions of microglia in host defense, demyelination, and remyelination following infection of susceptible mice with a neurotropic coronavirus. Treatment with PLX5622, an inhibitor of colony stimulating factor 1 receptor (CSF1R) that efficiently depletes microglia, prior to infection of the central nervous system (CNS) with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in increased mortality compared with control mice that correlated with impaired control of viral replication. Single cell RNA sequencing (scRNASeq) of CD45+ cells isolated from the CNS revealed that PLX5622 treatment resulted in muted CD4+ T cell activation profile that was associated with decreased expression of transcripts encoding MHC class II and CD86 in macrophages but not dendritic cells. Evaluation of spinal cord demyelination revealed a marked increase in white matter damage in PLX5622-treated mice that corresponded with elevated expression of transcripts encoding disease-associated proteins Osteopontin (Spp1), Apolipoprotein E (Apoe), and Triggering receptor expressed on myeloid cells 2 (Trem2) that were enriched within macrophages. In addition, PLX5622 treatment dampened expression of Cystatin F (Cst7), Insulin growth factor 1 (Igf1), and lipoprotein lipase (Lpl) within macrophage populations which have been implicated in promoting repair of damaged nerve tissue and this was associated with impaired remyelination. Collectively, these findings argue that microglia tailor the CNS microenvironment to enhance control of coronavirus replication as well as dampen the severity of demyelination and influence repair.


Subject(s)
Brain/immunology , Coronavirus Infections/immunology , Host-Pathogen Interactions/immunology , Microglia/immunology , Murine hepatitis virus/immunology , Organic Chemicals/toxicity , Animals , Brain/drug effects , Brain/virology , Coronavirus Infections/chemically induced , Host-Pathogen Interactions/drug effects , Immunity, Cellular/drug effects , Immunity, Cellular/immunology , Male , Mice , Mice, Inbred C57BL , Microglia/drug effects , Microglia/virology
15.
Exp Mol Pathol ; 115: 104474, 2020 08.
Article in English | MEDLINE | ID: covidwho-343529

ABSTRACT

The pathogenesis of viral infections involves an immune response by cytokines, causing a deleterious effect on organ function, in addition to tissue destruction due to viral replication. Clinical symptoms and laboratory findings of the human coronavirus disease COVID-19, caused by the novel coronavirus SARS CoV-2, indicate cytokine involvement. Our laboratory showed that an experimental murine coronavirus (MHV-A59) can be transmitted into the brain by intranasal or intracerebral exposure and that neurovirulence is mediated by cytokine secretion. In this study we investigated which cells in the brain produce cytokines, thus functioning as the brain's innate immune system. Using tissue cultures of microglia, and clonal populations of astrocytes, we found that microglia and type I astrocytes (but not types II and III), produced pro-inflammatory cytokines in response to MHV-A59 infection. A molecularly closely related, non-encephalitic strain of the virus (MHV-2) caused in vitro infection, but without cytokine induction. Furthermore, immunofluorescence and immunohistochemistry revealed that type I astrocytes and microglia have perivascular foot processes necessary for the formation of the perivascular glymphatic system, the anatomical site of the brain's innate immune system. Cytokine secretion by type I astrocytes and microglia, as part of the brain's glymphatic and innate immune system, contributes to the pathogenesis of an encephalitic coronavirus infection, and indicates the rationale for anti-cytokine therapies for COVID-19.


Subject(s)
Coronavirus Infections/immunology , Coronavirus Infections/transmission , Murine hepatitis virus/metabolism , Animals , Astrocytes/immunology , Betacoronavirus , Brain/immunology , Brain/pathology , COVID-19 , Cell Line , Cells, Cultured , Coronavirus/metabolism , Coronavirus Infections/virology , Cytokines/immunology , Humans , Mice , Microglia/immunology , Murine hepatitis virus/immunology , Murine hepatitis virus/pathogenicity , Pandemics , Pneumonia, Viral , SARS-CoV-2 , Virus Replication/immunology , Virus Replication/physiology
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