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1.
PLoS One ; 16(11): e0258645, 2021.
Article in English | MEDLINE | ID: covidwho-1518355

ABSTRACT

All approved coronavirus disease 2019 (COVID-19) vaccines in current use are safe, effective, and reduce the risk of severe illness. Although data on the immunological presentation of patients with COVID-19 is limited, increasing experimental evidence supports the significant contribution of B and T cells towards the resolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Despite the availability of several COVID-19 vaccines with high efficacy, more effective vaccines are still needed to protect against the new variants of SARS-CoV-2. Employing a comprehensive immunoinformatic prediction algorithm and leveraging the genetic closeness with SARS-CoV, we have predicted potential immune epitopes in the structural proteins of SARS-CoV-2. The S and N proteins of SARS-CoV-2 and SARS-CoVs are main targets of antibody detection and have motivated us to design four multi-epitope vaccines which were based on our predicted B- and T-cell epitopes of SARS-CoV-2 structural proteins. The cardinal epitopes selected for the vaccine constructs are predicted to possess antigenic, non-allergenic, and cytokine-inducing properties. Additionally, some of the predicted epitopes have been experimentally validated in published papers. Furthermore, we used the C-ImmSim server to predict effective immune responses induced by the epitope-based vaccines. Taken together, the immune epitopes predicted in this study provide a platform for future experimental validations which may facilitate the development of effective vaccine candidates and epitope-based serological diagnostic assays.


Subject(s)
Computational Biology , Epitope Mapping , SARS-CoV-2/immunology , Viral Structural Proteins/immunology , Amino Acid Sequence , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Databases as Topic , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/immunology , Histocompatibility Antigens Class I/metabolism , Humans , Models, Molecular , Protein Conformation , Reproducibility of Results , Viral Structural Proteins/chemistry
2.
Int J Mol Sci ; 22(6)2021 Mar 17.
Article in English | MEDLINE | ID: covidwho-1389395

ABSTRACT

As an essential modulator of IgG disposition, the neonatal Fc receptor (FcRn) governs the pharmacokinetics and functions many therapeutic modalities. In this review, we thoroughly reexamine the hitherto elucidated biological and thermodynamic properties of FcRn to provide context for our assessment of more recent advances, which covers antigen-binding fragment (Fab) determinants of FcRn affinity, transgenic preclinical models, and FcRn targeting as an immune-complex (IC)-clearing strategy. We further comment on therapeutic antibodies authorized for treating SARS-CoV-2 (bamlanivimab, casirivimab, and imdevimab) and evaluate their potential to saturate FcRn-mediated recycling. Finally, we discuss modeling and simulation studies that probe the quantitative relationship between in vivo IgG persistence and in vitro FcRn binding, emphasizing the importance of endosomal transit parameters.


Subject(s)
Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/metabolism , Receptors, Fc/chemistry , Receptors, Fc/metabolism , Animals , Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal/pharmacokinetics , COVID-19/drug therapy , Histocompatibility Antigens Class I/immunology , Humans , Immunoglobulin G/immunology , Immunoglobulin G/metabolism , Receptors, Fc/immunology , Tissue Distribution/immunology
3.
Int J Mol Sci ; 22(13)2021 Jun 22.
Article in English | MEDLINE | ID: covidwho-1304657

ABSTRACT

The innate immune system's natural killer (NK) cells exert their cytolytic function against a variety of pathological challenges, including tumors and virally infected cells. Their activation depends on net signaling mediated via inhibitory and activating receptors that interact with specific ligands displayed on the surfaces of target cells. The CD94/NKG2C heterodimer is one of the NK activating receptors and performs its function by interacting with the trimeric ligand comprised of the HLA-E/ß2m/nonameric peptide complex. Here, simulations of the all-atom multi-microsecond molecular dynamics in five immune complexes provide atomistic insights into the receptor-ligand molecular recognition, as well as the molecular events that facilitate the NK cell activation. We identify NKG2C, the HLA-Eα2 domain, and the nonameric peptide as the key elements involved in the molecular machinery of signal transduction via an intertwined hydrogen bond network. Overall, the study addresses the complex intricacies that are necessary to understand the mechanisms of the innate immune system.


Subject(s)
Antigen-Antibody Complex/chemistry , Histocompatibility Antigens Class I/chemistry , Models, Molecular , NK Cell Lectin-Like Receptor Subfamily C/chemistry , NK Cell Lectin-Like Receptor Subfamily D/chemistry , Peptides/chemistry , Amino Acid Sequence , Antigen-Antibody Complex/immunology , Antigen-Antibody Complex/metabolism , Binding Sites , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , Humans , Hydrogen Bonding , Ligands , NK Cell Lectin-Like Receptor Subfamily C/metabolism , NK Cell Lectin-Like Receptor Subfamily D/metabolism , Peptides/metabolism , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , Signal Transduction , Structure-Activity Relationship
4.
Genome Med ; 13(1): 101, 2021 06 14.
Article in English | MEDLINE | ID: covidwho-1269888

ABSTRACT

BACKGROUND: Early in the pandemic, we designed a SARS-CoV-2 peptide vaccine containing epitope regions optimized for concurrent B cell, CD4+ T cell, and CD8+ T cell stimulation. The rationale for this design was to drive both humoral and cellular immunity with high specificity while avoiding undesired effects such as antibody-dependent enhancement (ADE). METHODS: We explored the set of computationally predicted SARS-CoV-2 HLA-I and HLA-II ligands, examining protein source, concurrent human/murine coverage, and population coverage. Beyond MHC affinity, T cell vaccine candidates were further refined by predicted immunogenicity, sequence conservation, source protein abundance, and coverage of high frequency HLA alleles. B cell epitope regions were chosen from linear epitope mapping studies of convalescent patient serum, followed by filtering for surface accessibility, sequence conservation, spatial localization near functional domains of the spike glycoprotein, and avoidance of glycosylation sites. RESULTS: From 58 initial candidates, three B cell epitope regions were identified. From 3730 (MHC-I) and 5045 (MHC-II) candidate ligands, 292 CD8+ and 284 CD4+ T cell epitopes were identified. By combining these B cell and T cell analyses, as well as a manufacturability heuristic, we proposed a set of 22 SARS-CoV-2 vaccine peptides for use in subsequent murine studies. We curated a dataset of ~ 1000 observed T cell epitopes from convalescent COVID-19 patients across eight studies, showing 8/15 recurrent epitope regions to overlap with at least one of our candidate peptides. Of the 22 candidate vaccine peptides, 16 (n = 10 T cell epitope optimized; n = 6 B cell epitope optimized) were manually selected to decrease their degree of sequence overlap and then synthesized. The immunogenicity of the synthesized vaccine peptides was validated using ELISpot and ELISA following murine vaccination. Strong T cell responses were observed in 7/10 T cell epitope optimized peptides following vaccination. Humoral responses were deficient, likely due to the unrestricted conformational space inhabited by linear vaccine peptides. CONCLUSIONS: Overall, we find our selection process and vaccine formulation to be appropriate for identifying T cell epitopes and eliciting T cell responses against those epitopes. Further studies are needed to optimize prediction and induction of B cell responses, as well as study the protective capacity of predicted T and B cell epitopes.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Computational Biology/methods , Epitopes, B-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/chemistry , Amino Acid Sequence , Animals , COVID-19/virology , COVID-19 Vaccines/chemistry , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , Female , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/metabolism , Histocompatibility Antigens Class II/chemistry , Histocompatibility Antigens Class II/metabolism , Humans , Male , Mice , Mice, Inbred BALB C , Peptides/chemistry , Peptides/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology
5.
JAMA Neurol ; 78(8): 948-960, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1265359

ABSTRACT

Importance: Myalgia, increased levels of creatine kinase, and persistent muscle weakness have been reported in patients with COVID-19. Objective: To study skeletal muscle and myocardial inflammation in patients with COVID-19 who had died. Design, Setting, and Participants: This case-control autopsy series was conducted in a university hospital as a multidisciplinary postmortem investigation. Patients with COVID-19 or other critical illnesses who had died between March 2020 and February 2021 and on whom an autopsy was performed were included. Individuals for whom informed consent to autopsy was available and the postmortem interval was less than 6 days were randomly selected. Individuals who were infected with SARS-CoV-2 per polymerase chain reaction test results and had clinical features suggestive of COVID-19 were compared with individuals with negative SARS-CoV-2 polymerase chain reaction test results and an absence of clinical features suggestive of COVID-19. Main Outcomes and Measures: Inflammation of skeletal muscle tissue was assessed by quantification of immune cell infiltrates, expression of major histocompatibility complex (MHC) class I and class II antigens on the sarcolemma, and a blinded evaluation on a visual analog scale ranging from absence of pathology to the most pronounced pathology. Inflammation of cardiac muscles was assessed by quantification of immune cell infiltrates. Results: Forty-three patients with COVID-19 (median [interquartile range] age, 72 [16] years; 31 men [72%]) and 11 patients with diseases other than COVID-19 (median [interquartile range] age, 71 [5] years; 7 men [64%]) were included. Skeletal muscle samples from the patients who died with COVID-19 showed a higher overall pathology score (mean [SD], 3.4 [1.8] vs 1.5 [1.0]; 95% CI, 0-3; P < .001) and a higher inflammation score (mean [SD], 3.5 [2.1] vs 1.0 [0.6]; 95% CI, 0-4; P < .001). Relevant expression of MHC class I antigens on the sarcolemma was present in 23 of 42 specimens from patients with COVID-19 (55%) and upregulation of MHC class II antigens in 7 of 42 specimens from patients with COVID-19 (17%), but neither were found in any of the controls. Increased numbers of natural killer cells (median [interquartile range], 8 [8] vs 3 [4] cells per 10 high-power fields; 95% CI, 1-10 cells per 10 high-power fields; P < .001) were found. Skeletal muscles showed more inflammatory features than cardiac muscles, and inflammation was most pronounced in patients with COVID-19 with chronic courses. In some muscle specimens, SARS-CoV-2 RNA was detected by reverse transcription-polymerase chain reaction, but no evidence for a direct viral infection of myofibers was found by immunohistochemistry and electron microscopy. Conclusions and Relevance: In this case-control study of patients who had died with and without COVID-19, most individuals with severe COVID-19 showed signs of myositis ranging from mild to severe. Inflammation of skeletal muscles was associated with the duration of illness and was more pronounced than cardiac inflammation. Detection of viral load was low or negative in most skeletal and cardiac muscles and probably attributable to circulating viral RNA rather than genuine infection of myocytes. This suggests that SARS-CoV-2 may be associated with a postinfectious, immune-mediated myopathy.


Subject(s)
COVID-19/pathology , Muscle, Skeletal/pathology , Myocarditis/pathology , Myocardium/pathology , Myositis/pathology , Aged , Aged, 80 and over , Autopsy , CD8-Positive T-Lymphocytes/pathology , COVID-19/metabolism , COVID-19 Nucleic Acid Testing , COVID-19 Serological Testing , Case-Control Studies , Female , Histocompatibility Antigens Class I/metabolism , Histocompatibility Antigens Class II/metabolism , Humans , Killer Cells, Natural/pathology , Leukocytes/pathology , Macrophages/pathology , Male , Middle Aged , Muscle, Skeletal/metabolism , Myocarditis/metabolism , Myocardium/metabolism , Myositis/metabolism , RNA, Viral/metabolism , SARS-CoV-2 , Sarcolemma/metabolism , Time Factors
6.
Nat Immunol ; 22(1): 74-85, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065902

ABSTRACT

T cell immunity is central for the control of viral infections. To characterize T cell immunity, but also for the development of vaccines, identification of exact viral T cell epitopes is fundamental. Here we identify and characterize multiple dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR peptides as potential T cell epitopes in COVID-19 convalescent and unexposed individuals. SARS-CoV-2-specific peptides enabled detection of post-infectious T cell immunity, even in seronegative convalescent individuals. Cross-reactive SARS-CoV-2 peptides revealed pre-existing T cell responses in 81% of unexposed individuals and validated similarity with common cold coronaviruses, providing a functional basis for heterologous immunity in SARS-CoV-2 infection. Diversity of SARS-CoV-2 T cell responses was associated with mild symptoms of COVID-19, providing evidence that immunity requires recognition of multiple epitopes. Together, the proposed SARS-CoV-2 T cell epitopes enable identification of heterologous and post-infectious T cell immunity and facilitate development of diagnostic, preventive and therapeutic measures for COVID-19.


Subject(s)
COVID-19/immunology , Epitopes, T-Lymphocyte/immunology , Peptides/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Viral Vaccines/immunology , COVID-19/prevention & control , COVID-19/virology , Cross Reactions/immunology , HLA-DR Antigens/immunology , HLA-DR Antigens/metabolism , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , Humans , Immunologic Memory/immunology , SARS-CoV-2/physiology , T-Lymphocytes/metabolism , Viral Vaccines/administration & dosage
7.
Immunity ; 54(1): 132-150.e9, 2021 01 12.
Article in English | MEDLINE | ID: covidwho-957143

ABSTRACT

HLA class I (HLA-I) glycoproteins drive immune responses by presenting antigens to cognate CD8+ T cells. This process is often hijacked by tumors and pathogens for immune evasion. Because options for restoring HLA-I antigen presentation are limited, we aimed to identify druggable HLA-I pathway targets. Using iterative genome-wide screens, we uncovered that the cell surface glycosphingolipid (GSL) repertoire determines effective HLA-I antigen presentation. We show that absence of the protease SPPL3 augmented B3GNT5 enzyme activity, resulting in upregulation of surface neolacto-series GSLs. These GSLs sterically impeded antibody and receptor interactions with HLA-I and diminished CD8+ T cell activation. Furthermore, a disturbed SPPL3-B3GNT5 pathway in glioma correlated with decreased patient survival. We show that the immunomodulatory effect could be reversed through GSL synthesis inhibition using clinically approved drugs. Overall, our study identifies a GSL signature that inhibits immune recognition and represents a potential therapeutic target in cancer, infection, and autoimmunity.


Subject(s)
Aspartic Acid Endopeptidases/metabolism , CD8-Positive T-Lymphocytes/immunology , Glioma/immunology , Glycosphingolipids/metabolism , Glycosyltransferases/metabolism , HLA Antigens/metabolism , Histocompatibility Antigens Class I/metabolism , Immunotherapy/methods , Antigen Presentation , Aspartic Acid Endopeptidases/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Glioma/mortality , Glycosphingolipids/immunology , HLA Antigens/immunology , Histocompatibility Antigens Class I/immunology , Humans , Lymphocyte Activation , Signal Transduction , Survival Analysis , Tumor Escape
8.
Molecules ; 25(22)2020 Nov 19.
Article in English | MEDLINE | ID: covidwho-945885

ABSTRACT

Major histocompatibility complex class I (MHC I) plays a crucial role in the development of adaptive immune response in vertebrates. MHC molecules are cell surface protein complexes loaded with short peptides and recognized by the T-cell receptors (TCR). Peptides associated with MHC are named immunopeptidome. The MHC I immunopeptidome is produced by the proteasome degradation of intracellular proteins. The knowledge of the immunopeptidome repertoire facilitates the creation of personalized antitumor or antiviral vaccines. A huge number of publications on the immunopeptidome diversity of different human and mouse biological samples-plasma, peripheral blood mononuclear cells (PBMCs), and solid tissues, including tumors-appeared in the scientific journals in the last decade. Significant immunopeptidome identification efficiency was achieved by advances in technology: the immunoprecipitation of MHC and mass spectrometry-based approaches. Researchers optimized common strategies to isolate MHC-associated peptides for individual tasks. They published many protocols with differences in the amount and type of biological sample, amount of antibodies, type and amount of insoluble support, methods of post-fractionation and purification, and approaches to LC-MS/MS identification of immunopeptidome. These parameters have a large impact on the final repertoire of isolated immunopeptidome. In this review, we summarize and compare immunopeptidome isolation techniques with an emphasis on the results obtained.


Subject(s)
Histocompatibility Antigens Class I/metabolism , Peptides/isolation & purification , Proteome/metabolism , Proteomics , Animals , Antibodies/metabolism , Chromatography, Affinity , Histocompatibility Antigens Class I/genetics , Humans
9.
Hum Immunol ; 81(12): 697-701, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-838428

ABSTRACT

SARS-CoV2 might conduce to rapid respiratory complications challenging healthcare systems worldwide. Immunological mechanisms associated to SARS-CoV2 infection are complex and not yet clearly elucidated. Arguments are in favour of a well host-adapted virus. Here I draw a systemic immunological representation linking actual SARS-CoV2 infection literature that hopefully might guide healthcare decisions to treat COVID-19. I suggest HLA-G and HLA-E, non classical HLA class I molecules, in the core of COVID-19 complications. These molecules are powerful in immune tolerance and might inhibit/suppress immune cells functions during SARS-CoV2 infection promoting virus subversion. Dosing soluble forms of these molecules in COVID-19 patients' plasma might help the identification of critical cases. I recommend also developing new SARS-CoV2 therapies based on the use of HLA-G and HLA-E or their specific receptors antibodies in combination with FDA approved therapeutics to combat efficiently COVID-19.


Subject(s)
COVID-19/epidemiology , COVID-19/immunology , HLA-G Antigens/immunology , Histocompatibility Antigens Class I/immunology , SARS-CoV-2/physiology , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , HLA-G Antigens/metabolism , Histocompatibility Antigens Class I/metabolism , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Immune Tolerance , Immunization, Passive , Molecular Targeted Therapy , Signal Transduction/drug effects , Virus Internalization , Virus Replication
10.
Cells ; 9(9)2020 08 26.
Article in English | MEDLINE | ID: covidwho-730306

ABSTRACT

Natural killer cells are important in the control of viral infections. However, the role of NK cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has previously not been identified. Peripheral blood NK cells from SARS-CoV and SARS-CoV-2 naïve subjects were evaluated for their activation, degranulation, and interferon-gamma expression in the presence of SARS-CoV and SARS-CoV-2 spike proteins. K562 and lung epithelial cells were transfected with spike proteins and co-cultured with NK cells. The analysis was performed by flow cytometry and immune fluorescence. SARS-CoV and SARS-CoV-2 spike proteins did not alter NK cell activation in a K562 in vitro model. On the contrary, SARS-CoV-2 spike 1 protein (SP1) intracellular expression by lung epithelial cells resulted in NK cell-reduced degranulation. Further experiments revealed a concomitant induction of HLA-E expression on the surface of lung epithelial cells and the recognition of an SP1-derived HLA-E-binding peptide. Simultaneously, there was increased modulation of the inhibitory receptor NKG2A/CD94 on NK cells when SP1 was expressed in lung epithelial cells. We ruled out the GATA3 transcription factor as being responsible for HLA-E increased levels and HLA-E/NKG2A interaction as implicated in NK cell exhaustion. We show for the first time that NK cells are affected by SP1 expression in lung epithelial cells via HLA-E/NKG2A interaction. The resulting NK cells' exhaustion might contribute to immunopathogenesis in SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/chemistry , Coronavirus Infections/immunology , Histocompatibility Antigens Class I/metabolism , Killer Cells, Natural/immunology , Lymphocyte Activation/genetics , NK Cell Lectin-Like Receptor Subfamily C/metabolism , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/metabolism , Blood Donors , Bronchi/cytology , COVID-19 , Cell Degranulation/genetics , Coculture Techniques , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Epithelial Cells/metabolism , Humans , Interferon-gamma/metabolism , K562 Cells , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , RNA, Viral/genetics , SARS Virus/chemistry , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/metabolism , Severe Acute Respiratory Syndrome/virology , Spike Glycoprotein, Coronavirus/genetics , Transfection
11.
Crit Rev Immunol ; 40(2): 173-184, 2020.
Article in English | MEDLINE | ID: covidwho-663846

ABSTRACT

Mucosa-associated invariant T cells (MAIT cells) are unconventional, innate-like T lymphocytes with remarkable effector and immunoregulatory functions. They are abundant in the human peripheral blood and also enriched in mucosal layers and in the lungs, SARS-CoV-2's main ports of entry. Once activated, MAIT cells produce inflammatory cytokines and cytolytic effector molecules quickly and copiously. MAIT cells are best known for their antibacterial and antifungal properties. However, they are also activated during viral infections, typically in a cytokine-dependent manner, which may promote antiviral immunity. On the other hand, it is plausible to assume active roles for MAIT cells in infection-provoked cytokine storms and tissue damage. SARS-CoV-2 infection may be asymptomatic, mild, severe, or even fatal, depending on sex, age, the presence of preexisting morbidities, and the individual's immunological competence, or lack thereof, among other factors. Based on the available literature, I propose that MAIT cells regulate the host response to SARS-CoV-2 and constitute attractive targets in the prevention or clinical management of coronavirus disease 19 (COVID-19) and some of its complications. Unlike mainstream T cells, MAIT cells are restricted by a monomorphic antigen-presenting molecule called MHC-related protein 1 (MR1). Therefore, MR1 ligands should modify MAIT cell functions relatively uniformly in genetically diverse subjects and may be tested as immunotherapeutic agents or vaccine adjuvants in future studies.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Histocompatibility Antigens Class I/metabolism , Minor Histocompatibility Antigens/metabolism , Mucosal-Associated Invariant T Cells/immunology , Pneumonia, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19 , Coronavirus Infections/pathology , Cytokines/immunology , Humans , Mucosal-Associated Invariant T Cells/metabolism , Pandemics , Pneumonia, Viral/pathology , SARS-CoV-2
12.
Proc Natl Acad Sci U S A ; 117(27): 15902-15910, 2020 07 07.
Article in English | MEDLINE | ID: covidwho-611002

ABSTRACT

Neurotropic strains of mouse hepatitis virus (MHV), a coronavirus, cause acute and chronic demyelinating encephalomyelitis with similarities to the human disease multiple sclerosis. Here, using a lineage-tracking system, we show that some cells, primarily oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs), survive the acute MHV infection, are associated with regions of demyelination, and persist in the central nervous system (CNS) for at least 150 d. These surviving OLs express major histocompatibility complex (MHC) class I and other genes associated with an inflammatory response. Notably, the extent of inflammatory cell infiltration was variable, dependent on anatomic location within the CNS, and without obvious correlation with numbers of surviving cells. We detected more demyelination in regions with larger numbers of T cells and microglia/macrophages compared to those with fewer infiltrating cells. Conversely, in regions with less inflammation, these previously infected OLs more rapidly extended processes, consistent with normal myelinating function. Together, these results show that OLs are inducers as well as targets of the host immune response and demonstrate how a CNS infection, even after resolution, can induce prolonged inflammatory changes with CNS region-dependent impairment in remyelination.


Subject(s)
Central Nervous System/immunology , Coronavirus Infections/complications , Demyelinating Diseases/etiology , Oligodendroglia/immunology , Animals , Coronavirus Infections/immunology , Histocompatibility Antigens Class I/metabolism , Luminescent Proteins , Male , Mice , Murine hepatitis virus , Oligodendroglia/metabolism
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