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1.
Eur J Clin Invest ; 51(11): e13661, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1398398

ABSTRACT

BACKGROUND: Unravelling autoimmune targets triggered by SARS-CoV-2 infection may provide crucial insights into the physiopathology of the disease and foster the development of potential therapeutic candidate targets and prognostic tools. We aimed at determining (a) the association between anti-SARS-CoV-2 and anti-apoA-1 humoral response and (b) the degree of linear homology between SARS-CoV-2, apoA-1 and Toll-like receptor 2 (TLR2) epitopes. DESIGN: Bioinformatics modelling coupled with mimic peptides engineering and competition experiments were used to assess epitopes sequence homologies. Anti-SARS-CoV-2 and anti-apoA-1 IgG as well as cytokines were assessed by immunoassays on a case-control (n = 101), an intensive care unit (ICU; n = 126) and a general population cohort (n = 663) with available samples in the pre and post-pandemic period. RESULTS: Using bioinformatics modelling, linear sequence homologies between apoA-1, TLR2 and Spike epitopes were identified but without experimental evidence of cross-reactivity. Overall, anti-apoA-1 IgG levels were higher in COVID-19 patients or anti-SARS-CoV-2 seropositive individuals than in healthy donors or anti-SARS-CoV-2 seronegative individuals (P < .0001). Significant and similar associations were noted between anti-apoA-1, anti-SARS-CoV-2 IgG, cytokines and lipid profile. In ICU patients, anti-SARS-CoV-2 and anti-apoA-1 seroconversion rates displayed similar 7-day kinetics, reaching 82% for anti-apoA-1 seropositivity. In the general population, SARS-CoV-2-exposed individuals displayed higher anti-apoA-1 IgG seropositivity rates than nonexposed ones (34% vs 16.8%; P = .004). CONCLUSION: COVID-19 induces a marked humoral response against the major protein of high-density lipoproteins. As a correlate of poorer prognosis in other clinical settings, such autoimmunity signatures may relate to long-term COVID-19 prognosis assessment and warrant further scrutiny in the current COVID-19 pandemic.


Subject(s)
Antibodies, Viral/immunology , Apolipoprotein A-I/immunology , Autoantibodies/immunology , COVID-19/immunology , Cytokines/immunology , Immunity, Humoral/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Aged, 80 and over , Apolipoprotein A-I/chemistry , Computational Biology , Epitopes/chemistry , Female , Humans , Immunoglobulin G/immunology , Male , Middle Aged , Peptide Fragments/chemistry , Peptide Fragments/immunology , Peptides , SARS-CoV-2 , Sequence Homology, Amino Acid , Spike Glycoprotein, Coronavirus/chemistry , Toll-Like Receptor 2/chemistry , Toll-Like Receptor 2/immunology , Young Adult
3.
Front Immunol ; 12: 705772, 2021.
Article in English | MEDLINE | ID: covidwho-1376700

ABSTRACT

Autoimmune diseases (ADs) could occur due to infectious diseases and vaccination programs. Since millions of people are expected to be infected with SARS-CoV-2 and vaccinated against it, autoimmune consequences seem inevitable. Therefore, we have investigated the whole proteome of the SARS-CoV-2 for its ability to trigger ADs. In this regard, the entire proteome of the SARS-CoV-2 was chopped into more than 48000 peptides. The produced peptides were searched against the entire human proteome to find shared peptides with similar experimentally confirmed T-cell and B-cell epitopes. The obtained peptides were checked for their ability to bind to HLA molecules. The possible population coverage was calculated for the most potent peptides. The obtained results indicated that the SARS-CoV-2 and human proteomes share 23 peptides originated from ORF1ab polyprotein, nonstructural protein NS7a, Surface glycoprotein, and Envelope protein of SARS-CoV-2. Among these peptides, 21 peptides had experimentally confirmed equivalent epitopes. Amongst, only nine peptides were predicted to bind to HLAs with known global allele frequency data, and three peptides were able to bind to experimentally confirmed HLAs of equivalent epitopes. Given the HLAs which have already been reported to be associated with ADs, the ESGLKTIL, RYPANSIV, NVAITRAK, and RRARSVAS were determined to be the most harmful peptides of the SARS-CoV-2 proteome. It would be expected that the COVID-19 pandemic and the vaccination against this pathogen could significantly increase the ADs incidences, especially in populations harboring HLA-B*08:01, HLA-A*024:02, HLA-A*11:01 and HLA-B*27:05. The Southeast Asia, East Asia, and Oceania are at higher risk of AD development.


Subject(s)
Autoimmunity , COVID-19 Vaccines/immunology , COVID-19/immunology , Proteome/immunology , SARS-CoV-2/immunology , Viral Proteins/immunology , Autoimmune Diseases/etiology , Autoimmune Diseases/immunology , COVID-19/complications , COVID-19 Vaccines/adverse effects , Computer Simulation , Epitopes, B-Lymphocyte/immunology , HLA Antigens/immunology , Humans , Peptide Fragments/immunology , Peptide Library
4.
Front Immunol ; 12: 679841, 2021.
Article in English | MEDLINE | ID: covidwho-1369665

ABSTRACT

Understanding the course of the antibody response directed to individual epitopes of SARS-CoV-2 proteins is crucial for serological assays and establishment of vaccines. Twenty-one synthetic peptides were synthesized that have ten amino acids overlap and cover the complete membrane (M) protein. Plasma samples from 32 patients having acute disease and 30 patients from the convalescent phase were studied. Only peptide M01 (aa 1-20) and to a lesser extent peptide M21 (aa 201-222) showed specific reactivity as compared to historical control plasma samples. Peptide M01 was recognized by IgM- (71.9%) and IgG-specific antibodies (43.8%) during the acute phase as early as day 8 PIO. In a longitudinal analysis, a higher reactivity was observed for the IgM response directed to peptide M01 following day 20 PIO as compared to earlier time points of the acute phase. In the convalescent phase, antibody reactivity to the two M-specific peptides was significantly lower (<30% seropositivity). A fusion protein encoding major parts of RBD also showed higher rates of recognition during acute (50.0%) and lower rates in the convalescent phase (23.3%). Taken together, our results suggest that during the acute phase of COVID-19 antibodies are raised to two linear epitopes of the SARS-CoV-2 M protein, located at the very N- and C-termini, showing almost similar levels of reactivity as immunodominant linear epitopes derived from the spike and nucleocapsid protein. Anti-M is also present in the convalescent phase of COVID-19 patients, however at lower levels, with the N-terminus of the M protein as a preferred target.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Viral Matrix Proteins/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Viral/biosynthesis , Convalescence , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Immunodominant Epitopes/immunology , Immunoglobulin M/immunology , Male , Middle Aged , Patient Acuity , Peptide Fragments/immunology , Recombinant Fusion Proteins/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Matrix Proteins/genetics
5.
Viruses ; 13(8)2021 08 23.
Article in English | MEDLINE | ID: covidwho-1367926

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic causing over 195 million infections and more than 4 million fatalities as of July 2021.To date, it has been demonstrated that a number of mutations in the spike glycoprotein (S protein) of SARS-CoV-2 variants of concern abrogate or reduce the neutralization potency of several therapeutic antibodies and vaccine-elicited antibodies. Therefore, the development of additional vaccine platforms with improved supply and logistic profile remains a pressing need. In this work, we have validated the applicability of a peptide-based strategy focused on a preventive as well as a therapeutic purpose. On the basis of the involvement of the dipeptidyl peptidase 4 (DPP4), in addition to the angiotensin converting enzyme 2 (ACE2) receptor in the mechanism of virus entry, we analyzed peptides bearing DPP4 sequences by protein-protein docking and assessed their ability to block pseudovirus infection in vitro. In parallel, we have selected and synthetized peptide sequences located within the highly conserved receptor-binding domain (RBD) of the S protein, and we found that RBD-based vaccines could better promote elicitation of high titers of neutralizing antibodies specific against the regions of interest, as confirmed by immunoinformatic methodologies and in vivo studies. These findings unveil a key antigenic site targeted by broadly neutralizing antibodies and pave the way to the design of pan-coronavirus vaccines.


Subject(s)
Dipeptidyl Peptidase 4/chemistry , Peptide Fragments/immunology , Peptide Fragments/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/drug therapy , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Chlorocebus aethiops , Dipeptidyl Peptidase 4/metabolism , Epitopes, T-Lymphocyte/immunology , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Protein Binding , Protein Domains , Receptors, Coronavirus/chemistry , Receptors, Coronavirus/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Virus Internalization
6.
Am J Physiol Lung Cell Mol Physiol ; 321(2): L485-L489, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1299247

ABSTRACT

COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multisystem organ failure and viral sepsis characterized by respiratory failure, arrhythmias, thromboembolic complications, and shock with high mortality. Autopsy and preclinical evidence implicate aberrant complement activation in endothelial injury and organ failure. Erythrocytes express complement receptors and are capable of binding immune complexes; therefore, we investigated complement activation in patients with COVID-19 using erythrocytes as a tool to diagnose complement activation. We discovered enhanced C3b and C4d deposition on erythrocytes in COVID-19 sepsis patients and non-COVID sepsis patients compared with healthy controls, supporting the role of complement in sepsis-associated organ injury. Our data suggest that erythrocytes may contribute to a precision medicine approach to sepsis and have diagnostic value in monitoring complement dysregulation in COVID-19-sepsis and non-COVID sepsis and identifying patients who may benefit from complement targeted therapies.


Subject(s)
COVID-19/complications , Complement Activation/immunology , Complement C3b/immunology , Complement C4b/immunology , Erythrocytes/immunology , Peptide Fragments/immunology , Respiratory Insufficiency/diagnosis , Sepsis/diagnosis , COVID-19/immunology , COVID-19/virology , Complement C3b/metabolism , Complement C4b/metabolism , Erythrocytes/metabolism , Erythrocytes/virology , Female , Humans , Male , Middle Aged , Peptide Fragments/metabolism , Respiratory Insufficiency/immunology , Respiratory Insufficiency/metabolism , Respiratory Insufficiency/virology , SARS-CoV-2/isolation & purification , Sepsis/immunology , Sepsis/metabolism , Sepsis/virology
7.
Front Immunol ; 12: 641447, 2021.
Article in English | MEDLINE | ID: covidwho-1264330

ABSTRACT

The newly emerged novel coronavirus, SARS-CoV-2, the causative agent of COVID-19 has proven to be a threat to the human race globally, thus, vaccine development against SARS-CoV-2 is an unmet need driving mass vaccination efforts. The receptor binding domain of the spike protein of this coronavirus has multiple neutralizing epitopes and is associated with viral entry. Here we have designed and characterized the SARS-CoV-2 spike protein fragment 330-526 as receptor binding domain 330-526 (RBD330-526) with two native glycosylation sites (N331 and N343); as a potential subunit vaccine candidate. We initially characterized RBD330-526 biochemically and investigated its thermal stability, humoral and T cell immune response of various RBD protein formulations (with or without adjuvant) to evaluate the inherent immunogenicity and immunomodulatory effect. Our result showed that the purified RBD immunogen is stable up to 72 h, without any apparent loss in affinity or specificity of interaction with the ACE2 receptor. Upon immunization in mice, RBD generates a high titer humoral response, elevated IFN-γ producing CD4+ cells, cytotoxic T cells, and robust neutralizing antibodies against live SARS-CoV-2 virus. Our results collectively support the potential of RBD330-526 as a promising vaccine candidate against SARS-CoV-2.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , Immunity, Humoral/drug effects , Immunogenicity, Vaccine , Peptide Fragments/administration & dosage , Spike Glycoprotein, Coronavirus/administration & dosage , Th1 Cells/drug effects , Adjuvants, Immunologic/administration & dosage , Animals , Biomarkers/blood , COVID-19 Vaccines/immunology , Chlorocebus aethiops , Drug Stability , Glycosylation , HEK293 Cells , Humans , Immunization , Interferon-gamma/blood , Male , Mice, Inbred C57BL , Peptide Fragments/immunology , Protein Interaction Domains and Motifs , Protein Stability , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells/immunology , Th1 Cells/metabolism , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/immunology , Vero Cells
8.
Sci Rep ; 11(1): 5402, 2021 03 08.
Article in English | MEDLINE | ID: covidwho-1123146

ABSTRACT

Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABAA-receptors (GABAA-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood-brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABAA-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing-remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.


Subject(s)
Central Nervous System/pathology , Multiple Sclerosis/immunology , T-Lymphocytes/immunology , Taurine/analogs & derivatives , Animals , Antigen Presentation/drug effects , Antigen-Presenting Cells/drug effects , Antigen-Presenting Cells/immunology , Cell Proliferation/drug effects , Central Nervous System/drug effects , Central Nervous System/immunology , Disease Models, Animal , Disease Progression , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Mice, Inbred C57BL , Multiple Sclerosis/pathology , Myelin Proteolipid Protein/immunology , Peptide Fragments/immunology , Recurrence , Spleen/pathology , T-Lymphocytes/drug effects , Taurine/pharmacology , gamma-Aminobutyric Acid/pharmacology
10.
Proc Natl Acad Sci U S A ; 117(39): 24384-24391, 2020 09 29.
Article in English | MEDLINE | ID: covidwho-775833

ABSTRACT

An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2-specific CD8+ and CD4+ T cells in vitro, with CD4+ T cells being robust. We identified two HLA-A*02:01-restricted SARS-CoV-2-specfic CD8+ T cell epitopes, A2/S269-277 and A2/Orf1ab3183-3191 Using peptide-HLA tetramer enrichment, direct ex vivo assessment of A2/S269 +CD8+ and A2/Orf1ab3183 +CD8+ populations indicated that A2/S269 +CD8+ T cells were detected at comparable frequencies (∼1.3 × 10-5) in acute and convalescent HLA-A*02:01+ patients. These frequencies were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5 × 10-6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein-Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10-4) populations. Phenotyping A2/S269 +CD8+ T cells from COVID-19 convalescents ex vivo showed that A2/S269 +CD8+ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8+ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269 +CD8+ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8+ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8+ T cell immunity in COVID-19.


Subject(s)
Betacoronavirus/immunology , CD8-Positive T-Lymphocytes/immunology , Coronavirus Infections/immunology , HLA-A2 Antigen/immunology , Pneumonia, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , COVID-19 , Epitopes, T-Lymphocyte , Female , Humans , Immunologic Memory , Immunophenotyping , Leukocytes, Mononuclear/immunology , Lymphocyte Activation , Male , Middle Aged , Pandemics , Peptide Fragments/chemistry , Peptide Fragments/immunology , Polyproteins , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Proteins/chemistry , Viral Proteins/immunology
11.
Adv Chronic Kidney Dis ; 27(5): 404-411, 2020 09.
Article in English | MEDLINE | ID: covidwho-722379

ABSTRACT

Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, into host cells. Because RAS inhibitors have been suggested to increase ACE2 expression, health-care providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.


Subject(s)
Acute Lung Injury/metabolism , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/metabolism , Hypertension/drug therapy , Acute Lung Injury/epidemiology , Acute Lung Injury/immunology , Angiotensin I/immunology , Angiotensin I/metabolism , Angiotensin II/immunology , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/immunology , COVID-19/epidemiology , COVID-19/immunology , Comorbidity , Humans , Hypertension/epidemiology , Hypertension/metabolism , JNK Mitogen-Activated Protein Kinases/immunology , JNK Mitogen-Activated Protein Kinases/metabolism , Lung/immunology , Lung/metabolism , MAP Kinase Signaling System , Peptide Fragments/immunology , Peptide Fragments/metabolism , Protective Factors , Receptors, Coronavirus/immunology , Receptors, Coronavirus/metabolism , Renin-Angiotensin System , Risk Factors , SARS-CoV-2 , Up-Regulation
12.
Front Immunol ; 11: 1714, 2020.
Article in English | MEDLINE | ID: covidwho-714693

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third coronavirus leading to a global health outbreak. Despite the high mortality rates from SARS-CoV-1 and Middle-East respiratory syndrome (MERS)-CoV infections, which both sparked the interest of the scientific community, the underlying physiopathology of the SARS-CoV-2 infection, remains partially unclear. SARS-CoV-2 shares similar features with SARS-CoV-1, notably the use of the angiotensin conversion enzyme 2 (ACE2) as a receptor to enter the host cells. However, some features of the SARS-CoV-2 pandemic are unique. In this work, we focus on the association between obesity, metabolic syndrome, and type 2 diabetes on the one hand, and the severity of COVID-19 infection on the other, as it seems greater in these patients. We discuss how adipocyte dysfunction leads to a specific immune environment that predisposes obese patients to respiratory failure during COVID-19. We also hypothesize that an ACE2-cleaved protein, angiotensin 1-7, has a beneficial action on immune deregulation and that its low expression during the SARS-CoV-2 infection could explain the severity of infection. This introduces angiotensin 1-7 as a potential candidate of interest in therapeutic research on CoV infections.


Subject(s)
Adipokines/immunology , Angiotensin I/immunology , Betacoronavirus/immunology , Coronavirus Infections/pathology , Peptide Fragments/immunology , Pneumonia, Viral/pathology , Severe Acute Respiratory Syndrome/pathology , Adipokines/blood , Angiotensin-Converting Enzyme 2 , COVID-19 , Diabetes Mellitus, Type 2/immunology , Humans , Metabolic Syndrome/immunology , Obesity/immunology , Pandemics , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2
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