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1.
PLoS One ; 17(3): e0249723, 2022.
Article in English | MEDLINE | ID: covidwho-1896431

ABSTRACT

Approximately 10% of infants infected with SARS-CoV-2 will experience COVID-19 illness requiring advanced care. A potential mechanism to protect this population is passive immunization via the milk of a previously infected person. We and others have reported on the presence of SARS-CoV-2-specific antibodies in human milk. We now report the prevalence of SARS-CoV-2 IgA in the milk of 74 COVID-19-recovered participants, and find that 89% of samples are positive for Spike-specific IgA. In a subset of these samples, 95% exhibited robust IgA activity as determined by endpoint binding titer, with 50% considered high-titer. These IgA-positive samples were also positive for Spike-specific secretory antibody. Levels of IgA antibodies and secretory antibodies were shown to be strongly positively correlated. The secretory IgA response was dominant among the milk samples tested compared to the IgG response, which was present in 75% of samples and found to be of high-titer in only 13% of cases. Our IgA durability analysis using 28 paired samples, obtained 4-6 weeks and 4-10 months after infection, found that all samples exhibited persistently significant Spike-specific IgA, with 43% of donors exhibiting increasing IgA titers over time. Finally, COVID-19 and pre-pandemic control milk samples were tested for the presence of neutralizing antibodies; 6 of 8 COVID-19 samples exhibited neutralization of Spike-pseudotyped VSV (IC50 range, 2.39-89.4ug/mL) compared to 1 of 8 controls. IgA binding and neutralization capacities were found to be strongly positively correlated. These data are highly relevant to public health, not only in terms of the protective capacity of these antibodies for breastfed infants, but also for the potential use of such antibodies as a COVID-19 therapeutic, given that secretory IgA is highly in all mucosal compartments.


Subject(s)
Antibodies, Neutralizing/immunology , Immunoglobulin A/immunology , Milk, Human/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/immunology , Adult , Antibodies, Neutralizing/metabolism , COVID-19/diagnosis , COVID-19/prevention & control , COVID-19/virology , Female , Humans , Immunoglobulin A/metabolism , Neutralization Tests , SARS-CoV-2/isolation & purification , Young Adult
2.
Front Immunol ; 13: 837443, 2022.
Article in English | MEDLINE | ID: covidwho-1742219

ABSTRACT

An ideal protective vaccine against SARS-CoV-2 should not only be effective in preventing disease, but also in preventing virus transmission. It should also be well accepted by the population and have a simple logistic chain. To fulfill these criteria, we developed a thermostable, orally administered vaccine that can induce a robust mucosal neutralizing immune response. We used our platform based on retrovirus-derived enveloped virus-like particles (eVLPs) harnessed with variable surface proteins (VSPs) from the intestinal parasite Giardia lamblia, affording them resistance to degradation and the triggering of robust mucosal cellular and antibody immune responses after oral administration. We made eVLPs expressing various forms of the SARS-CoV-2 Spike protein (S), with or without membrane protein (M) expression. We found that prime-boost administration of VSP-decorated eVLPs expressing a pre-fusion stabilized form of S and M triggers robust mucosal responses against SARS-CoV-2 in mice and hamsters, which translate into complete protection from a viral challenge. Moreover, they dramatically boosted the IgA mucosal response of intramuscularly injected vaccines. We conclude that our thermostable orally administered eVLP vaccine could be a valuable addition to the current arsenal against SARS-CoV-2, in a stand-alone prime-boost vaccination strategy or as a boost for existing vaccines.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Coronavirus M Proteins/immunology , Giardia lamblia/immunology , Intestinal Mucosa/immunology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antigens, Protozoan/immunology , Cricetinae , Humans , Immunity , Immunization, Secondary , Immunoglobulin A/metabolism , Male , Mice , Mice, Inbred BALB C , Temperature , Vaccine Potency , Vaccines, Virus-Like Particle
3.
J Immunol ; 208(6): 1500-1508, 2022 03 15.
Article in English | MEDLINE | ID: covidwho-1715878

ABSTRACT

Oral fluids offer a noninvasive sampling method for the detection of Abs. Quantification of IgA and IgG Abs in saliva allows studies of the mucosal and systemic immune response after natural infection or vaccination. We developed and validated an enzyme immunoassay (EIA) to detect and quantify salivary IgA and IgG Abs against the prefusion-stabilized form of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein expressed in suspension-adapted HEK-293 cells. Normalization against total Ab isotype was performed to account for specimen differences, such as collection time and sample volume. Saliva samples collected from 187 SARS-CoV-2 confirmed cases enrolled in 2 cohorts and 373 prepandemic saliva samples were tested. The sensitivity of both EIAs was high (IgA, 95.5%; IgG, 89.7%) without compromising specificity (IgA, 99%; IgG, 97%). No cross-reactivity with endemic coronaviruses was observed. The limit of detection for SARS-CoV-2 salivary IgA and IgG assays were 1.98 ng/ml and 0.30 ng/ml, respectively. Salivary IgA and IgG Abs were detected earlier in patients with mild COVID-19 symptoms than in severe cases. However, severe cases showed higher salivary Ab titers than those with a mild infection. Salivary IgA titers quickly decreased after 6 wk in mild cases but remained detectable until at least week 10 in severe cases. Salivary IgG titers remained high for all patients, regardless of disease severity. In conclusion, EIAs for both IgA and IgG had high specificity and sensitivity for the confirmation of current or recent SARS-CoV-2 infections and evaluation of the IgA and IgG immune response.


Subject(s)
Antibodies, Viral/metabolism , COVID-19/diagnosis , Enzyme-Linked Immunosorbent Assay/methods , Immunoglobulin A/metabolism , Immunoglobulin G/metabolism , SARS-CoV-2/physiology , Saliva/metabolism , Adolescent , Adult , Aged , Asymptomatic Diseases , Child , Child, Preschool , Disease Progression , Enzyme-Linked Immunosorbent Assay/standards , Female , Humans , Infant , Male , Mass Screening , Middle Aged , Pandemics , Reference Standards , Sensitivity and Specificity , Severity of Illness Index , Young Adult
4.
Front Immunol ; 12: 755891, 2021.
Article in English | MEDLINE | ID: covidwho-1674329

ABSTRACT

The immune response promoted by SARS-CoV-2 vaccination is relevant to develop novel vaccines and optimized prevention strategies. We analyzed the adaptive immunity in healthy donors (HD) and convalescent individuals (CD), before and after administering BNT162b2 vaccine. Our results revealed specific changes in CD4+ T cell reactivity profile in vaccinated HD and CD, with an increase in S1 and S2 positive individuals, proportionally higher for S2. On the contrary, NCAP reactivity observed in HD and CD patients was no longer detectable after vaccination. Despite the substantial antibody response in CD, MPro-derived peptides did not elicit CD4+ lymphocyte activation in our assay in either condition. HD presented an increment in anti-S and anti-RBD IgG after first dose vaccination, which increased after the second vaccination. Conversely, anti-S and anti-RBD IgG and IgA titers increased in already positive CD after first dose administration, remaining stable after second dose inoculation. Interestingly, we found a strong significant correlation between S1-induced CD4+ response and anti-S IgA pre-vaccination, which was lost after vaccine administration.


Subject(s)
/immunology , CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , SARS-CoV-2/physiology , Adult , Cells, Cultured , Convalescence , Female , Healthy Volunteers , Humans , Immunization, Secondary , Immunoglobulin A/metabolism , Immunoglobulin G/metabolism , Male , Middle Aged , Spike Glycoprotein, Coronavirus/immunology , T-Cell Antigen Receptor Specificity , Vaccination
5.
PLoS One ; 17(2): e0263419, 2022.
Article in English | MEDLINE | ID: covidwho-1674014

ABSTRACT

Mucosal immunity plays a crucial role in controlling upper respiratory infections, including influenza. We established a quantitative ELISA to measure the amount of influenza virus-specific salivery IgA (sIgA) and salivary IgG (sIgG) antibodies using a standard antibody broadly reactive to the influenza A virus. We then analyzed saliva and serum samples from seven individuals infected with the A(H1N1)pdm09 influenza virus during the 2019-2020 flu seasons. We detected an early (6-10 days post-infection) increase of sIgA in five of the seven samples and a later (3-5 weeks) increase of sIgG in six of the seven saliva samples. Although the conventional parenteral influenza vaccine did not induce IgA production in saliva, vaccinated individuals with a history of influenza infection had higher basal levels of sIgA than those without a history. Interestingly, we observed sIgA and sIgG in an asymptomatic individual who had close contact with two influenza cases. Both early mucosal sIgA secretion and late systemically induced sIgG in the mucosal surface may protect against virus infection. Despite the small sample size, our results indicate that the saliva test system can be useful for analyzing upper mucosal immunity in influenza.


Subject(s)
Immunity, Mucosal/physiology , Influenza, Human/immunology , Saliva/immunology , Adult , Aged , Antibodies, Viral/analysis , Antibodies, Viral/metabolism , Antibody Formation , Cohort Studies , Female , History, 21st Century , Humans , Immunoglobulin A/analysis , Immunoglobulin A/metabolism , Immunoglobulin A, Secretory/analysis , Immunoglobulin A, Secretory/metabolism , Immunoglobulin G/analysis , Immunoglobulin G/metabolism , Influenza A Virus, H1N1 Subtype/immunology , Influenza Vaccines/therapeutic use , Influenza, Human/diagnosis , Influenza, Human/prevention & control , Japan , Longitudinal Studies , Male , Predictive Value of Tests , Prognosis , Saliva/chemistry , Saliva/metabolism , Young Adult
6.
Int Immunopharmacol ; 101(Pt A): 108280, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1487771

ABSTRACT

The COVID-19 pandemic, caused by a highly virulent and transmissible pathogen, has proven to be devastating to society. Mucosal vaccines that can induce antigen-specific immune responses in both the systemic and mucosal compartments are considered an effective measure to overcome infectious diseases caused by pathogenic microbes. We have recently developed a nasal vaccine system using cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium-propane and cholesteryl 3ß-N-(dimethylaminoethyl)carbamate in mice. However, the comprehensive molecular mechanism(s), especially the host soluble mediator involved in this process, by which cationic liposomes promote antigen-specific mucosal immune responses, remain to be elucidated. Herein, we show that intranasal administration of cationic liposomes elicited interleukin-6 (IL-6) expression at the site of administration. Additionally, both nasal passages and splenocytes from mice nasally immunized with cationic liposomes plus ovalbumin (OVA) were polarized to produce IL-6 when re-stimulated with OVA in vitro. Furthermore, pretreatment with anti-IL-6R antibody, which blocks the biological activities of IL-6, attenuated the production of OVA-specific nasal immunoglobulin A (IgA) but not OVA-specific serum immunoglobulin G (IgG) responses. In this study, we demonstrated that IL-6, exerted by nasally administered cationic liposomes, plays a crucial role in antigen-specific IgA induction.


Subject(s)
Immunity, Mucosal/immunology , Immunoglobulin A/metabolism , Interleukin-6/immunology , Vaccines/immunology , Administration, Intranasal , Animals , Antibody Formation/drug effects , Antigens/immunology , COVID-19/prevention & control , Cations/immunology , Cations/therapeutic use , Fatty Acids, Monounsaturated/immunology , Fatty Acids, Monounsaturated/therapeutic use , Female , Immunity, Mucosal/drug effects , Immunoglobulin G/blood , Interleukin-6/antagonists & inhibitors , Interleukin-6/genetics , Interleukin-6/metabolism , Liposomes/immunology , Liposomes/therapeutic use , Mice , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Ovalbumin/immunology , Quaternary Ammonium Compounds/immunology , Quaternary Ammonium Compounds/therapeutic use , Spleen/metabolism , Vaccines/administration & dosage
7.
EBioMedicine ; 73: 103637, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1471944

ABSTRACT

BACKGROUND: The dynamics of SARS-CoV-2 alpha variant shedding and immune responses at the nasal mucosa remain poorly characterised. METHODS: We measured infectious viral release, antibodies and cytokines in 426 PCR+ nasopharyngeal swabs from individuals harboring non-alpha or alpha variants. FINDINGS: With both lineages, viral titers were variable, ranging from 0 to >106 infectious units. Rapid antigenic diagnostic tests were positive in 94% of samples with infectious virus. 68 % of individuals carried infectious virus within two days after onset of symptoms. This proportion decreased overtime. Viable virus was detected up to 14 days. Samples containing anti-spike IgG or IgA did not generally harbor infectious virus. Ct values were slightly but not significantly lower with alpha. This variant was characterized by a fast decrease of infectivity overtime and a marked release of 13 cytokines (including IFN-b, IP-10 and IL-10). INTERPRETATION: The alpha variant displays modified viral decay and cytokine profiles at the nasopharyngeal mucosae during symptomatic infection. FUNDING: This retrospective study has been funded by Institut Pasteur, ANRS, Vaccine Research Institute, Labex IBEID, ANR/FRM and IDISCOVR, Fondation pour la Recherche Médicale.


Subject(s)
Cytokines/metabolism , Nasopharynx/virology , SARS-CoV-2/isolation & purification , Adult , Aged , Antibodies, Viral/metabolism , COVID-19/pathology , COVID-19/virology , Female , Humans , Immunoglobulin A/metabolism , Immunoglobulin G/metabolism , Male , Middle Aged , Retrospective Studies
8.
Front Immunol ; 12: 730766, 2021.
Article in English | MEDLINE | ID: covidwho-1463473

ABSTRACT

The SARS-CoV-2 pandemic has spread to all parts of the world and can cause life-threatening pneumonia and other severe disease manifestations known as COVID-19. This health crisis has resulted in a significant effort to stop the spread of this new coronavirus. However, while propagating itself in the human population, the virus accumulates mutations and generates new variants with increased fitness and the ability to escape the human immune response. Here we describe a color-based barcoded spike flow cytometric assay (BSFA) that is particularly useful to evaluate and directly compare the humoral immune response directed against either wild type (WT) or mutant spike (S) proteins or the receptor-binding domains (RBD) of SARS-CoV-2. This assay employs the human B lymphoma cell line Ramos, transfected for stable expression of WT or mutant S proteins or a chimeric RBD-CD8 fusion protein. We find that the alpha and beta mutants are more stably expressed than the WT S protein on the Ramos B cell surface and/or bind with higher affinity to the viral entry receptor ACE2. However, we find a reduce expression of the chimeric RBD-CD8 carrying the point mutation N501Y and E484K characteristic for the alpha and beta variant, respectively. The comparison of the humoral immune response of 12 vaccinated probands with 12 COVID-19 patients shows that after the boost, the S-specific IgG class immune response in the vaccinated group is similar to that of the patient group. However, in comparison to WT the specific IgG serum antibodies bind less well to the alpha variant and only poorly to the beta variant S protein. This is in line with the notion that the beta variant is an immune escape variant of SARS-CoV-2. The IgA class immune response was more variable than the IgG response and higher in the COVID-19 patients than in the vaccinated group. In summary, we think that our BSFA represents a useful tool to evaluate the humoral immunity against emerging variants of SARS-CoV-2 and to analyze new vaccination protocols against these variants.


Subject(s)
COVID-19/immunology , Cell Separation/methods , Flow Cytometry/methods , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Viral/metabolism , Antibody Formation , Female , Humans , Immunization, Secondary , Immunoglobulin A/metabolism , Immunoglobulin G/metabolism , Male , Middle Aged , Mutation/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccination
9.
Nat Immunol ; 22(11): 1452-1464, 2021 11.
Article in English | MEDLINE | ID: covidwho-1454797

ABSTRACT

There is limited understanding of the viral antibody fingerprint following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children. Herein, SARS-CoV-2 proteome-wide immunoprofiling of children with mild/moderate or severe coronavirus disease 2019 (COVID-19) versus multisystem inflammatory syndrome in children versus hospitalized control patients revealed differential cytokine responses, IgM/IgG/IgA epitope diversity, antibody binding and avidity. Apart from spike and nucleocapsid, IgG/IgA recognized epitopes in nonstructural protein (NSP) 2, NSP3, NSP12-NSP14 and open reading frame (ORF) 3a-ORF9. Peptides representing epitopes in NSP12, ORF3a and ORF8 demonstrated SARS-CoV-2 serodiagnosis. Antibody-binding kinetics with 24 SARS-CoV-2 proteins revealed antibody parameters that distinguish children with mild/moderate versus severe COVID-19 or multisystem inflammatory syndrome in children. Antibody avidity to prefusion spike correlated with decreased illness severity and served as a clinical disease indicator. The fusion peptide and heptad repeat 2 region induced SARS-CoV-2-neutralizing antibodies in rabbits. Thus, we identified SARS-CoV-2 antibody signatures in children associated with disease severity and delineate promising serodiagnostic and virus neutralization targets. These findings might guide the design of serodiagnostic assays, prognostic algorithms, therapeutics and vaccines in this important but understudied population.


Subject(s)
COVID-19 Serological Testing/methods , COVID-19/complications , COVID-19/immunology , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , Adolescent , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , COVID-19/diagnosis , Child , Child, Preschool , Disease Progression , Epitopes/metabolism , Female , Hospitalization , Humans , Immunity, Humoral , Immunoglobulin A/metabolism , Immunoglobulin G/metabolism , Immunoglobulin M/metabolism , Male , Prognosis , Proteome , Severity of Illness Index , Systemic Inflammatory Response Syndrome/diagnosis
10.
Clin Chem Lab Med ; 59(11): 1878-1884, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1341521

ABSTRACT

OBJECTIVES: Numerous analytical systems, rapidly made available on the market throughout the SARS-CoV-2 pandemic, aim to detect COVID-19, and to continuously update and improve the same systems. Medical laboratory professionals have also developed in-house analytical procedures in order to satisfy the enormous volume of requests for tests. These developments have highlighted the need control the analytical procedures used in order to guarantee patient safety. The External Quality Assessment (EQA) Scheme, an important quality assurance tool, aims to guarantee high standard performance for laboratory and analytical procedures. The aim of the present study was to report on the results collected in an experimental EQA scheme for the serological diagnosis of SARS-CoV-2. METHODS: All qualitative results collected in the different EQA surveys were summarized in order to identify the percentage of laboratory results in relation to typology of antibodies, results and samples. RESULTS: A total of 4,867 data sets were collected. The analysis of EQA data made, demonstrates a better agreement among laboratories results for total Ig than single immunoglobulins (IgG, IgM, IgA) in the case samples positive for SARS-CoV-2, and a wide divergence between IgM results for positive samples (only 34.9% were correct). Results for negative controls and specificity controls demonstrated a better overall agreement than results for positive samples. CONCLUSIONS: Working in collaboration with the IVD manufacturers, laboratory professionals must strive to achieve harmonization of results, and to develop well-defined protocols complying with the ISO 15189 requirements.


Subject(s)
Antibodies, Viral/immunology , COVID-19/diagnosis , SARS-CoV-2/immunology , Serologic Tests/methods , Antibodies, Viral/blood , COVID-19/immunology , Humans , Immunoglobulin A/blood , Immunoglobulin A/metabolism , Immunoglobulin G/blood , Immunoglobulin G/metabolism , Immunoglobulin M/blood , Immunoglobulin M/metabolism , Pilot Projects , Quality Assurance, Health Care , Retrospective Studies , Sensitivity and Specificity , Severity of Illness Index
11.
Int J Mol Sci ; 22(14)2021 Jul 14.
Article in English | MEDLINE | ID: covidwho-1323262

ABSTRACT

IgA, previously called Henoch-Schönlein vasculitis, is an essential immune component that drives the host immune response to the external environment. As IgA has the unique characteristic of a flexible response to broad types of microorganisms, it sometimes causes an autoreactive response in the host human body. IgA vasculitis and related organ dysfunction are representative IgA-mediated autoimmune diseases; bacterial and viral infections often trigger IgA vasculitis. Recent drug developments and the presence of COVID-19 have revealed that these agents can also trigger IgA vasculitis. These findings provide a novel understanding of the pathogenesis of IgA vasculitis. In this review, we focus on the characteristics of IgA and symptoms of IgA vasculitis and other organ dysfunction. We also mention the therapeutic approach, biomarkers, novel triggers for IgA vasculitis, and epigenetic modifications in patients with IgA vasculitis.


Subject(s)
Biomarkers/analysis , Epigenesis, Genetic , Immunoglobulin A/metabolism , Vasculitis/therapy , Animals , Humans , Vasculitis/diagnosis , Vasculitis/etiology , Vasculitis/metabolism
13.
Front Immunol ; 12: 695230, 2021.
Article in English | MEDLINE | ID: covidwho-1285296

ABSTRACT

A detailed understanding of the antibody response against SARS-CoV-2 is of high importance, especially with the emergence of novel vaccines. A multiplex-based assay, analyzing IgG, IgM, and IgA antibodies against the receptor binding domain (RBD), spike 1 (S1), and nucleocapsid proteins of the SARS-CoV-2 virus was set up. The multiplex-based analysis was calibrated against the Elecsys® Anti-SARS-CoV-2 assay on a Roche Cobas® instrument, using positive and negative samples. The calibration of the multiplex based assay yielded a sensitivity of 100% and a specificity of 97.7%. SARS-CoV-2 specific antibody levels were analyzed by multiplex in 251 samples from 221 patients. A significant increase in all antibody types (IgM, IgG, and IgA) against RBD was observed between the first and the third weeks of disease. Additionally, the S1 IgG antibody response increased significantly between weeks 1, 2, and 3 of disease. Class switching appeared to occur earlier for IgA than for IgG. Patients requiring hospital admission and intensive care had higher levels of SARS-CoV-2 specific IgA levels than outpatients. These findings describe the initial antibody response during the first weeks of disease and demonstrate the importance of analyzing different antibody isotypes against multiple antigens and include IgA when examining the immunological response to COVID-19.


Subject(s)
Antibodies, Viral/metabolism , COVID-19/immunology , Immunoglobulin A/metabolism , Immunoglobulin G/metabolism , Immunoglobulin M/metabolism , SARS-CoV-2/immunology , Adult , Aged , Antibody Formation , Female , Humans , Male , Middle Aged , Protein Domains/immunology , Spike Glycoprotein, Coronavirus/immunology
14.
Viruses ; 13(6)2021 05 21.
Article in English | MEDLINE | ID: covidwho-1244141

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) predominantly have a respiratory tract infection with various symptoms and high mortality is associated with respiratory failure second to severe disease. The risk factors leading to severe disease remain unclear. Here, we reanalyzed a published single-cell RNA-Seq (scRNA-Seq) dataset and found that bronchoalveolar lavage fluid (BALF) of patients with severe disease compared to those with mild disease contained decreased TH17-type cells, decreased IFNA1-expressing cells with lower expression of toll-like receptor 7 (TLR7) and TLR8, increased IgA-expressing B cells, and increased hyperactive epithelial cells (and/or macrophages) expressing matrix metalloproteinases (MMPs), hyaluronan synthase 2 (HAS2), and plasminogen activator inhibitor-1 (PAI-1), which may together contribute to the pulmonary pathology in severe COVID-19. We propose IFN-I (and TLR7/TLR8) and PAI-1 as potential biomarkers to predict the susceptibility to severe COVID-19.


Subject(s)
COVID-19/pathology , Lung/pathology , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Biomarkers/metabolism , Bronchoalveolar Lavage Fluid/immunology , COVID-19/immunology , COVID-19/metabolism , Databases, Genetic , Humans , Hyaluronan Synthases/metabolism , Immunoglobulin A/metabolism , Interferon-alpha/metabolism , Lung/immunology , Lung/metabolism , Matrix Metalloproteinases/metabolism , Mucin-1/metabolism , Plasminogen Activator Inhibitor 1/metabolism , RNA-Seq , SARS-CoV-2 , Th17 Cells/metabolism , Th17 Cells/pathology
15.
FEBS Lett ; 595(13): 1819-1824, 2021 07.
Article in English | MEDLINE | ID: covidwho-1220171

ABSTRACT

We previously observed enhanced immunoglobulin A (IgA) responses in severe COVID-19, which might confer damaging effects. Given the important role of IgA in immune and inflammatory responses, the aim of this study was to investigate the dynamic response of the IgA isotype switch factor TGF-ß1 in COVID-19 patients. We observed, in a total of 153 COVID-19 patients, that the serum levels of TGF-ß1 were increased significantly at the early and middle stages of COVID-19, and correlated with the levels of SARS-CoV-2-specific IgA, as well as with the APACHE II score in patients with severe disease. In view of the genetic association of the TGF-ß1 activator THBS3 with severe COVID-19 identified by the COVID-19 Host Genetics Initiative, this study suggests TGF-ß1 may play a key role in COVID-19.


Subject(s)
COVID-19/immunology , Immunoglobulin A/blood , SARS-CoV-2/immunology , Thrombospondins/genetics , Transforming Growth Factor beta1/blood , APACHE , Adult , Aged , Antibodies, Viral/blood , COVID-19/blood , COVID-19/genetics , Female , Humans , Immunoglobulin A/metabolism , Male , Middle Aged , Polymorphism, Single Nucleotide
16.
Front Immunol ; 12: 595343, 2021.
Article in English | MEDLINE | ID: covidwho-1133908

ABSTRACT

Likely as in other viral respiratory diseases, SARS-CoV-2 elicit a local immune response, which includes production and releasing of both cytokines and secretory immunoglobulin (SIgA). Therefore, in this study, we investigated the levels of specific-SIgA for SARS-CoV-2 and cytokines in the airways mucosa 37 patients who were suspected of COVID-19. According to the RT-PCR results, the patients were separated into three groups: negative for COVID-19 and other viruses (NEGS, n = 5); negative for COVID-19 but positive for the presence of other viruses (OTHERS, n = 5); and the positive for COVID-19 (COVID-19, n = 27). Higher specific-SIgA for SARS-CoV-2, IFN-ß, and IFN-γ were found in the COVID-19 group than in the other groups. Increased IL-12p70 levels were observed in OTHERS group as compared to COVID-19 group. When the COVID-19 group was sub stratified according to the illness severity, significant differences and correlations were found for the same parameters described above comparing severe COVID-19 to the mild COVID-19 group and other non-COVID-19 groups. For the first time, significant differences are shown in the airway's mucosa immune responses in different groups of patients with or without respiratory SARS-CoV-2 infection.


Subject(s)
Antibodies, Viral/metabolism , COVID-19/immunology , Immunoglobulin A/metabolism , Interferons/metabolism , Lung/pathology , Nasal Mucosa/metabolism , SARS-CoV-2/physiology , Adolescent , Adult , Aged , Brazil , Child , Disease Progression , Female , Humans , Male , Middle Aged , Nasal Mucosa/immunology , Young Adult
17.
Cell Mol Immunol ; 17(11): 1119-1125, 2020 11.
Article in English | MEDLINE | ID: covidwho-841899

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been redetected after discharge in some coronavirus disease 2019 (COVID-19) patients. The reason for the recurrent positivity of the test and the potential public health concern due to this occurrence are still unknown. Here, we analyzed the viral data and clinical manifestations of 289 domestic Chinese COVID-19 patients and found that 21 individuals (7.3%) were readmitted for hospitalization after detection of SARS-CoV-2 after discharge. First, we experimentally confirmed that the virus was involved in the initial infection and was not a secondary infection. In positive retests, the virus was usually found in anal samples (15 of 21, 71.4%). Through analysis of the intracellular viral subgenomic messenger RNA (sgmRNA), we verified that positive retest patients had active viral replication in their gastrointestinal tracts (3 of 16 patients, 18.7%) but not in their respiratory tracts. Then, we found that viral persistence was not associated with high viral titers, delayed viral clearance, old age, or more severe clinical symptoms during the first hospitalization. In contrast, viral rebound was associated with significantly lower levels of and slower generation of viral receptor-binding domain (RBD)-specific IgA and IgG antibodies. Our study demonstrated that the positive retest patients failed to create a robust protective humoral immune response, which might result in SARS-CoV-2 persistence in the gastrointestinal tract and possibly in active viral shedding. Further exploration of the mechanism underlying the rebound in SARS-CoV-2 in this population will be crucial for preventing virus spread and developing effective vaccines.


Subject(s)
Betacoronavirus/physiology , Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Gastrointestinal Tract/virology , Pneumonia, Viral/diagnosis , Antibodies, Viral/metabolism , COVID-19 , COVID-19 Testing , Coronavirus Infections/immunology , Epitopes/immunology , Humans , Immunity, Humoral , Immunoglobulin A/metabolism , Immunoglobulin G/metabolism , Pandemics , Pneumonia, Viral/immunology , Protein Binding , Protein Domains/immunology , SARS-CoV-2 , Serologic Tests , Spike Glycoprotein, Coronavirus/immunology , Viral Load , Virus Shedding
18.
PLoS One ; 15(4): e0231723, 2020.
Article in English | MEDLINE | ID: covidwho-827309

ABSTRACT

Understanding the immune responses against Porcine epidemic diarrhea virus (PEDV) is important to prevent infection and to design control strategies. We evaluated both systemic and mucosal immune responses to PEDV in pigs and assessed if prior exposure to virus protects against re-infection. Three-week-old pigs were infected with PEDV and immune response in blood, intestine, and mesenteric lymph node (MLN) was evaluated. At 30 dpi, virus exposed pigs were challenged with a field isolate of PEDV and immune response at 5 d post challenge was evaluated. We found that PEDV RNA persists in the intestine even after fecal shedding of the virus was stopped at 28 dpi and pigs previously exposed to PEDV are protected from virus shedding after re-infection. PEDV infection induced both humoral and cell mediated immune response with an increase in PEDV specific IgA and IgG antibodies in intestine and serum. Flow cytometry analysis showed a significantly higher frequency of B cells and lower frequency of T cells at 4 dpi. The frequency of CD4/CD8 double positive (DP) memory T cells was significantly increased in the MLN of challenged animals. These studies may provide further insights into understanding the mucosal immune response to PEDV and its role in protection against disease.


Subject(s)
Antibodies, Viral/analysis , Coronavirus Infections/immunology , Diarrhea/immunology , Porcine epidemic diarrhea virus/immunology , Animals , Antibodies, Viral/immunology , Antibodies, Viral/metabolism , B-Lymphocytes/immunology , Coronavirus Infections/blood , Coronavirus Infections/veterinary , Coronavirus Infections/virology , Diarrhea/blood , Diarrhea/veterinary , Diarrhea/virology , Disease Resistance/immunology , Feces/microbiology , Immunity, Cellular , Immunity, Humoral , Immunity, Mucosal , Immunoglobulin A/analysis , Immunoglobulin A/immunology , Immunoglobulin A/metabolism , Immunoglobulin G/analysis , Immunoglobulin G/immunology , Immunoglobulin G/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Porcine epidemic diarrhea virus/genetics , Porcine epidemic diarrhea virus/isolation & purification , RNA, Viral/isolation & purification , Swine , T-Lymphocytes/immunology , Virus Shedding
19.
J Hum Lact ; 36(4): 609-613, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-799479

ABSTRACT

INTRODUCTION: Human milk cannot currently be considered a major source of COVID-19 infection. On the other hand, it can contain specific antibodies that could modulate a possible newborn infection by SARS-CoV-2. MAIN ISSUE: A 32-year-old pregnant woman, gestational age 37 and 3/7 weeks, was admitted with a flu-like syndrome caused by COVID-19. The female newborn was appropriate for gestational age, with a birth weight of 2,890 g, length 48 cm, and head circumference 34 cm. MANAGEMENT: The mother-infant dyad remained in the rooming-in unit during hospitalization, exclusively breastfeeding and following World Health Organization recommendations for contact and airway precautions. On the 3rd day after delivery, two mother's milk samples (3 and 5 mL) were collected by hand expression. The samples were centrifuged for 10 min twice consecutively to separate fat, which was removed, and the remaining material was transferred to another tube to determine anti-SARS-CoV-2 Immunoglobulin A and Immunoglobulin G (ELISA, Kit EUROIMMUN AG, Luebeck, Germany). Anti-SARS-CoV-2 Immunoglobulin A was detected in the two samples evaluated, whose values were 2.5 and 1.9, respectively. No anti-SARSCoV-2 immunoglobulin G was detected. The exclusively-breastfed infant remained well through 45 days of age. CONCLUSION: The presence of SARS-CoV-2 Immunoglobulin A in the milk of mothers infected with COVID-19 may be related to protection against the transmission and severity of the disease in their infants.


Subject(s)
Antibodies, Viral/metabolism , COVID-19/immunology , Immunoglobulin A/metabolism , Infectious Disease Transmission, Vertical , Milk, Human/immunology , Pregnancy Complications, Infectious/immunology , SARS-CoV-2/immunology , Adult , Biomarkers/metabolism , Breast Feeding , COVID-19/diagnosis , COVID-19/prevention & control , COVID-19/transmission , COVID-19 Serological Testing , Female , Humans , Infant, Newborn , Pregnancy , Pregnancy Complications, Infectious/diagnosis , SARS-CoV-2/isolation & purification
20.
Front Immunol ; 11: 1959, 2020.
Article in English | MEDLINE | ID: covidwho-732901

ABSTRACT

The lung is the vital target organ of coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the majority of patients the most active virus replication seems to be found in the upper respiratory tract, severe cases however suffer from SARS-like disease associated with virus replication in lung tissues. Due to the current lack of suitable anti-viral drugs the induction of protective immunity such as neutralizing antibodies in the lung is the key aim of the only alternative approach-the development and application of SARS-CoV-2 vaccines. However, past experience from experimental animals, livestock, and humans showed that induction of immunity in the lung is limited following application of vaccines at peripheral sides such as skin or muscles. Based on several considerations we therefore propose here to consider the application of a Modified Vaccinia virus Ankara (MVA)-based vaccine to mucosal surfaces of the respiratory tract as a favorable approach to combat COVID-19.


Subject(s)
Betacoronavirus/chemistry , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/immunology , Vaccinia virus/immunology , Viral Vaccines/administration & dosage , Viral Vaccines/immunology , Administration, Mucosal , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Bronchi/immunology , COVID-19 , Coronavirus Infections/virology , Humans , Immunoglobulin A/metabolism , Lymphoid Tissue/immunology , Plasma Cells/immunology , Pneumonia, Viral/virology , Respiratory Mucosa/drug effects , Respiratory Mucosa/immunology , SARS-CoV-2 , T-Lymphocytes/immunology , Vaccination , Vaccines, Attenuated/immunology
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