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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332815

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized in association with increased Notch1 expression. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variant impacting inflammation and autoimmunity pathways, including dominant negative mutations in the Notch1 regulators NUMB and NUMBL . Notch1 signaling in Treg cells induced CD22, leading to their destabilization in an mTORC1 dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

2.
Research Square ; 2022.
Article in English | EuropePMC | ID: covidwho-1786451

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized in association with increased Notch1 expression. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variant impacting inflammation and autoimmunity pathways, including dominant negative mutations in the Notch1 regulators NUMB and NUMBL . Notch1 signaling in Treg cells induced CD22, leading to their destabilization in an mTORC1 dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

3.
Cell Reports Medicine ; 3(3):100558, 2022.
Article in English | ScienceDirect | ID: covidwho-1740280

ABSTRACT

Children were initially considered unsusceptible to severe COVID-19. Our knowledge after two years has changed dramatically, but there are still many unknowns. Here, we report the current knowledge about why children generally experience a milder COVID-19 course and highlight research questions about pediatric infection that require answers.

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-308828

ABSTRACT

BACKGROUND: Despite SARS-CoV-2 immunizations have started in most countries, children are not currently included in the vaccination programs, thus it remains crucial to define their anti-SARS-CoV-2 immune response in order to minimize the risk for other epidemic waves. This study seeks to provide a description of the virology ad anti-SARS-CoV-2 immunity in children with distinct symptomatology. METHODS: Between March and July 2020, we recruited 15 SARS-CoV-2 asymptomatic (AS) and 51 symptomatic children (SY), stratified according to WHO clinical classification. We measured SARS-CoV-2 viral load using ddPCR and qPCR in longitudinally collected nasopharyngeal swabs samples. To define anti-SARS-CoV-2 antibodies we measured neutralization activity and total IgG load (Diasorin). We also evaluated antigen-specific B and CD8+T-cells, using a labelled S1+S2 protein and ICAM expression, respectively. Plasma protein profiling was performed with Olink. RESULTS: Virological profiling showed that AS had lower viral load at diagnosis (p=0.004) and faster virus clearance (p=0.0002) compared to SY. Anti-SARS CoV-2 humoral and cellular response did not appear to be associated with the presence of symptoms. AS and SY showed similar titers of SARS-CoV-2 IgG, levels of neutralizing activity, and frequency of Ag-specific B and CD8+T-cells. Whereas pro-inflammatory plasma protein profile was associated to symptomatology. CONCLUSION: We demonstrated the development of anti-SARS-CoV-2 humoral and cellular response with any regards to symptomatology, suggesting the ability of both SY and AS to contribute towards herd immunity. The virological profiling of AS suggested that they have lower virus load associated with faster virus clearance.

5.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-308827

ABSTRACT

As the global COVID-19 pandemic progresses and with the school reopening, it is paramount to gain knowledge on adaptive immunity to SARS-CoV-2 in children in order to define possible immunization strategies and reconsider pandemic control measures. We analyzed anti-SARS-CoV-2 antibodies (Ab) and their neutralizing activity (PRNT) in 42 COVID-19-infected children 7 days after symptoms onset. Individuals with specific humoral responses presented faster virus clearance, and lower viral load associated to a reduced in vitro infectivity. We demonstrated that the frequencies of SARS-CoV-2 specific CD4-CD40L+ T-cells and Spike specific B-cells were associated with the anti-SARS-CoV-2 Ab and the magnitude of neutralizing activity. The plasma proteome confirmed the association between cellular and humoral SARS-CoV-2 immunity, with PRNT+ patients showing higher viral signal transduction molecules (SLAMF1, CD244, CLEC4G). This work shed lights on cellular and humoral anti-SARS-CoV-2 responses in children which may drive future vaccination trials endpoints and quarantine measures policies.Funding: This work was made possible by support from Bambino Gesù Children’s Hospital ricerca corrente 2020 to NC and ricerca corrente 2019 to PP, by PENTA and by Fondazione Cassa di Risparmio di Padova e Rovigo, Progetti di Ricerca Covid-19 (ADR participant).Conflict of Interest: The authors declare no competing interests.Ethical Approval: Local ethical committee approved the study and written informed consent was obtained from all participants or legal guardians.

7.
Front Immunol ; 12: 727850, 2021.
Article in English | MEDLINE | ID: covidwho-1477821

ABSTRACT

Mass SARS-Cov-2 vaccination campaign represents the only strategy to defeat the global pandemic we are facing. Immunocompromised patients represent a vulnerable population at high risk of developing severe COVID-19 and thus should be prioritized in the vaccination programs and in the study of the vaccine efficacy. Nevertheless, most data on efficacy and safety of the available vaccines derive from trials conducted on healthy individuals; hence, studies on immunogenicity of SARS-CoV2 vaccines in such populations are deeply needed. Here, we perform an observational longitudinal study analyzing the humoral and cellular response following the BNT162b2 mRNA COVID-19 vaccine in a cohort of patients affected by inborn errors of immunity (IEI) compared to healthy controls (HC). We show that both IEI and HC groups experienced a significant increase in anti-SARS-CoV-2 Abs 1 week after the second scheduled dose as well as an overall statistically significant expansion of the Ag-specific CD4+CD40L+ T cells in both HC and IEI. Five IEI patients did not develop any specific CD4+CD40L+ T cellular response, with one of these patients unable to also mount any humoral response. These data raise immunologic concerns about using Ab response as a sole metric of protective immunity following vaccination for SARS-CoV-2. Taken together, these findings suggest that evaluation of vaccine-induced immunity in this subpopulation should also include quantification of Ag-specific T cells.


Subject(s)
Antibodies, Viral/blood , CD4-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Immunogenicity, Vaccine/immunology , Primary Immunodeficiency Diseases/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , CD4 Lymphocyte Count , COVID-19/prevention & control , Female , Humans , Immunity, Cellular/immunology , Immunity, Humoral/immunology , Immunocompromised Host/immunology , Longitudinal Studies , Male , Middle Aged , Vaccination , Young Adult
8.
Cells ; 10(10)2021 09 26.
Article in English | MEDLINE | ID: covidwho-1438527

ABSTRACT

Specific memory B cells and antibodies are a reliable read-out of vaccine efficacy. We analysed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase, thus predicting a sustained protection from COVID-19. We show that although mucosal IgA is not induced by the vaccination, memory B cells migrate in response to inflammation and secrete IgA at mucosal sites. We show that the first vaccine dose may lead to an insufficient number of highly specific memory B cells and low concentration of serum antibodies, thus leaving vaccinees without the immune robustness needed to ensure viral elimination and herd immunity. We also clarify that the reduction of serum antibodies does not diminish the force and duration of the immune protection induced by vaccination. The vaccine does not induce sterilizing immunity. Infection after vaccination may be caused by the lack of local preventive immunity because of the absence of mucosal IgA.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/cytology , COVID-19 Vaccines/therapeutic use , COVID-19/immunology , COVID-19/prevention & control , Immunoglobulin A/immunology , Immunologic Memory , Adult , Antibodies, Neutralizing/blood , Antigens, Viral/immunology , B-Lymphocytes/immunology , Cryopreservation , Female , Health Personnel , Healthy Volunteers , Hospitals, Pediatric , Humans , Immunoglobulin G , Immunoglobulin M/immunology , Lactation , Male , Middle Aged , Mucous Membrane/immunology , Patient Safety , SARS-CoV-2 , Vaccination
9.
Pediatr Allergy Immunol ; 32(8): 1833-1842, 2021 11.
Article in English | MEDLINE | ID: covidwho-1282025

ABSTRACT

BACKGROUND: Although SARS-CoV-2 immunizations have started in most countries, children are not currently included in the vaccination programs; thus, it remains crucial to define their anti-SARS-CoV-2 immune response in order to minimize the risk for other epidemic waves. This study sought to provide a description of the virology ad anti-SARS-CoV-2 immunity in children with distinct symptomatology. METHODS: Between March and July 2020, we recruited 15 SARS-CoV-2 asymptomatic (AS) and 51 symptomatic (SY) children, stratified according to WHO clinical classification. We measured SARS-CoV-2 viral load using ddPCR and qPCR in longitudinally collected nasopharyngeal swab samples. To define anti-SARS-CoV-2 antibodies, we measured neutralization activity and total IgG load (DiaSorin). We also evaluated antigen-specific B and CD8+T cells, using a labeled S1+S2 protein and ICAM expression, respectively. Plasma protein profiling was performed with Olink. RESULTS: Virological profiling showed that AS patients had lower viral load at diagnosis (p = .004) and faster virus clearance (p = .0002) compared with SY patients. Anti-SARS-CoV-2 humoral and cellular response did not appear to be associated with the presence of symptoms. AS and SY patients showed similar titers of SARS-CoV-2 IgG, levels of neutralizing activity, and frequency of Ag-specific B and CD8+ T cells, whereas pro-inflammatory plasma protein profile was found to be associated with symptomatology. CONCLUSION: We demonstrated the development of anti-SARS-CoV-2 humoral and cellular response with any regard to symptomatology, suggesting the ability of both SY and AS patients to contribute toward herd immunity. The virological profiling of AS patients suggested that they have lower virus load associated with faster virus clearance.


Subject(s)
COVID-19 , Antibodies, Viral/blood , B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Child , Humans , Immunoglobulin G/blood , SARS-CoV-2 , Serologic Tests
10.
Eur J Gastroenterol Hepatol ; 33(1S Suppl 1): e1051-e1056, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1242125

ABSTRACT

Gut involvement is frequent in immunologic disorders, especially with inflammatory manifestations but also with cancer. In the last years, advances in functional and genetic testing have improved the diagnostic and therapeutic approach to immune dysregulation syndromes. CTLA-4 deficiency is a rare disease with variable phenotype, ranging from absence of symptoms to severe multisystem manifestations and complications. We describe a rare case of CTLA-4 deficiency in a boy with gastric cancer, very early onset inflammatory bowel disease and polyautoimmunity, the second-ever reported in the literature with the same characteristics. A 17-year-old boy was referred to Bambino Gesù Children's Hospital of Rome, a tertiary care center, for a gastric mass and a long-term history of very early onset inflammatory bowel disease, diabetes mellitus type 1, polyarthritis and psoriasis. Histology of gastric biopsies revealed the presence of neoplastic signet ring cells. Imaging staging showed localized cancer; therefore, the patient underwent subtotal gastrectomy with termino-lateral gastro-jejunal anastomosis. Immunological work up and genetic testing by next-generation sequencing panels for primary immunodeficiencies led to the diagnosis of CTLA-4 deficiency. Good disease control was obtained with the administration of Abatacept. The patient experienced an asymptomatic SARS-CoV-2 infection without any concern. Eighteen months after treatment initiation, the patient is alive and well. Immunologic and genetic testing, such as next-generation sequencing, should always be part of the diagnostic approach to patients with complex immune dysregulation syndrome, severe clinical course, poor response to treatments or cancer. The early recognition of the monogenic disease is the key for disease management and targeted therapy.


Subject(s)
Abatacept/therapeutic use , Autoimmune Diseases , CTLA-4 Antigen/deficiency , Inflammatory Bowel Diseases , Stomach Neoplasms , Adolescent , Asymptomatic Infections , Autoimmune Diseases/diagnosis , Autoimmune Diseases/drug therapy , Autoimmune Diseases/genetics , COVID-19 , CTLA-4 Antigen/genetics , Humans , Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/genetics , Male , Stomach Neoplasms/diagnosis , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics
11.
Cell Rep ; 34(11): 108852, 2021 03 16.
Article in English | MEDLINE | ID: covidwho-1135278

ABSTRACT

As the global COVID-19 pandemic progresses, it is paramount to gain knowledge on adaptive immunity to SARS-CoV-2 in children to define immune correlates of protection upon immunization or infection. We analyzed anti-SARS-CoV-2 antibodies and their neutralizing activity (PRNT) in 66 COVID-19-infected children at 7 (±2) days after symptom onset. Individuals with specific humoral responses presented faster virus clearance and lower viral load associated with a reduced in vitro infectivity. We demonstrated that the frequencies of SARS-CoV-2-specific CD4+CD40L+ T cells and Spike-specific B cells were associated with the anti-SARS-CoV-2 antibodies and the magnitude of neutralizing activity. The plasma proteome confirmed the association between cellular and humoral SARS-CoV-2 immunity, and PRNT+ patients show higher viral signal transduction molecules (SLAMF1, CD244, CLEC4G). This work sheds lights on cellular and humoral anti-SARS-CoV-2 responses in children, which may drive future vaccination trial endpoints and quarantine measures policies.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Adaptive Immunity/immunology , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , COVID-19/virology , Child , Humans , Immunity, Humoral/immunology , Proteome/immunology , SARS-CoV-2/immunology , Signal Transduction/immunology , Viral Load/immunology
12.
Cell ; 183(4): 968-981.e7, 2020 11 12.
Article in English | MEDLINE | ID: covidwho-746088

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.


Subject(s)
Coronavirus Infections/pathology , Pneumonia, Viral/pathology , Systemic Inflammatory Response Syndrome/pathology , Autoantibodies/blood , Betacoronavirus/isolation & purification , COVID-19 , Child , Child, Preschool , Coronavirus Infections/complications , Coronavirus Infections/virology , Cytokines/metabolism , Female , Humans , Immunity, Humoral , Infant , Male , Mucocutaneous Lymph Node Syndrome/complications , Mucocutaneous Lymph Node Syndrome/immunology , Mucocutaneous Lymph Node Syndrome/pathology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , Principal Component Analysis , Proteome/analysis , SARS-CoV-2 , Severity of Illness Index , Systemic Inflammatory Response Syndrome/etiology , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
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