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1.
J Infect Dis ; 224(8): 1333-1344, 2021 10 28.
Article in English | MEDLINE | ID: covidwho-1493827

ABSTRACT

BACKGROUND: Lymphopenia is a key feature for adult patients with coronavirus disease 2019 (COVID-19), although it is rarely observed in children. The underlying mechanism remains unclear. METHODS: Immunohistochemical and flow cytometric analyses were used to compare the apoptotic rate of T cells from COVID-19 adults and children and apoptotic responses of adult and child T cells to COVID-19 pooled plasma. Biological properties of caspases and reactive oxygen species were assessed in T cells treated by COVID-19 pooled plasma. RESULTS: Mitochondria apoptosis of peripheral T cells were identified in COVID-19 adult patient samples but not in the children. Furthermore, increased tumor necrosis factor-α and interleukin-6 in COVID-19 plasma induced mitochondria apoptosis and caused deoxyribonucleic acid damage by elevating reactive oxygen species levels of the adult T cells. However, the child T cells showed tolerance to mitochondrial apoptosis due to mitochondria autophagy. Activation of autophagy could decrease apoptotic sensitivity of the adult T cells to plasma from COVID-19 patients. CONCLUSIONS: Our results indicated that the mitochondrial apoptosis pathway was activated in T cells of COVID-19 adult patients specifically, which may shed light on the pathophysiological difference between adults and children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ).


Subject(s)
COVID-19/complications , Lymphopenia/blood , SARS-CoV-2/immunology , T-Lymphocytes/pathology , Adolescent , Adult , Age Factors , Aged , Apoptosis/immunology , Autophagy , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Child , Child, Preschool , Humans , Infant , Lymphopenia/immunology , Lymphopenia/pathology , Lymphopenia/virology , Male , Middle Aged , Mitochondria/immunology , Mitochondria/pathology , Reactive Oxygen Species/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology
2.
Int J Mol Sci ; 22(20)2021 Oct 18.
Article in English | MEDLINE | ID: covidwho-1470893

ABSTRACT

SputnikV is a vaccine against SARS-CoV-2 developed by the Gamaleya National Research Centre for Epidemiology and Microbiology. The vaccine has been shown to induce both humoral and cellular immune responses, yet the mechanisms remain largely unknown. Forty SputnikV vaccinated individuals were included in this study which aimed to demonstrate the location of immunogenic domains of the SARS-CoV-2 S protein using an overlapping peptide library. Additionally, cytokines in the serum of vaccinated and convalescent COVID-19 patients were analyzed. We have found antibodies from both vaccinated and convalescent sera bind to immunogenic regions located in multiple domains of SARS-CoV-2 S protein, including Receptor Binding Domain (RBD), N-terminal Domain (NTD), Fusion Protein (FP) and Heptad Repeats (HRs). Interestingly, many peptides were recognized by immunized and convalescent serum antibodies and correspond to conserved regions in circulating variants of SARS-CoV-2. This breadth of reactivity was still evident 90 days after the first dose of the vaccine, showing that the vaccine has induced a prolonged response. As evidenced by the activation of T cells, cellular immunity strongly suggests the high potency of the SputnikV vaccine against SARS-CoV-2 infection.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Immunity, Cellular , Immunity, Humoral , Adult , Amino Acid Sequence , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/immunology , Cytokines/metabolism , Female , Humans , Male , Peptides/chemistry , Peptides/immunology , Principal Component Analysis , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Vaccination
3.
Front Immunol ; 12: 740249, 2021.
Article in English | MEDLINE | ID: covidwho-1448730

ABSTRACT

Objective: To assess in rheumatoid arthritis (RA) patients, treated with different immunosuppressive therapies, the induction of SARS-CoV-2-specific immune response after vaccination in terms of anti-region-binding-domain (RBD)-antibody- and T-cell-specific responses against spike, and the vaccine safety in terms of clinical impact on disease activity. Methods: Health care workers (HCWs) and RA patients, having completed the BNT162b2-mRNA vaccination in the last 2 weeks, were enrolled. Serological response was evaluated by quantifying anti-RBD antibodies, while the cell-mediated response was evaluated by a whole-blood test quantifying the interferon (IFN)-γ-response to spike peptides. FACS analysis was performed to identify the cells responding to spike stimulation. RA disease activity was evaluated by clinical examination through the DAS28crp, and local and/or systemic clinical adverse events were registered. In RA patients, the ongoing therapeutic regimen was modified during the vaccination period according to the American College of Rheumatology indications. Results: We prospectively enrolled 167 HCWs and 35 RA patients. Anti-RBD-antibodies were detected in almost all patients (34/35, 97%), although the titer was significantly reduced in patients under CTLA-4-inhibitors (median: 465 BAU/mL, IQR: 103-1189, p<0.001) or IL-6-inhibitors (median: 492 BAU/mL, IQR: 161-1007, p<0.001) compared to HCWs (median: 2351 BAU/mL, IQR: 1389-3748). T-cell-specific response scored positive in most of RA patients [24/35, (69%)] with significantly lower IFN-γ levels in patients under biological therapy such as IL-6-inhibitors (median: 33.2 pg/mL, IQR: 6.1-73.9, p<0.001), CTLA-4-inhibitors (median: 10.9 pg/mL, IQR: 3.7-36.7, p<0.001), and TNF-α-inhibitors (median: 89.6 pg/mL, IQR: 17.8-224, p=0.002) compared to HCWs (median: 343 pg/mL, IQR: 188-756). A significant correlation between the anti-RBD-antibody titer and spike-IFN-γ-specific T-cell response was found in RA patients (rho=0.432, p=0.009). IFN-γ T-cell response was mediated by CD4+ and CD8+ T cells. Finally, no significant increase in disease activity was found in RA patients following vaccination. Conclusion: This study showed for the first time that antibody-specific and whole-blood spike-specific T-cell responses induced by the COVID-19 mRNA-vaccine were present in the majority of RA patients, who underwent a strategy of temporary suspension of immunosuppressive treatment during vaccine administration. However, the magnitude of specific responses was dependent on the immunosuppressive therapy administered. In RA patients, BNT162b2 vaccine was safe and disease activity remained stable.


Subject(s)
Antibodies, Viral/immunology , Arthritis, Rheumatoid/therapy , COVID-19 Vaccines/immunology , Immunotherapy/adverse effects , T-Lymphocytes/immunology , Aged , Arthritis, Rheumatoid/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , COVID-19/prevention & control , Female , Humans , Interferon-gamma/immunology , Lymphocyte Count , Male , Middle Aged , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/cytology , Vaccines, Synthetic/immunology
4.
Cells ; 10(10)2021 10 03.
Article in English | MEDLINE | ID: covidwho-1444118

ABSTRACT

The PD-L1/PD-1 immune checkpoint axis is the strongest T cell exhaustion inducer. As immune dysfunction occurs during obesity, we analyzed the impact of obesity on PD-L1/PD-1 expression in white adipose tissue (WAT) in mice and in human white adipocytes. We found that PD-L1 was overexpressed in WAT of diet-induced obese mice and was associated with increased expression of PD-1 in visceral but not subcutaneous WAT. Human in vitro cocultures with adipose-tissue-derived mesenchymal stem cells (ASC) and mononuclear cells demonstrated that the presence of ASC harvested from obese WAT (i) enhanced PD-L1 expression as compared with ASC from lean WAT, (ii) decreased Th1 cell cytokine secretion, and (iii) resulted in decreased cytolytic activity towards adipocytes. Moreover, (iv) the implication of PD-L1 in obese ASC-mediated T cell dysfunction was demonstrated through PD-L1 blockade. Finally, (v) conditioned media gathered from these cocultures enhanced PD-L1 expression in freshly differentiated adipocytes, depending on IFNγ. Altogether, our results suggest that PD-L1 is overexpressed in the WAT of obese individuals during IFNγ secretion, leading to T cell dysfunction and notably reduced cytolytic activity. Such a mechanism could shed light on why adipose-tissue-infiltrating viruses, such as SARS-CoV-2, can worsen disease in obese individuals.


Subject(s)
Adipose Tissue, White/metabolism , B7-H1 Antigen/biosynthesis , Gene Expression Regulation , Mesenchymal Stem Cells/cytology , Obesity/metabolism , T-Lymphocytes/immunology , Animals , COVID-19/immunology , Cell Differentiation , Coculture Techniques , Humans , Immunohistochemistry , Inflammation , Interferon-gamma/metabolism , Leukocytes, Mononuclear/cytology , Male , Mice , Mice, Inbred C57BL , Obesity/immunology , SARS-CoV-2 , T-Lymphocytes/cytology
6.
J Med Virol ; 93(9): 5295-5309, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1363691

ABSTRACT

The human immune system is not adequately equipped to eliminate new microbes and could result in serious damage on first exposure. This is primarily attributed to the exaggerated immune response (inflammatory disease), which may prove detrimental to the host, as evidenced by SARS-CoV-2 infection. From the experiences of Novel Coronavirus Disease-19 to date, male patients are likely to suffer from high-intensity inflammation and disease severity than the female population. Hormones are considered the significant pillars of sex differences responsible for the discrepancy in immune response exhibited by males and females. Females appear to be better equipped to counter invading respiratory viral pathogens, including the novel SARS-CoV-2, than males. It can be hypothesized that females are more shielded from disease severity, probably owing to the diverse action/influence of estrogen and other sex hormones on both cellular (thymus-derived T lymphocytes) and humoral immunity (antibodies).


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , COVID-19 , Estrogens/immunology , Sex Factors , COVID-19/epidemiology , COVID-19/immunology , Female , Humans , Immunity, Humoral , Male , T-Lymphocytes/cytology , T-Lymphocytes/immunology
7.
Cell Rep ; 36(8): 109570, 2021 08 24.
Article in English | MEDLINE | ID: covidwho-1356159

ABSTRACT

The rapid development of mRNA-based vaccines against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) led to the design of accelerated vaccination schedules that have been extremely effective in naive individuals. While a two-dose immunization regimen with the BNT162b2 vaccine has been demonstrated to provide a 95% efficacy in naive individuals, the effects of the second vaccine dose in individuals who have previously recovered from natural SARS-CoV-2 infection has not been investigated in detail. In this study, we characterize SARS-CoV-2 spike-specific humoral and cellular immunity in naive and previously infected individuals during and after two doses of BNT162b2 vaccination. Our results demonstrate that, while the second dose increases both the humoral and cellular immunity in naive individuals, COVID-19 recovered individuals reach their peak of immunity after the first dose. These results suggests that a second dose, according to the current standard regimen of vaccination, may be not necessary in individuals previously infected with SARS-CoV-2.


Subject(s)
COVID-19/prevention & control , T-Lymphocytes/immunology , Vaccines, Synthetic/administration & dosage , Antibodies, Viral/blood , CD40 Ligand/metabolism , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Humans , Immunity, Cellular , Immunity, Humoral , Immunoglobulin G/blood , Interferon-gamma/metabolism , Interleukin-2/metabolism , Peptides/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Vaccination , Vaccines, Synthetic/immunology
8.
Biomedica ; 41(Sp. 2): 86-102, 2021 10 15.
Article in English, Spanish | MEDLINE | ID: covidwho-1332335

ABSTRACT

INTRODUCTION: Immunological markers have been described during COVID-19 and persist after recovery. These immune markers are associated with clinical features among SARSCoV-2 infected individuals. Nevertheless, studies reporting a comprehensive analysis of the immune changes occurring during SARS-CoV-2 infection are still limited. OBJECTIVE: To evaluate the production of proinflammatory cytokines, the antibody response, and the phenotype and function of NK cells and T cells in a Colombian family cluster with SARS-CoV-2 infection. MATERIALS AND METHODS: Proinflammatory cytokines were evaluated by RT-PCR and ELISA. The frequency, phenotype, and function of NK cells (cocultures with K562 cells) and T-cells (stimulated with spike/RdRp peptides) were assessed by flow cytometry. Anti-SARS-CoV-2 antibodies were determined using indirect immunofluorescence and plaque reduction neutralization assay. RESULTS: During COVID-19, we observed a high proinflammatory-cytokine production and a reduced CD56bright-NK cell and cytotoxic response. Compared with healthy controls, infected individuals had a higher frequency of dysfunctional CD8+ T cells CD38+HLA-DR-. During the acute phase, CD8+ T cells stimulated with viral peptides exhibited a monofunctional response characterized by high IL-10 production. However, during recovery, we observed a bifunctional response characterized by the co-expression of CD107a and granzyme B or perforin. CONCLUSION: Although the proinflammatory response is a hallmark of SARS-CoV-2 infection, other phenotypic and functional alterations in NK cells and CD8+ T cells could be associated with the outcome of COVID-19. However, additional studies are required to understand these alterations and to guide future immunotherapy strategies.


Subject(s)
COVID-19/immunology , Killer Cells, Natural , SARS-CoV-2/immunology , T-Lymphocytes , Adult , Antibodies, Viral/analysis , CD56 Antigen/immunology , Case-Control Studies , Colombia , Family Health , Granzymes/metabolism , Humans , Interleukin-10/metabolism , Interleukin-1beta/blood , Interleukin-6/blood , Interleukin-8/blood , K562 Cells , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Lymphocyte Activation , Male , Middle Aged , Perforin/metabolism , Phenotype , Receptors, CCR7/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/blood , Young Adult
9.
Sci Rep ; 11(1): 15295, 2021 07 27.
Article in English | MEDLINE | ID: covidwho-1328858

ABSTRACT

The a priori T cell repertoire and immune response against SARS-CoV-2 viral antigens may explain the varying clinical course and prognosis of patients having a mild COVID-19 infection as opposed to those developing more fulminant multisystem organ failure and associated mortality. Using a novel SARS-Cov-2-specific artificial antigen presenting cell (aAPC), coupled with a rapid expansion protocol (REP) as practiced in tumor infiltrating lymphocytes (TIL) therapy, we generate an immune catalytic quantity of Virus Induced Lymphocytes (VIL). Using T cell receptor (TCR)-specific aAPCs carrying co-stimulatory molecules and major histocompatibility complex (MHC) class-I immunodominant SARS-CoV-2 peptide-pentamer complexes, we expand virus-specific VIL derived from peripheral blood mononuclear cells (PBMC) of convalescent COVID-19 patients up to 1000-fold. This is achieved in a clinically relevant 7-day vein-to-vein time-course as a potential adoptive cell therapy (ACT) for COVID-19. We also evaluate this approach for other viral pathogens using Cytomegalovirus (CMV)-specific VIL from donors as a control. Rapidly expanded VIL are enriched in virus antigen-specificity and show an activated, polyfunctional cytokine profile and T effector memory phenotype which may contribute to a robust immune response. Virus-specific T cells can also be delivered allogeneically via MHC-typing and patient human leukocyte antigen (HLA)-matching to provide pragmatic treatment in a large-scale therapeutic setting. These data suggest that VIL may represent a novel therapeutic option that warrants further clinical investigation in the armamentarium against COVID-19 and other possible future pandemics.


Subject(s)
Antigens, Viral/immunology , COVID-19/epidemiology , COVID-19/therapy , Immunotherapy, Adoptive , Pandemics , T-Lymphocytes/cytology , T-Lymphocytes/immunology , COVID-19/immunology , Humans
10.
Cells ; 10(6)2021 06 15.
Article in English | MEDLINE | ID: covidwho-1273393

ABSTRACT

The bone marrow (BM) is key to protective immunological memory because it harbors a major fraction of the body's plasma cells, memory CD4+ and memory CD8+ T-cells. Despite its paramount significance for the human immune system, many aspects of how the BM enables decade-long immunity against pathogens are still poorly understood. In this review, we discuss the relationship between BM survival niches and long-lasting humoral immunity, how intrinsic and extrinsic factors define memory cell longevity and show that the BM is also capable of adopting many responsibilities of a secondary lymphoid organ. Additionally, with more and more data on the differentiation and maintenance of memory T-cells and plasma cells upon vaccination in humans being reported, we discuss what factors determine the establishment of long-lasting immunological memory in the BM and what we can learn for vaccination technologies and antigen design. Finally, using these insights, we touch on how this holistic understanding of the BM is necessary for the development of modern and efficient vaccines against the pandemic SARS-CoV-2.


Subject(s)
Adaptive Immunity/physiology , Bone Marrow/physiology , Plasma Cells/cytology , T-Lymphocytes/cytology , Vaccinology , Bone Marrow Cells/cytology , Bone Marrow Cells/physiology , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Immunity, Cellular/physiology , Immunologic Memory/physiology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Vaccinology/methods , Vaccinology/trends
11.
Stem Cell Reports ; 16(5): 1165-1181, 2021 05 11.
Article in English | MEDLINE | ID: covidwho-1225410

ABSTRACT

SARS-CoV-2 infection is associated with lower blood oxygen levels, even in patients without hypoxia requiring hospitalization. This discordance illustrates the need for a more unifying explanation as to whether SARS-CoV-2 directly or indirectly affects erythropoiesis. Here, we show significantly enriched CD71+ erythroid precursors/progenitors in the blood circulation of COVID-19 patients. We found that these cells have distinctive immunosuppressive properties. In agreement, we observed a strong negative correlation between the frequency of these cells with T and B cell proportions in COVID-19 patients. The expansion of these CD71+ erythroid precursors/progenitors was negatively correlated with the hemoglobin levels. A subpopulation of abundant erythroid cells, CD45+ CD71+ cells, co-express ACE2, TMPRSS2, CD147, and CD26, and these can be infected with SARS-CoV-2. In turn, pre-treatment of erythroid cells with dexamethasone significantly diminished ACE2/TMPRSS2 expression and subsequently reduced their infectivity with SARS-CoV-2. This provides a novel insight into the impact of SARS-CoV-2 on erythropoiesis and hypoxia seen in COVID-19 patients.


Subject(s)
Adaptive Immunity/immunology , COVID-19/pathology , Erythroid Precursor Cells/virology , Erythropoiesis/physiology , Hemoglobins/analysis , Oxygen/blood , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , COVID-19/immunology , Dexamethasone/pharmacology , Erythroid Precursor Cells/immunology , Female , Humans , Lymphocyte Count , Male , Mice , Mice, Inbred BALB C , Middle Aged , SARS-CoV-2/immunology , Serine Endopeptidases/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Young Adult
12.
FASEB J ; 35(5): e21577, 2021 05.
Article in English | MEDLINE | ID: covidwho-1172658

ABSTRACT

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is an emerging respiratory pathogen that has rapidly spread in human populations. Severe forms of infection associate cytokine release syndrome and acute lung injury due to hyperinflammatory responses even though virus clearance is achieved. Key components of inflammation include immune cell recruitment in infected tissues, a step which is under the control of endothelial cells. Here, we review endothelial cell responses in inflammation and infection due to SARS-CoV-2 together with phenotypic and functional alterations of monocytes, T and B lymphocytes with which they interact. We surmise that endothelial cells function as an integrative and active platform for the various cells recruited, where fine tuning of immune responses takes place and which provides opportunities for therapeutic intervention.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , COVID-19/pathology , Endothelial Cells/pathology , Myeloid Cells/immunology , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Cytokines/immunology , Humans , Immunologic Memory , Myeloid Cells/cytology , T-Lymphocytes/cytology , T-Lymphocytes/immunology
14.
Nat Commun ; 12(1): 1112, 2021 02 18.
Article in English | MEDLINE | ID: covidwho-1091491

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.


Subject(s)
COVID-19/diagnosis , Interleukin-3/blood , Animals , COVID-19/mortality , Chemokine CXCL12/immunology , Dendritic Cells/cytology , Disease Models, Animal , Female , Germany , Humans , Immunity, Innate , Interferons/blood , Lung/immunology , Lung/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Prospective Studies , Severity of Illness Index , T-Lymphocytes/cytology , Viral Load
16.
Trends Immunol ; 42(1): 18-30, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065237

ABSTRACT

Severe infection with severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is characterized by massive cytokine release and T cell loss. The exaggerated host immune response, incapable of viral clearance, instead aggravates respiratory distress, as well as cardiac, and/or damage to other organs. The mortality pattern of SARS-CoV-2 infection, higher in older versus younger adults and almost absent in children, is possibly caused by the effects of age and pre-existing comorbidities on innate and adaptive immunity. Here, we speculate that the abnormal and excessive immune response to SARS-CoV-2 infection partly depends on T cell immunological memory, which is more pronounced in adults compared with children, and may significantly contribute to immunopathology and massive collateral damage in coronavirus disease 2019 (COVID-19) patients.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Immunity, Innate/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , COVID-19/prevention & control , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Immunologic Memory/immunology , Models, Immunological , SARS-CoV-2/physiology , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolism
17.
Cell Death Dis ; 11(10): 921, 2020 10 27.
Article in English | MEDLINE | ID: covidwho-894382

ABSTRACT

The immunological mechanisms underlying the clinical presentation of SARS-CoV-2 infection and those influencing the disease outcome remain to be defined. Myeloid-derived suppressor cells (MDSC) have been described to be highly increased during COVID-19, however, their role remains elusive. We performed an in depth analysis of MDSC in 128 SARS-CoV-2 infected patients. Polymorphonuclear (PMN)-MDSC expanded during COVID-19, in particular in patients who required intensive care treatments, and correlated with IL-1ß, IL-6, IL-8, and TNF-α plasma levels. PMN-MDSC inhibited T-cells IFN-γ production upon SARS-CoV-2 peptides stimulation, through TGF-ß- and iNOS-mediated mechanisms, possibly contrasting virus elimination. Accordingly, a multivariate regression analysis found a strong association between PMN-MDSC percentage and fatal outcome of the disease. The PMN-MDSC frequency was higher in non-survivors than survivors at the admission time, followed by a decreasing trend. Interestingly, this trend was associated with IL-6 increase in non-survivors but not in survivors. In conclusion, this study indicates PMN-MDSC as a novel factor in the pathogenesis of SARS-CoV2 infection, and open up to new therapeutic options.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Myeloid-Derived Suppressor Cells/immunology , Pneumonia, Viral/pathology , T-Lymphocytes/immunology , Aged , Area Under Curve , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/virology , Female , Humans , Interferon-gamma/metabolism , Interleukin-1beta/blood , Interleukin-6/blood , Male , Middle Aged , Myeloid-Derived Suppressor Cells/cytology , Neutrophils/cytology , Neutrophils/immunology , Neutrophils/metabolism , Nitric Oxide Synthase Type II/metabolism , Pandemics , Peptides/immunology , Peptides/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Proportional Hazards Models , ROC Curve , SARS-CoV-2 , Survival Rate , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Transforming Growth Factor beta/blood , Transforming Growth Factor beta/metabolism
18.
Sci Rep ; 10(1): 17718, 2020 10 19.
Article in English | MEDLINE | ID: covidwho-880700

ABSTRACT

COVID-19 has been widely spreading. We aimed to examine adaptive immune cells in non-severe patients with persistent SARS-CoV-2 shedding. 37 non-severe patients with persistent SARS-CoV-2 presence that were transferred to Zhongnan hospital of Wuhan University were retrospectively recruited to the PP (persistently positive) group, which was further allocated to PPP group (n = 19) and PPN group (n = 18), according to their testing results after 7 days (N = negative). Epidemiological, demographic, clinical and laboratory data were collected and analyzed. Data from age- and sex-matched non-severe patients at disease onset (PA [positive on admission] patients, n = 37), and lymphocyte subpopulation measurements from matched 54 healthy subjects were extracted for comparison (HC). Compared with PA patients, PP patients had much improved laboratory findings. The absolute numbers of CD3+ T cells, CD4+ T cells, and NK cells were significantly higher in PP group than that in PA group, and were comparable to that in healthy controls. PPP subgroup had markedly reduced B cells and T cells compared to PPN group and healthy subjects. Finally, paired results of these lymphocyte subpopulations from 10 PPN patients demonstrated that the number of T cells and B cells significantly increased when the SARS-CoV-2 tests turned negative. Persistent SARS-CoV-2 presence in non-severe COVID-19 patients is associated with reduced numbers of adaptive immune cells. Monitoring lymphocyte subpopulations could be clinically meaningful in identifying fully recovered COVID-19 patients.


Subject(s)
B-Lymphocytes/cytology , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , T-Lymphocytes/cytology , Adult , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Betacoronavirus/isolation & purification , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , COVID-19 , Case-Control Studies , Coronavirus Infections/immunology , Coronavirus Infections/virology , Female , Humans , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Male , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
19.
Eur Rev Med Pharmacol Sci ; 24(17): 9182-9187, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-790180

ABSTRACT

COVID-19 pandemic has underlined that unknown viral infections, which jump from animals to humans, can be extremely dangerous. In case of new viruses as SARS-CoV2, available drugs can fail to contrast the virus aggressiveness leading patients to death. Long time is necessary to create a vaccine, but immediate solutions are necessary to stop the mortality COVID-19 related. We have learned that the immune-system is the key to reduce the severity of COVID-19 and, through its modulation, it has been possible saving people's life. In this short communication, we discuss the use of nutraceuticals to modulate and stimulate the immune answer for reducing the severity of COVID-19 symptoms. The nutraceuticals are safe and can be administered to all ages. In addition, combination of natural anti-viral elements and immune-stimulating molecules already successfully tested against others upper-respiratory tract infections-could be efficient against SARS-CoV2. We believe that these natural molecules could really be a valid ally against COVID-19, especially in this moment in which a SARS-CoV2 vaccine is still not available.


Subject(s)
Coronavirus Infections/therapy , Dietary Supplements , Pneumonia, Viral/therapy , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Lactobacillus/physiology , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Selenium/pharmacology , Selenium/therapeutic use , Severity of Illness Index , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Virus Replication/drug effects
20.
Cell ; 183(4): 982-995.e14, 2020 11 12.
Article in English | MEDLINE | ID: covidwho-756809

ABSTRACT

Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases. All MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with intact neutralization capability. Cytokine profiling identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28). Immunophenotyping of peripheral blood revealed reductions of non-classical monocytes, and subsets of NK and T lymphocytes, suggesting extravasation to affected tissues. Finally, profiling the autoantigen reactivity of MIS-C plasma revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal, and immune-cell antigens. All patients were treated with anti-IL-6R antibody and/or IVIG, which led to rapid disease resolution.


Subject(s)
Inflammation/pathology , Systemic Inflammatory Response Syndrome/pathology , Adolescent , Antibodies, Viral/blood , Autoantibodies/blood , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , COVID-19 , Chemokine CCL3/metabolism , Child , Child, Preschool , Coronavirus Infections/complications , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Immunity, Humoral , Infant , Infant, Newborn , Inflammation/metabolism , Interleukin-17/metabolism , Interleukin-18/metabolism , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Young Adult
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