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1.
Int J Mol Sci ; 23(5)2022 Mar 06.
Article in English | MEDLINE | ID: covidwho-1732070

ABSTRACT

Almost two years have passed since the outbreak reported for the first time in Wuhan of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome (SARS)-CoV-2 coronavirus, rapidly evolved into a pandemic. This infectious disease has stressed global health care systems. The mortality rate is higher, particularly in elderly population and in patients with comorbidities such as hypertension, diabetes mellitus, cardiovascular disease, chronic lung disease, chronic renal disease, and malignancy. Among them, subjects with diabetes have a high risk of developing severe form of COVID-19 and show increased mortality. How diabetes contributes to COVID-19 severity remains unclear. It has been hypothesized that it may be correlated with the effects of hyperglycemia on systemic inflammatory responses and immune system dysfunction. Vitamin D (VD) is a modulator of immune-response. Data from literature showed that vitamin D deficiency in COVID-19 patients increases COVID-19 severity, likely because of its negative impact on immune and inflammatory responses. Therefore, the use of vitamin D might play a role in some aspects of the infection, particularly the inflammatory state and the immune system function of patients. Moreover, a piece of evidence highlighted a link among vitamin D deficiency, obesity and diabetes, all factors associated with COVID-19 severity. Given this background, we performed an overview of the systematic reviews to assess the association between vitamin D supplementation and inflammatory markers in patients with diabetes; furthermore, vitamin D's possible role in COVID-19 patients was assessed as well. Three databases, namely MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews, were reviewed to retrieve the pertinent data. The aim of this review is to provide insight into the recent advances about the molecular basis of the relationship between vitamin D, immune response, inflammation, diabetes and COVID-19.


Subject(s)
COVID-19/immunology , Diabetes Mellitus/immunology , Immune System/immunology , Inflammation/immunology , Obesity/immunology , Vitamin D/immunology , COVID-19/virology , Humans , Immune System/drug effects , Meta-Analysis as Topic , SARS-CoV-2/physiology , Systematic Reviews as Topic , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Vitamin D/administration & dosage , Vitamins/administration & dosage , Vitamins/immunology
2.
Purinergic Signal ; 18(1): 13-59, 2022 03.
Article in English | MEDLINE | ID: covidwho-1694363

ABSTRACT

Hyperinflammation plays an important role in severe and critical COVID-19. Using inconsistent criteria, many researchers define hyperinflammation as a form of very severe inflammation with cytokine storm. Therefore, COVID-19 patients are treated with anti-inflammatory drugs. These drugs appear to be less efficacious than expected and are sometimes accompanied by serious adverse effects. SARS-CoV-2 promotes cellular ATP release. Increased levels of extracellular ATP activate the purinergic receptors of the immune cells initiating the physiologic pro-inflammatory immune response. Persisting viral infection drives the ATP release even further leading to the activation of the P2X7 purinergic receptors (P2X7Rs) and a severe yet physiologic inflammation. Disease progression promotes prolonged vigorous activation of the P2X7R causing cell death and uncontrolled ATP release leading to cytokine storm and desensitisation of all other purinergic receptors of the immune cells. This results in immune paralysis with co-infections or secondary infections. We refer to this pathologic condition as hyperinflammation. The readily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immune function. The issue is that the half-maximal effective concentration for P2X7R inhibition of lidocaine is much higher than the maximal tolerable plasma concentration where adverse effects start to develop. To overcome this, we selectively inhibit the P2X7Rs of the immune cells of the lymphatic system inducing clonal expansion of Tregs in local lymph nodes. Subsequently, these Tregs migrate throughout the body exerting anti-inflammatory activities suppressing systemic and (distant) local hyperinflammation. We illustrate this with six critically ill COVID-19 patients treated with lidocaine.


Subject(s)
Adenosine Triphosphate/metabolism , COVID-19/immunology , Cytokine Release Syndrome/etiology , Inflammation/etiology , Lidocaine/therapeutic use , Purinergic P2X Receptor Antagonists/therapeutic use , Receptors, Purinergic/physiology , Anti-Inflammatory Agents/therapeutic use , Critical Care , Cytokine Release Syndrome/drug therapy , Humans , Inflammation/drug therapy , Infusions, Subcutaneous , Lidocaine/administration & dosage , Lidocaine/pharmacology , Lymph Nodes/immunology , Lymphatic System/immunology , Male , Maximum Tolerated Dose , Middle Aged , Models, Immunological , Purinergic P2X Receptor Antagonists/administration & dosage , Purinergic P2X Receptor Antagonists/pharmacology , Receptors, Purinergic/drug effects , Receptors, Purinergic P1/drug effects , Receptors, Purinergic P1/physiology , Receptors, Purinergic P2X7/physiology , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Signal Transduction , T-Lymphocytes, Regulatory/immunology
3.
Life Sci ; 294: 120392, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1670857

ABSTRACT

The SARS coronavirus 2 (SARS CoV-2) causes Coronavirus Disease (COVID-19), is an emerging viral infection. SARS CoV-2 infects target cells by attaching to Angiotensin-Converting Enzyme (ACE2). SARS CoV-2 could cause cardiac damage in patients with severe COVID-19, as ACE2 is expressed in cardiac cells, including cardiomyocytes, pericytes, and fibroblasts, and coronavirus could directly infect these cells. Cardiovascular disorders are the most frequent comorbidity found in COVID-19 patients. Immune cells such as monocytes, macrophages, and T cells may produce inflammatory cytokines and chemokines that contribute to COVID-19 pathogenesis if their functions are uncontrolled. This causes a cytokine storm in COVID-19 patients, which has been associated with cardiac damage. Tregs are a subset of immune cells that regulate immune and inflammatory responses. Tregs suppress inflammation and improve cardiovascular function through a variety of mechanisms. This is an exciting research area to explore the cellular, molecular, and immunological mechanisms related to reducing risks of cardiovascular complications in severe COVID-19. This review evaluated whether Tregs can affect COVID-19-related cardiovascular complications, as well as the mechanisms through which Tregs act.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/prevention & control , SARS-CoV-2 , T-Lymphocytes, Regulatory/physiology , Adoptive Transfer , Animals , Cardiovascular Diseases/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Humans , Inflammation/immunology , T-Lymphocytes, Regulatory/immunology
4.
Cell Rep ; 38(8): 110399, 2022 02 22.
Article in English | MEDLINE | ID: covidwho-1664737

ABSTRACT

Follicular helper T (Tfh) cells promote, whereas follicular regulatory T (Tfr) cells restrain, germinal center (GC) reactions. However, the precise roles of these cells in the complex GC reaction remain poorly understood. Here, we perturb Tfh or Tfr cells after SARS-CoV-2 spike protein vaccination in mice. We find that Tfh cells promote the frequency and somatic hypermutation (SHM) of Spike-specific GC B cells and regulate clonal diversity. Tfr cells similarly control SHM and clonal diversity in the GC but do so by limiting clonal competition. In addition, deletion of Tfh or Tfr cells during primary vaccination results in changes in SHM after vaccine boosting. Aged mice, which have altered Tfh and Tfr cells, have lower GC responses, presenting a bimodal distribution of SHM. Together, these data demonstrate that GC responses to SARS-CoV-2 spike protein vaccines require a fine balance of positive and negative follicular T cell help to optimize humoral immunity.


Subject(s)
COVID-19/prevention & control , Germinal Center/immunology , Spike Glycoprotein, Coronavirus/administration & dosage , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/immunology , Aging , Animals , Antibodies, Viral/blood , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , COVID-19/virology , Germinal Center/cytology , Germinal Center/metabolism , Immunity, Humoral , Mice , Mice, Inbred C57BL , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/metabolism , Vaccination , Vaccines, Subunit/immunology
5.
J Med Virol ; 94(5): 2089-2101, 2022 05.
Article in English | MEDLINE | ID: covidwho-1626431

ABSTRACT

COVID-19 is a disease characterized by acute respiratory failure and is a major health problem worldwide. Here, we aimed to investigate the role of CD39 expression in Treg cell subsets in COVID-19 immunopathogenesis and its relationship to disease severity. One hundred and ninety COVID-19 patients (juveniles, adults) and 43 volunteers as healthy controls were enrolled in our study. Flow cytometric analysis was performed using a 10-color monoclonal antibody panel from peripheral blood samples. In adult patients, CD39+ Tregs increased with disease severity. In contrast, CD39+ Tregs were decreased in juvenile patients in an age-dependent manner. Overall, our study reveals an interesting profile of CD39-expressing Tregs in adult and juvenile cases of COVID-19. Our results provide a better understanding of the possible role of Tregs in the mechanism of immune response in COVID-19 cases.


Subject(s)
Apyrase , COVID-19 , T-Lymphocytes, Regulatory , Adult , Apyrase/biosynthesis , Apyrase/immunology , Apyrase/metabolism , COVID-19/immunology , COVID-19/metabolism , Forkhead Transcription Factors , Humans , Severity of Illness Index , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology
6.
Front Immunol ; 12: 789735, 2021.
Article in English | MEDLINE | ID: covidwho-1581322

ABSTRACT

Background: The host immune response has a prominent role in the progression and outcome of SARS-CoV-2 infection. Lymphopenia has been described as an important feature of SARS-CoV-2 infection and has been associated with severe disease manifestation. Lymphocyte dysregulation and hyper-inflammation have been shown to be associated with a more severe clinical course; however, a T cell subpopulation whose dysfunction correlate with disease progression has yet to be identify. Methods: We performed an immuno-phenotypic analysis of T cell sub-populations in peripheral blood from patients affected by different severity of COVID-19 (n=60) and undergoing a different clinical evolution. Clinical severity was established based on a modified WHO score considering both ventilation support and respiratory capacity (PaO2/FiO2 ratio). The ability of circulating cells at baseline to predict the probability of clinical aggravation was explored through multivariate regression analyses. Results: The immuno-phenotypic analysis performed by multi-colour flow cytometry confirmed that patients suffering from severe COVID-19 harboured significantly reduced circulating T cell subsets, especially for CD4+ T, Th1, and regulatory T cells. Peripheral T cells also correlated with parameters associated with disease severity, i.e., PaO2/FiO2 ratio and inflammation markers. CD4+ T cell subsets showed an important significant association with clinical evolution, with patients presenting markedly decreased regulatory T cells at baseline having a significantly higher risk of aggravation. Importantly, the combination of gender and regulatory T cells allowed distinguishing between improved and worsened patients with an area under the ROC curve (AUC) of 82%. Conclusions: The present study demonstrates the association between CD4+ T cell dysregulation and COVID-19 severity and progression. Our results support the importance of analysing baseline regulatory T cell levels, since they were revealed able to predict the clinical worsening during hospitalization. Regulatory T cells assessment soon after hospital admission could thus allow a better clinical stratification and patient management.


Subject(s)
COVID-19/epidemiology , COVID-19/immunology , Hospitalization , Lymphocyte Count , SARS-CoV-2/immunology , T-Lymphocytes, Regulatory/immunology , Biomarkers , COVID-19/diagnosis , COVID-19/virology , COVID-19 Serological Testing , Cytokines/blood , Cytokines/metabolism , Disease Progression , Humans , Immunophenotyping , Inflammation Mediators/blood , Inflammation Mediators/metabolism , Prognosis , Public Health Surveillance , ROC Curve , Severity of Illness Index , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/metabolism
7.
PLoS Pathog ; 17(12): e1010085, 2021 12.
Article in English | MEDLINE | ID: covidwho-1559373

ABSTRACT

Regulatory T (Treg) cells, which constitute about 5-10% of CD4+T cells expressing Foxp3 transcription factor and CD25(IL-2 receptor α chain), are key regulators in controlling immunological self-tolerance and various immune responses. However, how Treg cells control antigen-specific immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. In this study, we examined the effect of transient breakdown of the immunological tolerance induced by Treg-cell depletion on adaptive immune responses against administered SARS-CoV-2 antigen, spike protein 1 (S1). Notably, without the use of adjuvants, transient Treg-cell depletion in mice induced anti-S1 antibodies that neutralized authentic SARS-CoV-2, follicular helper T cell formation and S1-binding germinal center B cell responses, but prevented the onset of developing autoimmune diseases. To further clarify the mechanisms, we investigated maturation of dendritic cells (DCs), which is essential to initiate antigen-specific immunity. We found that the transient Treg-cell depletion resulted in maturation of both migratory and resident DCs in draining lymph nodes that captured S1-antigen. Moreover, we observed S1-specific CD4+ T cells and CD8+ T cells with interferon-γ production. Thus, captured S1 was successfully presented by DCs, including cross-presentation to CD8+ T cells. These data indicate that transient Treg-cell depletion in the absence of adjuvants induces maturation of antigen-presenting DCs and succeeds in generating antigen-specific humoral and cellular immunity against emerging SARS-CoV-2 antigens. Finally, we showed that SARS-CoV-2 antigen-specific immune responses induced by transient Treg-cell depletion in the absence of adjuvants were compatible with those induced with an effective adjuvant, polyriboinosinic:polyribocytidyl acid (poly IC) and that the combination of transient Treg-cell depletion with poly IC induced potent responses. These findings highlight the capacity for manipulating Treg cells to induce protective adaptive immunity to SARS-CoV-2 with activating antigen-presenting DCs, which may improve the efficacy of ongoing vaccine therapies and help enhance responses to emerging SARS-CoV-2 variants.


Subject(s)
Adaptive Immunity/immunology , Antigens, Viral/immunology , COVID-19/immunology , Forkhead Transcription Factors/immunology , SARS-CoV-2/immunology , Animals , Antigen Presentation/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/virology , Chlorocebus aethiops , Dendritic Cells/immunology , Female , Germinal Center/immunology , Humans , Immune Tolerance , Mice , Mice, Inbred C57BL , Mice, Inbred MRL lpr , T-Lymphocytes, Regulatory/immunology , Vero Cells
8.
J Reprod Immunol ; 149: 103464, 2022 02.
Article in English | MEDLINE | ID: covidwho-1561228

ABSTRACT

We studied the T cell response to SARS-CoV-2 spike and non-spike peptide epitopes in eight convalescent pregnant women together with the immune monitoring that included innate tolerogenic dendritic cell populations important to maintain the immunological mother/fetus interface to address a potential risk for the antiviral cellular response in the outcome of pregnancy. Four subjects had pre-existing chronic inflammatory conditions that could have potentially affected the SARS-CoV-2-specific T cell response. Seven of eight subjects responded to SARS-CoV-2 peptides with differences within CD4+ T helper (Th) and CD8+ cytotoxic T cells (CTL). SARS-CoV-2-specific inducible regulatory T cells (iTreg) were numerous in circulation. CD4+ T cell memory included central memory T cells (TCM) and effector memory (TEM). As far as the CD8+ memory repertoire, TCM and TEM were very low or absent in eight of eight subjects and only effector cells that revert to CD45RA+, defined as TEMRA were measurable in circulation. T cells were in the normal range in all subjects regardless of pre-existing inflammatory conditions. The immune phenotype indicated the expansion and activation of tolerogenic myeloid dendritic cells including CD14+ cDC2 and CD4+ ILT-4+ tmDC. In summary, SARS-CoV-2 infection induced a physiological anti-viral T cell response in pregnant women that included SARS-CoV-2-specific iTreg with no negative effects on the tolerogenic innate dendritic cell repertoire relevant to the immune homeostasis of the maternal-fetal interface. All eight subjects studied delivered full-term, healthy infants.


Subject(s)
COVID-19/immunology , Placenta/immunology , Pregnancy Complications, Infectious/immunology , SARS-CoV-2/immunology , T-Lymphocytes, Regulatory/immunology , Adult , Female , Humans , Pregnancy , Prospective Studies
9.
Int Arch Allergy Immunol ; 183(3): 350-359, 2022.
Article in English | MEDLINE | ID: covidwho-1523107

ABSTRACT

INTRODUCTION: In the trials of corona virus vaccines, detailed analyses of subsets of lymphocytes were not carried out. We present perhaps the most comprehensive immunological analysis of 29 subsets of B and T cells in 2 healthy subjects receiving 2 doses of the Pfizer SARS-CoV-2 (COVID-19) vaccine. METHODS: Analyses were performed prior to vaccination, 3 weeks following the 1st dose, and 4 weeks following the 2nd dose. Total, naïve (TN), and different memory and effector subsets (TCM, TEM, and TEMRA) of CD4+ and CD8+ T cells; SARS-CoV-2 spike protein-specific tetramer+, and cytotoxic CD8+ T; subsets of T follicular cells (TFH, TFH1, TFH2, TFH1/TFH17, and TFH17); B-cell subsets (mature B cells, naive B cells, transitional B cells, marginal zone B cells, class-switched memory B cells, germinal center B cells, and CD21low B cells), and plasmablasts; and regulatory lymphocytes (CD4+ Treg, CD8+ Treg, Breg, and TFR cells) were evaluated with specific monoclonal antibodies by flow cytometry. RESULTS: A lack of COVID-19 IgG antibodies after the 1st dose in one of 2 subjects was associated with increased regulatory lymphocytes and decreased plasmablasts. Seroconversion after the 2nd dose in this subject was associated with decreased TFR cells and increased plasmablasts. In both subjects, CD4 TEM and CD8 TCM were markedly increased following the 2nd dose. TFH1 and regulatory lymphocytes were increased (except Breg) following the 1st dose. A striking increase in SARS-CoV-2-specific CD8+ T cells was observed following the 2nd dose. CONCLUSION: Our data support the need for 2nd dose of vaccine to induce strong SARS-CoV-2 CD8 T-cell specific response and generation of memory subsets of CD4+ and CD8+ T cells. Regulatory lymphocytes appear to play a role in the magnitude of response.


Subject(s)
Antibodies, Viral/blood , COVID-19/prevention & control , SARS-CoV-2/immunology , Vaccination , Aged , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Humans , Immunoglobulin G/blood , Male , Middle Aged , T-Lymphocytes, Regulatory/immunology
10.
Viral Immunol ; 34(9): 639-645, 2021 11.
Article in English | MEDLINE | ID: covidwho-1517820

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may produce a systemic disease, the coronavirus disease-19 (COVID-19), with high morbidity and mortality. Even though we do not fully understand the interaction of innate and adaptive immunity in the control and complications of the viral infection, it is well recognized that SARS-CoV-2 induces an immunodepression that impairs the elimination of the virus and favors its rapid dissemination in the organism. Even less is known about the possible participation of inhibitory cells of the innate immune system, such as the myeloid-derived suppressor cells (MDSCs), or the adaptive immune system, such as the T regulatory cells (Tregs). That is why we aimed to study blood levels of MDSCs, as well as lymphocyte subpopulations, including Tregs, and activated (OX-40+) and inhibited (PD-1) T lymphocytes in patients with mild COVID-19 in comparison with data obtained from control donors. We have found that 20 hospitalized patients with COVID-19 and no health history of immunosuppression had a significant increase in the number of peripheral monocytic MDSCs (M-MDSC), but a decrease in Tregs, as well as an increase in the number of inhibited or exhausted T cells, whereas the number of activated T cells was significantly decreased compared with that from 20 healthy controls. Moreover, there was a significant negative correlation (r = 0.496) between the number of M-MDSC and the number of activated T cells. Therefore, M-MDSC rather than Tregs may contribute to the immunosuppression observed in patients with COVID-19.


Subject(s)
COVID-19/immunology , Myeloid-Derived Suppressor Cells/immunology , SARS-CoV-2/immunology , T-Lymphocytes, Regulatory/immunology , Aged , COVID-19/blood , COVID-19/classification , Female , Humans , Lymphocyte Activation , Lymphocyte Count/methods , Lymphocyte Subsets , Male , Middle Aged , SARS-CoV-2/pathogenicity
11.
Biomed Pharmacother ; 144: 112230, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1517059

ABSTRACT

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has become a serious challenge for medicine and science. Analysis of the molecular mechanisms associated with the clinical manifestations and severity of COVID-19 has identified several key points of immune dysregulation observed in SARS-CoV-2 infection. For diabetic patients, factors including higher binding affinity and virus penetration, decreased virus clearance and decreased T cell function, increased susceptibility to hyperinflammation, and cytokine storm may make these patients susceptible to a more severe course of COVID-19 disease. Metabolic changes induced by diabetes, especially hyperglycemia, can directly affect the immunometabolism of lymphocytes in part by affecting the activity of the mTOR protein kinase signaling pathway. High mTOR activity can enhance the progression of diabetes due to the activation of effector proinflammatory subpopulations of lymphocytes and, conversely, low activity promotes the differentiation of T-regulatory cells. Interestingly, metformin, an extensively used antidiabetic drug, inhibits mTOR by affecting the activity of AMPK. Therefore, activation of AMPK and/or inhibition of the mTOR-mediated signaling pathway may be an important new target for drug therapy in COVID-19 cases mostly by reducing the level of pro-inflammatory signaling and cytokine storm. These suggestions have been partially confirmed by several retrospective analyzes of patients with diabetes mellitus hospitalized for severe COVID-19.


Subject(s)
COVID-19/drug therapy , Diabetes Mellitus/drug therapy , Hypoglycemic Agents/therapeutic use , Immunity, Cellular/drug effects , Metformin/therapeutic use , Severity of Illness Index , COVID-19/epidemiology , COVID-19/immunology , COVID-19/metabolism , Diabetes Mellitus/epidemiology , Diabetes Mellitus/immunology , Diabetes Mellitus/metabolism , Humans , Hypoglycemic Agents/pharmacology , Immunity, Cellular/physiology , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/metabolism , Metformin/pharmacology , Mortality/trends , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/immunology , TOR Serine-Threonine Kinases/metabolism
12.
PLoS One ; 16(11): e0258743, 2021.
Article in English | MEDLINE | ID: covidwho-1511818

ABSTRACT

BCG vaccination is known to induce innate immune memory, which confers protection against heterologous infections. However, the effect of BCG vaccination on the conventional adaptive immune cells subsets is not well characterized. We investigated the impact of BCG vaccination on the frequencies of T cell subsets and common gamma c (γc) cytokines in a group of healthy elderly individuals (age 60-80 years) at one month post vaccination as part of our clinical study to examine the effect of BCG on COVID-19. Our results demonstrate that BCG vaccination induced enhanced frequencies of central (p<0.0001) and effector memory (p<0.0001) CD4+ T cells and diminished frequencies of naïve (p<0.0001), transitional memory (p<0.0001), stem cell memory (p = 0.0001) CD4+ T cells and regulatory T cells. In addition, BCG vaccination induced enhanced frequencies of central (p = 0.0008), effector (p<0.0001) and terminal effector memory (p<0.0001) CD8+ T cells and diminished frequencies of naïve (p<0.0001), transitional memory (p<0.0001) and stem cell memory (p = 0.0034) CD8+T cells. BCG vaccination also induced enhanced plasma levels of IL-7 (p<0.0001) and IL-15 (p = 0.0020) but diminished levels of IL-2 (p = 0.0033) and IL-21 (p = 0.0020). Thus, BCG vaccination was associated with enhanced memory T cell subsets as well as memory enhancing γc cytokines in elderly individuals, suggesting its ability to induce non-specific adaptive immune responses.


Subject(s)
BCG Vaccine/immunology , Cytokines/immunology , Immunologic Memory/immunology , Interleukin Receptor Common gamma Subunit/immunology , Aged , Aged, 80 and over , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Female , Humans , Interleukins/immunology , Male , Middle Aged , Mycobacterium tuberculosis/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Vaccination/methods
13.
Front Immunol ; 12: 747143, 2021.
Article in English | MEDLINE | ID: covidwho-1497080

ABSTRACT

Regulatory T cells (Tregs) are the major determinant of peripheral immune tolerance. Many Treg subsets have been described, however thymus-derived and peripherally induced Tregs remain the most important subpopulations. In multiple sclerosis, a prototypical autoimmune disorder of the central nervous system, Treg dysfunction is a pathogenic hallmark. In contrast, induction of Treg proliferation and enhancement of their function are central immune evasion mechanisms of infectious pathogens. In accordance, Treg expansion is compartmentalized to tissues with high viral replication and prolonged in chronic infections. In friend retrovirus infection, Treg expansion is mainly based on excessive interleukin-2 production by infected effector T cells. Moreover, pathogens seem also to enhance Treg functions as shown in human immunodeficiency virus infection, where Tregs express higher levels of effector molecules such as cytotoxic T-lymphocyte-associated protein 4, CD39 and cAMP and show increased suppressive capacity. Thus, insights into the molecular mechanisms by which intracellular pathogens alter Treg functions might aid to find new therapeutic approaches to target central nervous system autoimmunity. In this review, we summarize the current knowledge of the role of pathogens for Treg function in the context of autoimmune neuroinflammation. We discuss the mechanistic implications for future therapies and provide an outlook for new research directions.


Subject(s)
Autoimmune Diseases/immunology , Autoimmune Diseases/microbiology , /microbiology , T-Lymphocytes, Regulatory/immunology , Animals , Humans , /immunology
14.
Front Immunol ; 12: 741796, 2021.
Article in English | MEDLINE | ID: covidwho-1477826

ABSTRACT

Background: The immune response plays a pivotal role in dictating the clinical outcome in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected adults, but it is still poorly investigated in the pediatric population. Methods: Of 209 enrolled subjects, 155 patients were confirmed by PCR and/or serology as having coronavirus disease 2019 (COVID-19). Blood samples were obtained at a median of 2.8 (interquartile, 2.1-3.7) and 6.1 (5.3-7.2) months after baseline (symptom onset and/or first positive virus detection). The immune profiles of activation, senescence, exhaustion, and regulatory cells were analyzed by flow cytometry. Neutralizing antibodies (nAbs) were detected by a plaque reduction neutralization test. In available nasopharyngeal swabs at baseline, SARS-CoV-2 levels were quantified by digital droplet PCR (ddPCR). Results: Overall, COVID-19 patients had higher levels of immune activation, exhaustion, and regulatory cells compared to non-COVID-19 subjects. Within the COVID-19 group, activated and senescent cells were higher in adults than in children and inversely correlated with the nAbs levels. Conversely, Tregs and Bregs regulatory cells were higher in COVID-19 children compared to adults and positively correlated with nAbs. Higher immune activation still persisted in adults after 6 months of infection, while children maintained higher levels of regulatory cells. SARS-CoV-2 levels did not differ among age classes. Conclusions: Adults displayed higher immune activation and lower production of anti-SARS-CoV-2 nAbs than children. The different immune response was not related to different viral load. The higher expression of regulatory cells in children may contribute to reduce the immune activation, thus leading to a greater specific response against the virus.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Asymptomatic Infections , B-Lymphocytes, Regulatory/immunology , COVID-19/pathology , T-Lymphocytes, Regulatory/immunology , Adult , Child , Child, Preschool , Cytokines/blood , Female , Humans , Lymphocyte Count , Male , Middle Aged , Pathogen-Associated Molecular Pattern Molecules/blood , Prospective Studies , SARS-CoV-2/immunology , Severity of Illness Index , Viral Load/immunology
15.
Life Sci ; 286: 120063, 2021 Dec 01.
Article in English | MEDLINE | ID: covidwho-1472089

ABSTRACT

COVID-19 is a multi-faceted disease ranging from asymptomatic to severely ill condition that primarily affects the lungs and could advance to other organs as well. It's causing factor, SARS-CoV-2 is recognized to develop robust cell-mediated immunity that responsible to either control or exaggerate the infection. As an important cell subset that control immune responses and are significantly dysregulated in COVID-19, Tregs is proposed to be considered for COVID-19 management. Among its hallmark, TNFR2 is recently recognized to play important role in the function and survival of Tregs. This review gathers available TNFR2 agonists to directly target Tregs as a potential approach to overcome immune dysregulation that affect the severity in COVID-19. Furthermore, this review performs a rigid body docking of TNF-TNFR2 interaction and such interaction with TNFR2 agonist to predict the optimal targeting approach.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Receptors, Tumor Necrosis Factor, Type II/physiology , T-Lymphocytes, Regulatory/immunology , COVID-19/virology , Humans , Lymphocyte Activation , SARS-CoV-2/isolation & purification
16.
Nat Immunol ; 22(12): 1490-1502, 2021 12.
Article in English | MEDLINE | ID: covidwho-1454796

ABSTRACT

Despite extensive studies into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the effect of maternal infection on the neonate is unclear. To investigate this, we characterized the immunology of neonates born to mothers with confirmed SARS-CoV-2 infection during pregnancy. Here we show that maternal SARS-CoV-2 infection affects the neonatal immune system. Despite similar proportions of B cells, CD4+ T cells and CD8+ T cells, increased percentages of natural killer cells, Vδ2+ γδ T cells and regulatory T cells were detected in neonates born to mothers with recent or ongoing infection compared with those born to recovered or uninfected mothers. Increased plasma cytokine levels were also evident in neonates and mothers within the recent or ongoing infection group. Cytokine functionality was enhanced in neonates born to SARS-CoV-2-exposed mothers, compared to those born to uninfected mothers. In most neonates, this immune imprinting was nonspecific, suggesting vertical transmission of SARS-CoV-2 is limited, a finding supported by a lack of SARS-CoV-2-specific IgM in neonates despite maternal IgG transfer.


Subject(s)
COVID-19/immunology , Infant, Newborn, Diseases/immunology , Infectious Disease Transmission, Vertical , Pregnancy Complications, Infectious/immunology , SARS-CoV-2/immunology , Adult , Antibodies, Viral/immunology , COVID-19/diagnosis , COVID-19/virology , Cytokines/blood , Cytokines/immunology , Cytokines/metabolism , Female , Humans , Immunity, Innate/immunology , Immunoglobulin G/immunology , Infant, Newborn , Infant, Newborn, Diseases/diagnosis , Infant, Newborn, Diseases/virology , Killer Cells, Natural/immunology , Pregnancy , Pregnancy Complications, Infectious/virology , Receptors, Antigen, T-Cell, gamma-delta/immunology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , SARS-CoV-2/physiology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes, Regulatory/immunology
18.
Front Immunol ; 12: 716084, 2021.
Article in English | MEDLINE | ID: covidwho-1430699

ABSTRACT

A binary model for the classification of chronic diseases has formerly been proposed. The model classifies chronic diseases as "high Treg" or "low Treg" diseases according to the extent of regulatory T cells (Treg) activity (frequency or function) observed. The present paper applies this model to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The model correctly predicts the efficacy or inefficacy of several immune-modulating drugs in the treatment of severe coronavirus disease 2019 (COVID-19) disease. It also correctly predicts the class of pathogens mostly associated with SARS-CoV-2 infection. The clinical implications are the following: (a) any search for new immune-modulating drugs for the treatment of COVID-19 should exclude candidates that do not induce "high Treg" immune reaction or those that do not spare CD8+ T cells; (b) immune-modulating drugs, which are effective against SARS-CoV-2, may not be effective against any variant of the virus that does not induce "low Treg" reaction; (c) any immune-modulating drug, which is effective in treating COVID-19, will also alleviate most coinfections; and (d) severe COVID-19 patients should avoid contact with carriers of "low Treg" pathogens.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/drug therapy , Immunomodulation/drug effects , T-Lymphocytes, Regulatory/immunology , Adrenal Cortex Hormones/therapeutic use , COVID-19/immunology , Chronic Disease/classification , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Janus Kinase Inhibitors/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Sirolimus/therapeutic use
19.
Proc Natl Acad Sci U S A ; 118(37)2021 09 14.
Article in English | MEDLINE | ID: covidwho-1373495

ABSTRACT

The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19-linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.


Subject(s)
COVID-19/etiology , T-Lymphocytes, Regulatory/physiology , Adult , Aged , CD4-Positive T-Lymphocytes/virology , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Profiling , Gene Expression Regulation , Humans , Inflammation/metabolism , Inflammation/virology , Interleukin-18/genetics , Interleukin-18/metabolism , Interleukin-2 Receptor alpha Subunit/genetics , Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Lymphocytes, Tumor-Infiltrating/physiology , Male , Middle Aged , Severity of Illness Index , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/virology , Transcription Factors/genetics , Transcription Factors/metabolism
20.
Cell Signal ; 87: 110121, 2021 11.
Article in English | MEDLINE | ID: covidwho-1370457

ABSTRACT

The SARS-CoV-2 virus has caused a worldwide COVID-19 pandemic. In less than a year and a half, more than 200 million people have been infected and more than four million have died. Despite some improvement in the treatment strategies, no definitive treatment protocol has been developed. The pathogenesis of the disease has not been clearly elucidated yet. A clear understanding of its pathogenesis will help develop effective vaccines and drugs. The immunopathogenesis of COVID-19 is characteristic with acute respiratory distress syndrome and multiorgan involvement with impaired Type I interferon response and hyperinflammation. The destructive systemic effects of COVID-19 cannot be explained simply by the viral tropism through the ACE2 and TMPRSS2 receptors. In addition, the recently identified mutations cannot fully explain the defect in all cases of Type I interferon synthesis. We hypothesize that retinol depletion and resulting impaired retinoid signaling play a central role in the COVID-19 pathogenesis that is characteristic for dysregulated immune system, defect in Type I interferon synthesis, severe inflammatory process, and destructive systemic multiorgan involvement. Viral RNA recognition mechanism through RIG-I receptors can quickly consume a large amount of the body's retinoid reserve, which causes the retinol levels to fall below the normal serum levels. This causes retinoid insufficiency and impaired retinoid signaling, which leads to interruption in Type I interferon synthesis and an excessive inflammation. Therefore, reconstitution of the retinoid signaling may prove to be a valid strategy for management of COVID-19 as well for some other chronic, degenerative, inflammatory, and autoimmune diseases.


Subject(s)
COVID-19/pathology , Signal Transduction/physiology , Vitamin A/metabolism , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Central Nervous System/metabolism , DEAD Box Protein 58/metabolism , Humans , Immune Tolerance , Interferon Type I/metabolism , Receptors, Immunologic/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Viral Tropism/physiology , Vitamin A/blood
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