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1.
Front Immunol ; 13: 916411, 2022.
Article in English | MEDLINE | ID: covidwho-2022705

ABSTRACT

Coronavirus disease 2019 (COVID-19) has been raging all around the world since the beginning of 2020, and leads to acute respiratory distress syndrome (ARDS) with strong cytokine storm which contributes to widespread tissue damage and even death in severe patients. Over-activated immune response becomes one of the characteristics of severe COVID-19 patients. Regulatory T cells (Treg) play an essential role in maintaining the immune homeostasis, which restrain excessive inflammation response. So FOXP3+ Tregs might participate in the suppression of inflammation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Besides suppressive function, tissue resident Tregs are also responsible for tissue repair. In this review, we mainly summarize the latest research focusing on the change of FOXP3+ Tregs in the COVID-19 patients, discuss the relationship between disease severity and number change of Tregs and speculate the potential role of FOXP3+ Tregs during SARS-CoV-2 infection. Furthermore, we introduce some potential Treg-based therapies to improve patients' outcomes, which include small molecular drugs, antibody drugs, CAR-Treg and cytokine treatment. We hope to reduce tissue damage of severe COVID-19 patients and offer better prognosis through Treg-based therapy.


Subject(s)
COVID-19 , T-Lymphocytes, Regulatory , COVID-19/immunology , Cytokine Release Syndrome , Forkhead Transcription Factors , Humans , Inflammation , SARS-CoV-2 , T-Lymphocytes, Regulatory/immunology
2.
Front Immunol ; 13: 886822, 2022.
Article in English | MEDLINE | ID: covidwho-1957156

ABSTRACT

Immunometabolism has been the focus of extensive research over the last years, especially in terms of augmenting anti-tumor immune responses. Regulatory T cells (Tregs) are a subset of CD4+ T cells, which have been known for their immunosuppressive roles in various conditions including anti-tumor immune responses. Even though several studies aimed to target Tregs in the tumor microenvironment (TME), such approaches generally result in the inhibition of the Tregs non-specifically, which may cause immunopathologies such as autoimmunity. Therefore, specifically targeting the Tregs in the TME would be vital in terms of achieving a successful and specific treatment. Recently, an association between Tregs and isoleucine, which represents one type of branched-chain amino acids (BCAAs), has been demonstrated. The presence of isoleucine seems to affect majorly Tregs, rather than conventional T cells. Considering the fact that Tregs bear several distinct metabolic features in the TME, targeting their immunometabolic pathways may be a rational approach. In this Review, we provide a general overview on the potential distinct metabolic features of T cells, especially focusing on BCAAs in Tregs as well as in their subtypes.


Subject(s)
Amino Acids, Branched-Chain , Neoplasms , Amino Acids, Branched-Chain/metabolism , Humans , Isoleucine/pharmacology , T-Lymphocytes, Regulatory , Tumor Microenvironment
3.
Front Cell Infect Microbiol ; 12: 893044, 2022.
Article in English | MEDLINE | ID: covidwho-1952262

ABSTRACT

Severe COVID-19 in children is rare, but the reasons underlying are unclear. Profound alterations in T cell responses have been well characterized in the course of adult severe COVID-19, but little is known about the T cell function in children with COVID-19. Here, we made three major observations in a cohort of symptomatic children with acute COVID-19: 1) a reduced frequency of circulating FoxP3+ regulatory T cells, 2) the prevalence of a TH17 polarizing microenvironment characterized by high plasma levels of IL-6, IL-23, and IL17A, and an increased frequency of CD4+ T cells expressing ROR-γt, the master regulator of TH17 development, and 3) high plasma levels of ATP together with an increased expression of the P2X7 receptor. Moreover, that plasma levels of ATP displayed an inverse correlation with the frequency of regulatory T cells but a positive correlation with the frequency of CD4+ T cells positive for the expression of ROR-γt. Collectively, our data indicate an imbalance in CD4+ T cell profiles during pediatric COVID-19 that might favor the course of inflammatory processes. This finding also suggests a possible role for the extracellular ATP in the acquisition of an inflammatory signature by the T cell compartment offering a novel understanding of the involved mechanisms.


Subject(s)
COVID-19 , Nuclear Receptor Subfamily 1, Group F, Member 3 , Adenosine Triphosphate/metabolism , Adult , CD4-Positive T-Lymphocytes/metabolism , Child , Humans , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , T-Lymphocytes, Regulatory , Th17 Cells
5.
Theranostics ; 12(10): 4606-4628, 2022.
Article in English | MEDLINE | ID: covidwho-1897098

ABSTRACT

Rationale: Evident immunosuppression has been commonly seen among septic patients, and it is demonstrated to be a major driver of morbidity. Nevertheless, a comprehensive view of the host immune response to sepsis is lacking as the majority of studies on immunosuppression have focused on a specific type of immune cells. Methods: We applied multi-compartment, single-cell RNA sequencing (scRNA-seq) to dissect heterogeneity within immune cell subsets during sepsis progression on cecal ligation and puncture (CLP) mouse model. Flow cytometry and multiplex immunofluorescence tissue staining were adopted to identify the presence of 'mature DCs enriched in immunoregulatory molecules' (mregDC) upon septic challenge. To explore the function of mregDC, sorted mregDC were co-cultured with naïve CD4+ T cells. Intracellular signaling pathways that drove mregDC program were determined by integrating scRNA-seq and bulk-seq data, combined with inhibitory experiments. Results: ScRNA-seq analysis revealed that sepsis induction was associated with substantial alterations and heterogeneity of canonical immune cell types, including T, B, natural killer (NK), and myeloid cells, across three immune-relevant tissue sites. We found a unique subcluster of conventional dendritic cells (cDCs) that was characterized by specific expression of maturation- and migration-related genes, along with upregulation of immunoregulatory molecules, corresponding to the previously described 'mregDCs' in cancer. Flow cytometry and in stiu immunofluorescence staining confirmed the presence of sepsis-induced mregDC at protein level. Functional experiments showed that sepsis-induced mregDCs potently activated naive CD4+ T cells, while promoted CD4+ T cell conversion to regulatory T cells. Further observations indicated that the mregDC program was initiated via TNFRSF-NF-κB- and IFNGR2-JAK-STAT3-dependent pathways within 24 h of septic challenge. Additionally, we confirmed the detection of mregDC in human sepsis using publicly available data from a recently published single-cell study of COVID-19 patients. Conclusions: Our study generates a comprehensive single-cell immune landscape for polymicrobial sepsis, in which we identify the significant alterations and heterogeneity in immune cell subsets that take place during sepsis. Moreover, we find a conserved and potentially targetable immunoregulatory program within DCs that associates with hyperinflammation and organ dysfunction early following sepsis induction.


Subject(s)
COVID-19 , Sepsis , Animals , Dendritic Cells , Gene Expression Profiling , Humans , Mice , T-Lymphocytes, Regulatory
6.
Phytomedicine ; 101: 154100, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1895371

ABSTRACT

BACKGROUND: A number of studies have shown that gastrointestinal manifestations co-exist with respiratory symptoms in coronavirus disease 2019 (COVID-19) patients. Xuanfei Baidu decoction (XFBD) was recommended by the National Health Commission to treat mild and moderate COVID-19 patients and proved to effectively alleviate intestinal symptoms. However, the exact mechanisms remain elusive. PURPOSE: This study aimed at exploring potential mechanisms of XFBD by utilizing a mouse model of dextran sulfate sodium (DSS)-induced acute experimental colitis, mimicking the disease conditions of intestinal microecological disorders. METHODS: The network pharmacology approach was employed to identify the potential targets and pathways of XFBD on the intestinal disorders. Mice with DSS-induced intestinal disorders were utilized to evaluate the protective effect of XFBD in vivo, including body weight, disease activity index (DAI) score, colon length, spleen weight, and serum tumor necrosis factor-α (TNF-α) level. Colon tissues were used to perform hematoxylin-eosin (H&E) staining, western blot analysis, and transcriptome sequencing. Macrophages, neutrophils and the proportions of T helper cell (Th) 1 and Th2 cells were measured by flow cytometry. Intestinal contents were collected for 16S rRNA gene sequencing. RESULTS: Network pharmacology analysis indicated that XFBD inhibited the progression of COVID-19-related intestinal diseases by repressing inflammation. In mice with DSS-induced intestinal inflammation, XFBD treatment significantly reduced weight loss, the spleen index, the disease activity index, TNF-α levels, and colonic tissue damage, and prevented colon shortening. Transcriptomics and flow cytometry results suggested that XFBD remodeled intestinal immunity by downregulating the Th1/Th2 ratio. Western blot analysis showed that XFBD exerted its anti-inflammatory effects by blocking the nuclear factor-κB (NF-κB) signaling pathway. Indicator analysis of microbiota showed that 75 operational taxonomic units (OTUs) were affected after XFBD administration. Among them, Akkermansia, Muribaculaceae, Lachnospiraceae, and Enterorhabdus were simultaneously negatively correlated with intestinal disorders' parameters, and Bacteroides, Escherichia-Shigella, Eubacterium nodatum,Turicibacter, and Clostridium sensu stricto 1, showed positive correlations with intestinal disorders' parameters. CONCLUSIONS: Our data indicate that XFBD treatment attenuated intestinal disorders associated with inhibiting inflammation, remodeling of intestinal immunity, and improving intestinal flora. These findings provide a scientific basis for the clinical use of XFBD and offer a potential therapeutic approach for the treatment of COVID-19 patients with intestinal symptoms.


Subject(s)
COVID-19 , Colitis, Ulcerative , Colitis , Drugs, Chinese Herbal , Gastrointestinal Microbiome , T-Lymphocytes, Regulatory/immunology , Animals , COVID-19/drug therapy , Colitis/chemically induced , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/pathology , Colon/pathology , Dextran Sulfate/adverse effects , Disease Models, Animal , Drugs, Chinese Herbal/therapeutic use , Humans , Inflammation/drug therapy , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , RNA, Ribosomal, 16S , Tumor Necrosis Factor-alpha/metabolism
7.
Clin Appl Thromb Hemost ; 28: 10760296221107889, 2022.
Article in English | MEDLINE | ID: covidwho-1892132

ABSTRACT

AIM: Our study's objectives were to study the clinical and laboratory characteristics that may serve as biomarkers for predicting disease severity, IL-10 levels, and frequencies of different T cell subsets in comorbid COVID-19 patients. METHODS: Sixty-two hospitalized COVID-19 patients with comorbidities were assessed clinically and radiologically. Blood samples were collected to assess the T lymphocyte subsets by flow cytometry and IL-10 levels by ELISA. RESULTS: The most common comorbidities observed in COVID-19 patients were diabetes mellitus (DM), hypertension, and malignancies. Common symptoms and signs included fever, cough, dyspnea, fatigue, myalgia, and sore throat. CRP, ferritin, D dimer, LDH, urea, creatinine, and direct bilirubin were significantly increased in patients than controls. Lymphocyte count and CD4+ and CD8+ T-cells were significantly decreased in comorbid COVID-19 patients, and CD25 and CD45RA expression were increased. CD4+ and CD8+ regulatory T cells (Tregs) and IL-10 levels were significantly decreased in patients. CONCLUSIONS: Many parameters were found to be predictive of severity in the comorbid patients in our study. Significant reductions in the levels and activation of CD4+ and CD8+ T-cells were found. In addition, CD4+ and CD8+ Tregs were significant decreased in patients, probably pointing to a prominent role of CD8+ Tregs in dampening CD4+ T-cell activation.


Subject(s)
COVID-19 , T-Lymphocyte Subsets , CD8-Positive T-Lymphocytes , COVID-19/immunology , Comorbidity , Humans , Interleukin-10 , Lymphocyte Count , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory
8.
Trends Immunol ; 43(6): 415-416, 2022 06.
Article in English | MEDLINE | ID: covidwho-1864571

ABSTRACT

Mouse Ly49+CD8+ regulatory T cells (Tregs) can subdue autoreactive CD4+ T cells to suppress autoimmunity. Recently, Li et al. demonstrated that killer-cell immunoglobulin-like receptor (KIR)+CD8+ T cells are the human equivalent of Ly49+CD8+ regulatory T cells and kill pathogenic CD4+ T cells, which can be increased in certain human autoimmune diseases and viral infections.


Subject(s)
Autoimmune Diseases , Autoimmunity , Animals , CD8-Positive T-Lymphocytes , Humans , Mice , Receptors, KIR , T-Lymphocytes, Regulatory
9.
Nat Immunol ; 23(5): 645, 2022 05.
Article in English | MEDLINE | ID: covidwho-1860384
11.
J Immunol Res ; 2022: 5545319, 2022.
Article in English | MEDLINE | ID: covidwho-1807699

ABSTRACT

Coronavirus disease 2019 (COVID-19) has been raised as a pandemic disease since December 2019. Immunosuppressive cells including T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are key players in immunological tolerance and immunoregulation; however, they contribute to the pathogenesis of different diseases including infections. Tregs have been shown to impair the protective role of CD8+ T lymphocytes against viral infections. In COVID-19 patients, most studies reported reduction, while few other studies found elevation in Treg levels. Moreover, Tregs have a dual role, depending on the different stages of COVID-19 disease. At early stages of COVID-19, Tregs have a critical role in decreasing antiviral immune responses, and consequently reducing the viral clearance. On the other side, during late stages, Tregs reduce inflammation-induced organ damage. Therefore, inhibition of Tregs in early stages and their expansion in late stages have potentials to improve clinical outcomes. In viral infections, MDSC levels are highly increased, and they have the potential to suppress T cell proliferation and reduce viral clearance. Some subsets of MDSCs are expanded in the blood of COVID-19 patients; however, there is a controversy whether this expansion has pathogenic or protective effects in COVID-19 patients. In conclusion, further studies are required to investigate the role and function of immunosuppressive cells and their potentials as prognostic biomarkers and therapeutic targets in COVID-19 patients.


Subject(s)
COVID-19 , Myeloid-Derived Suppressor Cells , Humans , Immune Tolerance , Immunosuppressive Agents , Pandemics , T-Lymphocytes, Regulatory
12.
Science ; 376(6590): 243-244, 2022 04 15.
Article in English | MEDLINE | ID: covidwho-1794537

ABSTRACT

A subset of CD8+ T cells regulate chronic inflammation by killing pathogenic CD4+ T cells.


Subject(s)
CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , T-Lymphocytes, Regulatory
13.
BMJ Open ; 12(4): e061864, 2022 04 15.
Article in English | MEDLINE | ID: covidwho-1794490

ABSTRACT

INTRODUCTION: Regulatory T cell (Treg) therapy has been demonstrated to facilitate long-term allograft survival in preclinical models of transplantation and may permit reduction of immunosuppression and its associated complications in the clinical setting. Phase 1 clinical trials have shown Treg therapy to be safe and feasible in clinical practice. Here we describe a protocol for the TWO study, a phase 2b randomised control trial of Treg therapy in living donor kidney transplant recipients that will confirm safety and explore efficacy of this novel treatment strategy. METHODS AND ANALYSIS: 60 patients will be randomised on a 1:1 basis to Treg therapy (TR001) or standard clinical care (control). Patients in the TR001 arm will receive an infusion of autologous polyclonal ex vivo expanded Tregs 5 days after transplantation instead of standard monoclonal antibody induction. Maintenance immunosuppression will be reduced over the course of the post-transplant period to low-dose tacrolimus monotherapy. Control participants will receive a standard basiliximab-based immunosuppression regimen with long-term tacrolimus and mycophenolate mofetil immunosuppression. The primary endpoint is biopsy proven acute rejection over 18 months; secondary endpoints include immunosuppression burden, chronic graft dysfunction and drug-related complications. ETHICS AND DISSEMINATION: Ethical approval has been provided by the National Health Service Health Research Authority South Central-Oxford A Research Ethics Committee (reference 18/SC/0054). The study also received authorisation from the UK Medicines and Healthcare products Regulatory Agency and is being run in accordance with the principles of Good Clinical Practice, in collaboration with the registered trials unit Oxford Clinical Trials Research Unit. Results from the TWO study will be published in peer-reviewed scientific/medical journals and presented at scientific/clinical symposia and congresses. TRIAL REGISTRATION NUMBER: ISRCTN: 11038572; Pre-results.


Subject(s)
Kidney Transplantation , T-Lymphocytes, Regulatory , Graft Rejection/prevention & control , Humans , Immunosuppression Therapy , Immunosuppressive Agents/adverse effects , Kidney Transplantation/methods , Living Donors , Randomized Controlled Trials as Topic , State Medicine , Tacrolimus/therapeutic use
14.
Nat Rev Immunol ; 22(4): 208, 2022 04.
Article in English | MEDLINE | ID: covidwho-1783995
15.
J Immunol ; 208(8): 1989-1997, 2022 04 15.
Article in English | MEDLINE | ID: covidwho-1776403

ABSTRACT

Regulatory T cells (Tregs) are critical for regulating immunopathogenic responses in a variety of infections, including infection of mice with JHM strain of mouse hepatitis virus (JHMV), a neurotropic coronavirus that causes immune-mediated demyelinating disease. Although virus-specific Tregs are known to mitigate disease in this infection by suppressing pathogenic effector T cell responses of the same specificity, it is unclear whether these virus-specific Tregs form memory populations and persist similar to their conventional T cell counterparts of the same epitope specificity. Using congenically labeled JHMV-specific Tregs, we found that virus-specific Tregs persist long-term after murine infection, through at least 180 d postinfection and stably maintain Foxp3 expression. We additionally demonstrate that these cells are better able to proliferate and inhibit virus-specific T cell responses postinfection than naive Tregs of the same specificity, further suggesting that these cells differentiate into memory Tregs upon encountering cognate Ag. Taken together, these data suggest that virus-specific Tregs are able to persist long-term in the absence of viral Ag as memory Tregs.


Subject(s)
Coronavirus Infections , Murine hepatitis virus , Animals , Antigens, Viral/chemistry , Antigens, Viral/immunology , Mice , T-Lymphocytes, Regulatory
16.
Arch Iran Med ; 25(2): 127-132, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-1754281

ABSTRACT

BACKGROUND: Severe cases of coronavirus disease 2019 (COVID-19) often experience hyper-inflammatory reactions, acute respiratory distress syndrome (ARDS), blood clotting, and organ damage. The most prominent immunopathology of advanced COVID-19 is cytokine release syndrome, or "cytokine storm" which is attributed to a defect of immune-regulating mechanisms. This study aimed to evaluate the role of regulatory T cells (Tregs) as one of the main cells that maintain immune homeostasis. METHODS: A systematic search was performed on PubMed, Scopus and Google Scholar. All English articles related to Treg's role in COVID-19 were extracted and evaluated by two researchers independently. Study eligibility was assessed based on modified Evidence-based librarianship (EBL) checklist. RESULTS: Nineteen eligible studies comparing Treg cells in COVID-19 patients with the control group or comparing alterations of this cell in severe and moderate patients were evaluated. Currently, there is no consensus regarding the increase or decrease of Tregs in COVID-19 patients compared to the control group. However, it was observed that Tregs in severe COVID-19 patients were significantly lower than moderate patients, resulting in uncontrolled inflammation and cytokine storm. CONCLUSION: Regulatory T cells can be one of the determinants of disease severity and prognosis in patients with COVID-19 by inhibiting rampant inflammation and preventing cytokine storms.


Subject(s)
COVID-19 , T-Lymphocytes, Regulatory , Cytokine Release Syndrome , Cytokines , Humans , Inflammation , SARS-CoV-2
17.
Virulence ; 13(1): 569-577, 2022 12.
Article in English | MEDLINE | ID: covidwho-1740687

ABSTRACT

We aimed to determine the levels of follicular helper T (Tfh) and follicular regulatory T (Tfr) cells in COVID-19 patients and determine whether their levels correlated with disease severity and presence of hyperglycemia. This study was carried out in 34 hospitalized COVID-19 patients and 20 healthy controls. Levels of total circulating Tfh, inducible T-cell costimulator (ICOS)+ activated Tfh, and Tfr cells were assessed in all participants by flow cytometry. Total CD4+CXCR5+ Tfh cells and ICOS+Foxp3-activated Tfh cells increased and ICOS+Foxp3+ Tfr cells decreased in COVID-19 patients, especially in diabetic patients and those with severe disease. Activated ICOS+ Tfh cells were directly correlated with lactate dehydrogenase, D-dimer, ferritin, and respiratory rate and inversely correlated with the partial pressure of carbon dioxide. COVID-19 is associated with marked activation of Tfh cells and a profound drop in Tfr cells, especially in severe and diabetic patients. Future studies on expanded cohorts of patients are needed to clarify the relationship between SARS-CoV-2 and acute-onset diabetes.


Subject(s)
COVID-19 , Hyperglycemia , CD4-Positive T-Lymphocytes , Humans , SARS-CoV-2 , T-Lymphocytes, Regulatory
18.
Science ; 376(6590): eabi9591, 2022 04 15.
Article in English | MEDLINE | ID: covidwho-1731250

ABSTRACT

In this work, we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8+ T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases.


Subject(s)
Autoimmune Diseases , COVID-19 , Animals , CD8-Positive T-Lymphocytes , Humans , Mice , Receptors, KIR , T-Lymphocytes, Regulatory
19.
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
20.
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
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