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1.
J Perinat Med ; 50(2): 139-143, 2022 Feb 23.
Article in English | MEDLINE | ID: covidwho-1561422

ABSTRACT

OBJECTIVES: To investigate the long-term effects of the SARS-CoV-2 infection on the fetal immune system by fetal thymus size measurements with ultrasound (USG). METHODS: This prospective study was conducted in the Turkish Ministry of Health Ankara City Hospital between November 1, 2020 and April 1, 2021, with recovered, pregnant women, four weeks after they had been confirmed for the SARS-CoV-2 infection by real-time polymerase-chain-reaction (RT-PCR). COVID-19 recovered (CR) pregnant women compared with age-matched pregnant controls in terms of demographic features, fetal thymic-thoracic ratio (TTR), and laboratory parameters. RESULTS: There was no difference in demographic features between the two groups. TTR found significantly lower in the CR group than the control group (p=0.001). The fetal TTR showed a significant and moderate correlation with maternal monocyte counts, monocyte to lymphocyte ratio (MLR), and red cell distribution width (RDW); while it did not correlate with lymphocyte counts, c-reactive protein (CRP), and procalcitonin levels. CONCLUSIONS: The 2019 novel coronavirus disease (COVID-19) reduces fetal thymus size in pregnant women with mild or moderate symptoms after recovery from the infection.


Subject(s)
COVID-19/pathology , Fetus/pathology , Pregnancy Complications, Infectious/pathology , Thymus Gland/pathology , Adult , COVID-19/diagnostic imaging , Female , Fetus/diagnostic imaging , Humans , Organ Size , Pregnancy , Pregnancy Complications, Infectious/diagnostic imaging , Prospective Studies , Thymus Gland/diagnostic imaging , Ultrasonography, Prenatal , Young Adult
2.
Signal Transduct Target Ther ; 6(1): 414, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1556321

ABSTRACT

Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 µM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.


Subject(s)
Antiviral Agents/administration & dosage , Azides/administration & dosage , COVID-19/drug therapy , Deoxycytidine/analogs & derivatives , SARS-CoV-2/metabolism , Thymus Gland , Adult , Aged , Aged, 80 and over , Animals , Coronavirus OC43, Human/metabolism , Deoxycytidine/administration & dosage , Female , Humans , Male , Middle Aged , Rats , Thymus Gland/metabolism , Thymus Gland/virology
3.
Clin Epigenetics ; 13(1): 210, 2021 11 24.
Article in English | MEDLINE | ID: covidwho-1533277

ABSTRACT

BACKGROUND: The thymic microenvironment is mainly comprised of thymic epithelial cells, the cytokines, exosomes, surface molecules, and hormones from the cells, and plays a vital role in the development, differentiation, maturation and homeostasis of T lymphocytes. However, the thymus begins to degenerate as early as the second year of life and continues through aging in human beings, leading to a decreased output of naïve T cells, the limited TCR diversity and an expansion of monoclonal memory T cells in the periphery organs. These alternations will reduce the adaptive immune response to tumors and emerging infectious diseases, such as COVID-19, also it is easier to suffer from autoimmune diseases in older people. In the context of global aging, it is important to investigate and clarify the causes and mechanisms of thymus involution. MAIN BODY: Epigenetics include histone modification, DNA methylation, non-coding RNA effects, and chromatin remodeling. In this review, we discuss how senescent thymic epithelial cells determine and control age-related thymic atrophy, how this process is altered by epigenetic modification. How the thymus adipose influences the dysfunctions of the thymic epithelial cells, and the prospects of targeting thymic epithelial cells for the treatment of thymus atrophy. CONCLUSION: Epigenetic modifications are emerging as key regulators in governing the development and senescence of thymic epithelial cells. It is beneficial to re-establish effective thymopoiesis, identify the potential therapeutic strategy and rejuvenate the immune function in the elderly.


Subject(s)
Aging/physiology , Epigenesis, Genetic/physiology , Epithelial Cells/pathology , Thymus Gland/pathology , Atrophy , Humans
4.
Front Immunol ; 12: 706244, 2021.
Article in English | MEDLINE | ID: covidwho-1468338

ABSTRACT

The immune system's ability to resist the invasion of foreign pathogens and the tolerance to self-antigens are primarily centered on the efficient functions of the various subsets of T lymphocytes. As the primary organ of thymopoiesis, the thymus performs a crucial role in generating a self-tolerant but diverse repertoire of T cell receptors and peripheral T cell pool, with the capacity to recognize a wide variety of antigens and for the surveillance of malignancies. However, cells in the thymus are fragile and sensitive to changes in the external environment and acute insults such as infections, chemo- and radiation-therapy, resulting in thymic injury and degeneration. Though the thymus has the capacity to self-regenerate, it is often insufficient to reconstitute an intact thymic function. Thymic dysfunction leads to an increased risk of opportunistic infections, tumor relapse, autoimmunity, and adverse clinical outcome. Thus, exploiting the mechanism of thymic regeneration would provide new therapeutic options for these settings. This review summarizes the thymus's development, factors causing thymic injury, and the strategies for improving thymus regeneration.


Subject(s)
Regeneration/physiology , Thymus Gland/physiology , Animals , Humans
7.
Biomed Pharmacother ; 141: 111835, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1271574

ABSTRACT

Thymic stromal lymphopoietin (TSLP) produced by mast cells is involved in allergic inflammation pathogenesis. Chloroquine (CQ) is known to be an anti-malarial drug; however, additional protective functions of CQ have been discovered. This study aims to clarify an anti-inflammatory effect of CQ through modulating TSLP levels using an in vitro model of phorbol myristate acetate (PMA) + A23187-activated human mast cell line (HMC-1) and an in vivo model of PMA-irritated ear edema. CQ treatment reduced the production and mRNA expression levels of TSLP in activated HMC-1 cells. CQ down-regulated caspase-1 (CASP1), MAPKs, and NF-κB levels enhanced by stimulation with PMA + A23187. Moreover, ear thickness in ear edema was suppressed following CQ treatment. CQ decreased CASP1 and NF-κB levels in the ear tissue. TSLP levels in the ear tissue and serum were reduced following CQ treatment. Collectively, the above findings elucidate that CQ inhibits the pro-inflammatory mechanisms of TSLP via the down-regulation of distinct intracellular signaling cascade in mast cells. Therefore, CQ may have protective roles against TSLP-mediated inflammatory disorders.


Subject(s)
Caspase 1/drug effects , Caspase Inhibitors/pharmacology , Chloroquine/pharmacology , Cytokines/biosynthesis , Mast Cells/drug effects , Signal Transduction/drug effects , Stromal Cells/metabolism , Thymus Gland/metabolism , Animals , Calcimycin/pharmacology , Cell Line , Ear Diseases/drug therapy , Edema/drug therapy , Humans , MAP Kinase Signaling System/drug effects , Male , Mice , Mice, Inbred ICR , NF-kappa B/drug effects , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Stromal Cells/drug effects , Tetradecanoylphorbol Acetate/pharmacology , Thymus Gland/drug effects
8.
Annu Rev Biomed Eng ; 23: 461-491, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1191179

ABSTRACT

Modeling immunity in vitro has the potential to be a powerful tool for investigating fundamental biological questions, informing therapeutics and vaccines, and providing new insight into disease progression. There are two major elements to immunity that are necessary to model: primary immune tissues and peripheral tissues with immune components. Here, we systematically review progress made along three strategies to modeling immunity: ex vivo cultures, which preserve native tissue structure; microfluidic devices, which constitute a versatile approach to providing physiologically relevant fluid flow and environmental control; and engineered tissues, which provide precise control of the 3D microenvironment and biophysical cues. While many models focus on disease modeling, more primary immune tissue models are necessary to advance the field. Moving forward, we anticipate that the expansion of patient-specific models may inform why immunity varies from patient to patient and allow for the rapid comprehension and treatment of emerging diseases, such as coronavirus disease 2019.


Subject(s)
COVID-19/immunology , Tissue Engineering/methods , Adaptive Immunity , Animals , Biophysics , Humans , Immune System , Immunity, Innate , In Vitro Techniques , Lab-On-A-Chip Devices , Lymphocytes/immunology , Macrophages/immunology , Mice , Microfluidics , SARS-CoV-2 , Thymus Gland/immunology , Tissue Array Analysis
9.
Cells ; 10(3)2021 03 12.
Article in English | MEDLINE | ID: covidwho-1167427

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution/degeneration. How these changes contribute to differences in COVID-19 disease severity between young and aged patients is an urgent area of investigation. Therefore, we attempt to connect various clues in this field by reviewing and discussing recent research on the role of the thymus and T cells in COVID-19 immunity during aging (a synergistic effect of diminished responses to pathogens and enhanced responses to self) impacting age-related clinical severity of COVID-19. We also address potential combinational strategies to rejuvenate multiple aging-impacted immune system checkpoints by revival of aged thymic function, boosting peripheral T cell responses, and alleviating chronic, basal inflammation to improve the efficiency of anti-SARS-CoV-2 immunity and vaccination in the elderly.


Subject(s)
COVID-19/immunology , Cellular Senescence/immunology , T-Lymphocytes/immunology , Thymus Gland/immunology , Aged , Aged, 80 and over , Aging/immunology , Aging/pathology , Autoimmunity , COVID-19/drug therapy , COVID-19/physiopathology , Humans , Inflammation/immunology , Inflammation/pathology , SARS-CoV-2/immunology , Thymus Gland/drug effects , Thymus Gland/physiopathology , Thymus Gland/virology
10.
Clin Infect Dis ; 71(16): 2150-2157, 2020 11 19.
Article in English | MEDLINE | ID: covidwho-1153175

ABSTRACT

BACKGROUND: Thymosin alpha 1 (Tα1) had been used in the treatment of viral infections as an immune response modifier for many years. However, clinical benefits and the mechanism of Tα1 treatment for COVID-19 patients are still unclear. METHODS: We retrospectively reviewed the clinical outcomes of 76 severe COVID-19 cases admitted to 2 hospitals in Wuhan, China, from December 2019 to March 2020. The thymus output in peripheral blood mononuclear cells from COVID-19 patients was measured by T-cell receptor excision circles (TRECs). The levels of T-cell exhaustion markers programmed death-1 (PD-1) and T-cell immunoglobulin and mucin domain protein 3 (Tim-3) on CD8+ T cells were detected by flow cytometry. RESULTS: Compared with the untreated group, Tα1 treatment significantly reduced the mortality of severe COVID-19 patients (11.11% vs 30.00%, P = .044). Tα1 enhanced blood T-cell numbers in COVID-19 patients with severe lymphocytopenia. Under such conditions, Tα1 also successfully restored CD8+ and CD4+ T-cell numbers in elderly patients. Meanwhile, Tα1 reduced PD-1 and Tim-3 expression on CD8+ T cells from severe COVID-19 patients compared with untreated cases. It is of note that restoration of lymphocytopenia and acute exhaustion of T cells were roughly parallel to the rise of TRECs. CONCLUSIONS: Tα1 treatment significantly reduced mortality of severe COVID-19 patients. COVID-19 patients with counts of CD8+ T cells or CD4+ T cells in circulation less than 400/µL or 650/µL, respectively, gained more benefits from Tα1. Tα1 reversed T-cell exhaustion and recovered immune reconstitution through promoting thymus output during severe acute respiratory syndrome-coronavirus 2 infection.


Subject(s)
COVID-19/mortality , Lymphopenia/metabolism , SARS-CoV-2/pathogenicity , Thymalfasin/metabolism , Adult , Aged , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , COVID-19/virology , Female , Humans , Male , Middle Aged , Retrospective Studies , Thymalfasin/genetics , Thymus Gland/metabolism
11.
J R Soc Interface ; 18(176): 20200982, 2021 03.
Article in English | MEDLINE | ID: covidwho-1138038

ABSTRACT

Here, we report that COVID-19 hospitalization rates follow an exponential relationship with age, doubling for every 16 years of age or equivalently increasing by 4.5% per year of life (R2 = 0.98). This mirrors the well-studied exponential decline of both thymus volume and T-cell production, which halve every 16 years. COVID-19 can therefore be added to the list of other diseases with this property, including those caused by methicillin-resistant Staphylococcus aureus, MERS-CoV, West Nile virus, Streptococcus pneumoniae and certain cancers, such as chronic myeloid leukaemia and brain cancers. In addition, the incidence of severe disease and mortality due to COVID-19 are both higher in men, consistent with the degree to which thymic involution (and the decrease in T-cell production with age) is more severe in men compared to women. Since these properties are shared with some non-contagious diseases, we hypothesized that the age dependence does not come from social-mixing patterns, i.e. that the probability of hospitalization given infection rises exponentially, doubling every 16 years. A Bayesian analysis of daily hospitalizations, incorporating contact matrices, found that this relationship holds for every age group except for the under 20s. While older adults have fewer contacts than young adults, our analysis suggests that there is an approximate cancellation between the effects of fewer contacts for the elderly and higher infectiousness due to a higher probability of developing severe disease. Our model fitting suggests under 20s have 49-75% additional immune protection beyond that predicted by strong thymus function alone, consistent with increased juvenile cross-immunity from other viruses. We found no evidence for differences between age groups in susceptibility to infection or infectiousness to others (given disease state), i.e. the only important factor in the age dependence of hospitalization rates is the probability of hospitalization given infection. These findings suggest the existence of a T-cell exhaustion threshold, proportional to thymic output and that clonal expansion of peripheral T-cells does not affect disease risk. The strikingly simple inverse relationship between risk and thymic T-cell output adds to the evidence that thymic involution is an important factor in the decline of the immune system with age and may also be an important clue in understanding disease progression, not just for COVID-19 but other diseases as well.


Subject(s)
Aging/immunology , COVID-19/pathology , Hospitalization/statistics & numerical data , SARS-CoV-2 , T-Lymphocytes/physiology , Thymus Gland/cytology , Adolescent , Adult , Aged , Aged, 80 and over , Aging/pathology , Bayes Theorem , Child , Female , Humans , Male , Middle Aged , Risk Factors , Young Adult
12.
Turk J Med Sci ; 51(3): 991-1000, 2021 06 28.
Article in English | MEDLINE | ID: covidwho-1110505

ABSTRACT

Background/aim: To investigate the relationship between imaging findings and peripheral blood cell counts of COVID-19 patients and the degree of thymus fat involution of these patients. Materials and methods: Computed tomography (CT) images of 87 patients with COVID-19 positive through RT-PCR testing were evaluated retrospectively by two radiologists. Ground glass densities and other signs of viral pneumonia were recorded, lung involvement was scored quantitatively. The patients thymus fat involution was graded on CT. Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratios (PLR), lymphocyte and platelet counts were calculated. Imaging findings and degrees of thymus fat involution were compared with laboratory data. Results: Quantitative scoring of lung involvement was calculated at mean 6.63 ± 4.70 (1­23) for observer 1 and mean 6.55 ± 4.65 (1­23) for observer 2 (K = 0.824­1.000). Statistical significance was determined between the increase in age and the increase in scores of lung findings (p = 0.003). Lymphocyte count (p = 0.0001) and PLR (p = 0.001) were significantly lower in patients with severe CT involvement. A statistically significantcorrelation was found between increased thymus fat component and presence of COVID-19 lung involvement in CT (r = 0.461). Conclusion: The severity of imaging findings for COVID-19 patients significantly correlates with the degree of fat involution in patients' thymus tissue.


Subject(s)
COVID-19/diagnosis , Lung/diagnostic imaging , Pandemics , Thymus Gland/diagnostic imaging , Tomography, X-Ray Computed/methods , Adult , COVID-19/blood , COVID-19/epidemiology , Female , Follow-Up Studies , Humans , Lymphocyte Count , Male , Platelet Count , Retrospective Studies , Severity of Illness Index , Turkey/epidemiology , Young Adult
13.
Stem Cell Rev Rep ; 17(1): 285-290, 2021 02.
Article in English | MEDLINE | ID: covidwho-1082312

ABSTRACT

The paper presents the results of a standard and complex treatment method using the peptide drug thymus thymalin in patients with COVID-19. One of the mechanisms of the immunomodulatory effect of thymalin is considered to be the ability of this peptide drug to influence the differentiation of human hematopoietic stem cells (HSCs). It was found that, as a result of standard treatment, patients in the control group showed a decrease in the concentration of the pro-inflammatory cytokine IL-6, C-reactive protein, D-dimer. The addition of thymalin to standard therapy accelerated the decline in both these indicators and the indicators of the T cell system. This has helped reduce the risk of blood clots in COVID-19 patients. The revealed properties of the thymus peptide preparation are the rationale for its inclusion in the complex treatment of coronavirus infection. Peptideswith potential biological activity against SARS-CoV-2 virus [29]. Note: Nitrogen atoms are shown in blue, oxygen atoms - in red, carbon atoms - in gray, hydrogen atoms - in white, and phosphorus atoms - in yellow.


Subject(s)
COVID-19/drug therapy , Cell Differentiation/drug effects , SARS-CoV-2/drug effects , Thymus Hormones/therapeutic use , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Cytokines/genetics , Hematopoiesis/drug effects , Hematopoietic Stem Cells/drug effects , Humans , SARS-CoV-2/pathogenicity , Thymus Gland/metabolism , Thymus Hormones/genetics , Thymus Hormones/metabolism
16.
Hum Vaccin Immunother ; 17(3): 638-643, 2021 03 04.
Article in English | MEDLINE | ID: covidwho-872898

ABSTRACT

The thymus is a largely neglected organ but plays a significant role in the regulation of adaptive immune responses. The effect of aging on the thymus and immune senescence is well established, and the resulting inflammaging is found to be implicated in the development of many chronic diseases including atherosclerosis, hypertension and type 2 diabetes. Both aging and diseases of inflammaging are associated with severe COVID-19 disease, and a dysfunctional thymus may be a predisposing factor. In addition, insults on the thymus during childhood may lead to abnormal thymic function and may explain severe COVID-19 disease among younger individuals; therefore, measurement of thymic function may assist COVID-19 care. Those with poor thymic function may be treated prophylactically with convalescent serum or recombinant antibodies, and they may respond better to high-dose or adjuvanted COVID-19 vaccines. Treatments inducing thymic regeneration may improve patients' overall health and may be incorporated in COVID-19 management.


Subject(s)
Antibodies/therapeutic use , COVID-19/drug therapy , COVID-19/immunology , Thymus Gland/immunology , Animals , COVID-19/virology , COVID-19 Vaccines/immunology , Humans , Inflammation/drug therapy , Inflammation/immunology , Inflammation/virology , Severity of Illness Index , Thymus Gland/virology
17.
Eur J Pediatr ; 180(3): 983-986, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-848315

ABSTRACT

A new type of coronavirus named as SARS-CoV-2 pandemic has begun to threaten human health. As with other types of coronaviruses, SARS-CoV-2 affects children less frequently, and it has been observed that the disease is mild. In the pathogenesis of a standard viral infection, the pathogen's contact with the mucosa is initially followed by an innate immunity response. T cells are the primary decisive element in adaptive immunity capability. For this reason, the adaptive immune response mediated by the thymus is a process that regulates the immune response responsible for preventing invasive damage from a virus. Regulatory T cells (T-reg) are active during the early periods of life and have precise roles in immunomodulation. The thymus is highly active in the intrauterine and neonatal period; it begins to shrink after birth and continues its activity until adolescence. The loss of T-reg function by age results in difficulty with the control of the immune response, increased inflammation as shown in coronavirus disease (COVID-19) as an inflammatory storm. Also, the thymus is typically able to replace the T cells destroyed by apoptosis caused by the virus. Thymus and T cells are the key factors of pathogenesis of SARS-CoV-2 in children.Conclusion: We speculated that thymus activity and T lymphocyte function in children protect them against the virus effects. Stimulating and preventing the inhibition of the thymus can be possible treatment components against COVID-19. What is Known: • The SARS-CoV-2 infection does not often progress with an invasive clinic in children. • Thymus activity and T lymphocyte functions are highly active in children. What is New: • Effective thymus activity and T lymphocyte function in children protect them against the invasive SARS-CoV-2 infection. • Stimulating and preventing the inhibition of the thymus can be possible treatment components against COVID-19.


Subject(s)
Adaptive Immunity , COVID-19/immunology , T-Lymphocytes/immunology , Thymus Gland/immunology , COVID-19/diagnosis , Child , Humans , Severity of Illness Index
18.
Can J Microbiol ; 67(1): 23-28, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-637554

ABSTRACT

Understanding the pathogenesis of certain viral agents is essential for developing new treatments and obtaining a clinical cure. With the onset of the new coronavirus (SARS-CoV-2) pandemic in the beginning of 2020, a rush to conduct studies and develop drugs has led to the publication of articles that seek to address knowledge gaps and contribute to the global scientific research community. There are still no reports on the infectivity or repercussions of SARS-CoV-2 infection on the central lymphoid organ, the thymus, nor on thymocytes or thymic epithelial cells. In this brief review, we present a hypothesis about lymphopenia observed in SARS patients and the probable pathological changes that the thymus may undergo due to this new virus.


Subject(s)
COVID-19/complications , COVID-19/immunology , Lymphopenia/complications , Thymus Gland/virology , Animals , Humans , Lymphopenia/immunology , Lymphopenia/virology , Mice , Models, Immunological , Pandemics , Thymus Gland/immunology
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