Molecular Bases for Pharmacotherapy of COVID -19

2021 ◽  
Vol 6 (5) ◽  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Mortality Rate ◽  
Large Scale ◽  
Tissue Injury ◽  
Diffuse Alveolar Damage ◽  
New Drugs ◽  
Patient Death ◽  
Double Positive ◽  
Host Cell Membrane

The most large-scale challenge aroused at the beginning of Y2020 was the global spread of the coronavirus disease 2019 (COVID-19), caused by a zoonotic beta-coronavirus. One year after we have nearly 270 thousand confirmed cases with mortality rate 1.3% in Georgia, and almost 120 billion confirmed cases with mortality rate 2.2% worldwide. As it is known, COVID-19 is triggered by coronavirus species 2 or SARS-CoV-2, which inters in the human body by binding to the angiotensin-converting enzyme 2 (ACE2) molecule on the host cell membrane via the viral spike protein and expresses complex pathological changes in many organs linked with vascular injuries. The most severe expression of this disease exposed by microscopic examination is bilateral diffuse alveolar damage with fibroblasts exudates, indicating Acute Respiratory Distress Syndrome (ARDS). Immune system plays crucial role in tissue damage. As clinical researches showed, the number of peripheral CD4+ and CD8 + T cells were significantly reduced, while their activity was hyper-expressed as evidenced by the high proportions of HLADR (CD4 3•47%) and CD38 (CD8 39•4%) double-positive fractions. Moreover, there was identified an amplified concentration of highly pro inflammatory CCR6+ Th17 in CD4 T cells. This date explains that severe tissue injury in later stages of COVID-19 is depend on the immune system abnormalities, but not on SARS-CoV-2 direct cell destruction. In the same time the scientists and doctors found out abnormalities in coagulation function in most of the severe COVID-19 patients, which were expressed in elevation of D-Dimer level and prolongation of prothrombin time, some of whom terminated in disseminated intravascular coagulation (DIC), deep venous thrombosis (DVT) or fatal pulmonary thromboembolism (PTE). At the later stage in some severe patients it was identified thrombocytopenia as a result of excessive platelets consuming, which significantly affected on treatment and prognosis. More than 300 drugs are used for the treatment of COVID-19 worldwide. Now, the most popular treatments include Remdesivir, Hydroxychloroquine, Betamethasone, Tocilizumab, anti HIV drugs, and convalescent plasma. In the same time, WHO supports vaccines distribution for immunization. Currently, almost 8 vaccines are approved by different countries and more than 180 vaccines are under the clinical trails. Conclusion & Significance: Up till now it is challenging problem to combat SARS-CoV-2 with not well-defined origin and inexplicable biological characteristics as well as to control a pandemic of COVID-19 with such a high R0, a long incubation period and different disease outcomes. Unfortunately, we have limited understandings of particular mechanisms running to abnormal expression of immune system and coagulation processes. In the same time, we don’t have complete picture of vasculopathy leading to the tissue injury and patient death. Therefore, it is problematic to manage SARS-CoV-2 induced processes successfully using available drugs with no significant restoring effect on the organ damages in severe COVID-19 patients. So, we need new targets and new drugs for the prophylaxes and treatment of COVID-19 even we have vaccines available.

scholarly journals The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tian-Yu Lei ◽  
Ying-Ze Ye ◽  
Xi-Qun Zhu ◽  
Daniel Smerin ◽  
Li-Juan Gu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Immune Responses ◽  
Ischaemic Stroke ◽  
Immune Cells ◽  
Tissue Injury ◽  
Recovery Period ◽  
Vital Functions ◽  
Anti Inflammatory

AbstractThrough considerable effort in research and clinical studies, the immune system has been identified as a participant in the onset and progression of brain injury after ischaemic stroke. Due to the involvement of all types of immune cells, the roles of the immune system in stroke pathology and associated effects are complicated. Past research concentrated on the functions of monocytes and neutrophils in the pathogenesis of ischaemic stroke and tried to demonstrate the mechanisms of tissue injury and protection involving these immune cells. Within the past several years, an increasing number of studies have elucidated the vital functions of T cells in the innate and adaptive immune responses in both the acute and chronic phases of ischaemic stroke. Recently, the phenotypes of T cells with proinflammatory or anti-inflammatory function have been demonstrated in detail. T cells with distinctive phenotypes can also influence cerebral inflammation through various pathways, such as regulating the immune response, interacting with brain-resident immune cells and modulating neurogenesis and angiogenesis during different phases following stroke. In view of the limited treatment options available following stroke other than tissue plasminogen activator therapy, understanding the function of immune responses, especially T cell responses, in the post-stroke recovery period can provide a new therapeutic direction. Here, we discuss the different functions and temporal evolution of T cells with different phenotypes during the acute and chronic phases of ischaemic stroke. We suggest that modulating the balance between the proinflammatory and anti-inflammatory functions of T cells with distinct phenotypes may become a potential therapeutic approach that reduces the mortality and improves the functional outcomes and prognosis of patients suffering from ischaemic stroke.

scholarly journals The analysis of the long-term impact of SARS-CoV-2 on the cellular immune system in individuals recovering from COVID-19 reveals a profound NKT cell impairment

2020 ◽  
Author(s):  
jia liu ◽  
Xuecheng Yang ◽  
Hua Wang ◽  
Ziwei Li ◽  
Hui Deng ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Annexin V ◽  
Double Positive ◽  
Peripheral Blood Mononuclear ◽  
Cellular Immune System ◽  
Cellular Immune

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects millions of people and killed hundred-thousands of individuals. While acute and intermediate interactions between SARS-CoV-2 and the immune system have been studied extensively, long-term impacts on the cellular immune system remained to be analyzed. Here, we comprehensively characterized immunological changes in peripheral blood mononuclear cells in 49 COVID-19 convalescent individuals (CI) in comparison to 27 matched SARS-CoV-2 unexposed individuals (UI). Despite recovery from the disease for more than 2 months, CI showed significant decreases in frequencies of invariant NKT and NKT-like cells compared to UI. Concomitant with the decrease in NKT-like cells, an increase in the percentage of Annexin V and 7-AAD double positive NKT-like cells was detected, suggesting that the reduction in NKT-like cells results from cell death months after recovery. Significant increases in regulatory T cell frequencies, TIM-3 expression on CD4 and CD8 T cells, as well as PD-L1 expression on B cells were also observed in CI, while the cytotoxic potential of T cells and NKT-like cells, defined by GzmB expression, was significantly diminished. However, both CD4 and CD8 T cells of CI showed increased Ki67 expression and were fully capable to proliferate and produce effector cytokines upon TCR stimulation. Collectively, we provide the first comprehensive characterization of immune signatures in patients recovering from SARS-CoV-2 infection, suggesting that the cellular immune system of COVID-19 patients is still under a sustained influence even months after the recovery from disease.

scholarly journals Maternal Exposure Results in Long-Term Deoxynivalenol Persistence in Piglets’ Plasma and Modulates the Immune System

Toxins ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 615 ◽  
Author(s):  
Hana Štěpánová ◽  
Karolina Hlavová ◽  
Kamil Šťastný ◽  
Eduard Gopfert ◽  
Lenka Levá ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Γδ T Cells ◽  
High Sensitivity ◽  
Postnatal Period ◽  
Double Positive ◽  
Toxicological Effects ◽  
Immune Parameters ◽  
The Impact

Deoxynivalenol (DON)-contaminated feed represents a serious problem for pigs due to their high sensitivity to its toxicological effects. The aim of the present study was to evaluate the impact of intrauterine DON exposure on the immune system of piglets. Pure DON was intravenously administered to sows at the end of gestation (during the last 2–3 days of gestation, one dose of 300 µg per day). The plasma concentration of DON was analyzed using liquid chromatography combined with high-resolution Orbitrap-based mass spectrometry (LC–MS/MS (HR)) and selected immune parameters were monitored six times in piglets from birth to 18 weeks. DON was found in the plasma of 90% of newborn piglets at a mean concentration of 6.28 ng/mL and subsequently, at one, three, and seven weeks after birth with decreasing concentrations. Trace amounts were still present in the plasma 14 weeks after birth. Flow cytometry revealed a significant impact of DON on T lymphocyte subpopulations during the early postnatal period. Lower percentages of regulatory T cells, T helper lymphocytes, and their double positive CD4+CD8+ subset were followed by increased percentages of cytotoxic T lymphocytes and γδ T cells. The capacity to produce pro-inflammatory cytokines was also significantly lower after intrauterine DON exposure. In conclusion, this study revealed a long-term persistence of DON in the plasma of the piglets as a consequence of short-term intrauterine exposure, leading to altered immune parameters.

scholarly journals An Immune Atlas of Nephrolithiasis: Single-Cell Mass Cytometry on SIRT3 Knockout and Calcium Oxalate-Induced Renal Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Wei Zhang ◽  
Ling Li ◽  
Ti Zhang ◽  
Xiaomin Gao ◽  
Zeyu Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Renal Injury ◽  
Large Scale ◽  
Immune Cell ◽  
Critical Role ◽  
Cell Mass ◽  
T Cell Subsets ◽  
High Recurrence Rate ◽  
Immune Cell Population

Background. As a common urological disease with a high recurrence rate, nephrolithiasis caused by CaOx may elicit a strong immunologic response. We present a CyTOF-based atlas of the immune landscape in nephrolithiasis models to understand how the immune system contributes to, and is affected by, the underlying response caused by SIRT3 knockout and CaOx inducement. Materials and Methods. We performed a large-scale CyTOF analysis of immune cell abundance profiles in nephrolithiasis. The immunophenotyping data were collected from four different mouse models, including the SIRT3 wild-type or knockout, including and excluding CaOx inducement. Unsupervised analysis strategies, such as SPADE and viSNE, revealed the intrarenal resident immune components and the immune alterations caused by SIRT3 knockout and CaOx-induced renal injury. Results. An overview analysis of the immune landscape identified T cells and macrophages as the main immune cell population in nephrolithiasis models. Highly similar phenotypes were observed among CD4+ and CD8+ T cell subsets, including cells expressing Ki67, Ly6C, Siglec-F, and TCRβ. Macrophages expressed a characteristic panel of markers with varied expression levels including MHC II, SIRPα, CD11c, Siglec-F, F4/80, CD64, and CD11b, indicating more subtle differences in marker expression than T cells. The SIRT3KO/CaOx and SIRT3WT/CaOx groups exhibited global differences in the intrarenal immune landscape, whereas only small differences existed between the SIRT3KO/CaOx and SIRT3KO/Ctrl groups. Among the major immune lineages, the response of CD4+ T cells, NK cells, monocytes, and M1 to CaOx inducement was regulated by SIRT3 expression in contrast to the expression changes of B cells, DCs, and granulocytes caused by CaOx inducement. The panel of immune markers influenced by CaOx inducement significantly varied with and without SIRT3 knockout. Conclusion. In a CaOx-induced nephrolithiasis model, SIRT3 has a critical role in regulating the immune system, especially in reducing inflammatory injury. The characteristic panel of altered immune clusters and markers provides novel insights leading to improved prediction and management of nephrolithiasis.

scholarly journals Demonstration of large-scale migration of cortical thymocytes to peripheral lymphoid tissues in cyclosporin A-treated rats.

1993 ◽  
Vol 178 (1) ◽  
pp. 285-293 ◽  
Author(s):  
H H Zadeh ◽  
I Goldschneider
Keyword(s):  
T Cells ◽  
Cyclosporin A ◽  
Large Scale ◽  
Fluorescein Isothiocyanate ◽  
Cell Receptor ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Lymphoid Tissues ◽  
Double Positive ◽  
Large Numbers ◽  
Alpha Beta

Young adult Lewis rats were maintained on diets containing 0.015 or 0.027% cyclosporin A (CSA) for periods of up to 6 wk. All animals showed complete depletion of medullary thymocytes (CD4+8- and CD4-8+, T cell receptor [TCR] alpha/beta hi, Thy-1med/low, terminal deoxynucleotidyl transferase negative [TdT-]) and a 50% reduction in the number of TdT- cortical thymocytes (CD4+8+, TCR alpha/beta low, Thy-1med) within 1 wk of CSA treatment. In addition, about half of the animals displayed a 50% reduction in the number of TdT+ cortical thymocytes (CD4+8+, TCR alpha/beta low, Thy-1hi). These intrathymic changes were accompanied by a reciprocal increase in the number of double-positive (DP; CD4+8+) T cells in lymph nodes (LN) and spleens. To confirm that the latter T cells were recent thymic emigrants (RTE), CSA-treated rats were injected intrathymically with fluorescein isothiocyanate, and the phenotype of the labeled T cells appearing in LN was determined 16 h later. The results demonstrated that, in addition to those RTE exported in normal animals (> 90% medullary origin), the emigration of DP thymocytes, including large numbers of TdT+ thymocytes, was markedly increased. The presence of TdT+ cells, which normally do not leave the thymus, clearly identifies the DP RTE as originating from the thymus cortex. Intrathymic labeling studies also directly demonstrated that export of all thymocyte subsets ceases within 9 d of CSA treatment; and thymectomy experiments confirmed that the CSA-induced increase in phenotypically immature T cells resulted primarily from the disturbance of thymocyte maturation and emigration, rather than from a direct effect on preexisting T cells. These results suggest that a wave of cortical thymocytes, many of which presumably have not yet undergone negative selection, is released from the thymus during the first week of CSA treatment. The presence of these potentially unselected cells in peripheral lymphoid tissues may help to explain the increased frequency of autoreactive T cells observed in CSA-treated animals.

scholarly journals Developing and Activated T Cell Survival Depends on Differential Signaling Pathways to Regulate Anti-Apoptotic Bcl-xL

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Ruiqing Wang ◽  
Huimin Xie ◽  
Zhaofeng Huang ◽  
Weirong Shang ◽  
Zuoming Sun
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
Positive Selection ◽  
Developmental Process ◽  
Selection Process ◽  
Double Positive ◽  
Activated T Cells ◽  
Peripheral T Cells

Survival of T cells in both the central and peripheral immune system determines its ultimate function in the regulation of immune responses. In the thymus, developing T cells undergo positive and negative selection to generate a T cell repertoire that responds to foreign, but not self, antigens. During T cell development, the T cell receptorαchain is rearranged. However, the first round of rearrangement may fail, which triggers another round ofαchain rearrangement until either successful positive selection or cell death occurs. Thus, the lifespan of double positive (CD4+CD8+; DP) thymocytes determines how many rounds ofαchain rearrangement can be carried out and influences the likelihood of completing positive selection. The anti-apoptotic protein Bcl-xLis the ultimate effector regulating the survival of CD4+CD8+thymocytes subject to the selection process, and the deletion of Bcl-xLleads to premature apoptosis of thymocytes prior to the completion of the developmental process. In addition to its critical function in the thymus, Bcl-xLalso regulates the survival of peripheral T cells. Upon engagement with antigens, T cells are activated and differentiated into effectors. Activated T cells upregulate Bcl-xLto enhance their own survival. Bcl-xL-mediated survival is required for the generation of effectors that carry out the actual immune responses. In the absence of Bcl-xL, mature T cells undergo apoptosis prior to the completion of the differentiation process to become effector cells. Therefore, Bcl-xLensures the survival of both developing and peripheral T cells, which is essential for a functional immune system.

scholarly journals The concurrent maturation of mouse and human thymocytes in human fetal thymus implanted in NIH-beige-nude-xid mice is associated with the reconstitution of the murine immune system.

1993 ◽  
Vol 177 (3) ◽  
pp. 821-832 ◽  
Author(s):  
T R Kollmann ◽  
M M Goldstein ◽  
H Goldstein
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Keyhole Limpet Hemocyanin ◽  
Cell Receptor ◽  
Scid Mice ◽  
Double Positive ◽  
Fetal Thymus

To determine whether the human thymus provides an environment for the maturation of murine T cells, human fetal thymus and liver (hu-thy/liv) were implanted into congenitally athymic NIH-beige-nude-xid (BNX) mice or C.B-17 scid/scid (SCID) mice. 3 mo after implantation, in contrast to the hu-thy/liv implant in SCID mice, which was populated only with human CD4/CD8 single- and double-positive thymocytes, the hu-thy/liv implant in BNX mice contained a chimeric population of human and mouse CD4/CD8 single- and double-positive thymocytes. Immunohistochemical staining of the hu-thy/liv implant in BNX mice indicated that the population of double-positive mouse thymocytes was localized to discrete areas of the human fetal thymus. Quantitative improvements in mouse T cell and immunoglobulin (Ig) G parameters were observed after grafting of the human fetal thymus and liver tissue into BNX mice. In addition, in contrast to the nonimplanted BNX mice, the implanted BNX mice were capable of mounting a keyhole limpet hemocyanin-specific IgG response and their peripheral T cells were responsive to stimulation with mitogens and antibodies directed to the T cell receptor. Furthermore, after in vivo priming, T cells present in lymph nodes of the implanted BNX mice were capable of mounting an antigen-induced in vitro T cell-dependent proliferative response. Thus, concurrent with the continued maturation of human T cells, murine T cells differentiated within the human fetal thymus implanted in the BNX mice and mediated the phenotypic and functional reconstitution of the murine immune system. Mice with a reconstituted immune system that contain a human thymic implant that is infectible with human immunodeficiency virus (HIV) should prove useful in the investigation of T cell maturation in the thymus and in the evaluation of potential HIV vaccines.

A Drug Target Interaction Prediction Based on LINE-RF Learning

2020 ◽  
Vol 15 (7) ◽  
pp. 750-757
Author(s):  
Jihong Wang ◽  
Yue Shi ◽  
Xiaodan Wang ◽  
Huiyou Chang
Keyword(s):  
Network Topology ◽  
Drug Target ◽  
Large Scale ◽  
Representation Learning ◽  
New Drugs ◽  
Combination Method ◽  
Learning Methods ◽  
Network Representation ◽  
On Line ◽  
Clinical Experiments

Background: At present, using computer methods to predict drug-target interactions (DTIs) is a very important step in the discovery of new drugs and drug relocation processes. The potential DTIs identified by machine learning methods can provide guidance in biochemical or clinical experiments. Objective: The goal of this article is to combine the latest network representation learning methods for drug-target prediction research, improve model prediction capabilities, and promote new drug development. Methods: We use large-scale information network embedding (LINE) method to extract network topology features of drugs, targets, diseases, etc., integrate features obtained from heterogeneous networks, construct binary classification samples, and use random forest (RF) method to predict DTIs. Results: The experiments in this paper compare the common classifiers of RF, LR, and SVM, as well as the typical network representation learning methods of LINE, Node2Vec, and DeepWalk. It can be seen that the combined method LINE-RF achieves the best results, reaching an AUC of 0.9349 and an AUPR of 0.9016. Conclusion: The learning method based on LINE network can effectively learn drugs, targets, diseases and other hidden features from the network topology. The combination of features learned through multiple networks can enhance the expression ability. RF is an effective method of supervised learning. Therefore, the Line-RF combination method is a widely applicable method.

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