ABSTRACT
Here, we review thematic publications in available literature sources of the databases PubMed, Scopus, Web of Science, eLibrary, 49 of which were dated of the years 1997-2022. Analysis of such reports is aimed at assessing features of cytokine storm-induced hyperinflammatory reaction with signs of immunosuppression accompanied by pronounced lymphopenia and lowered count of CD4(+)T helpers during severe COVID-19. The prognostic factor for unfavorable prognosis was based on the marker of systemic inflammatory reaction correlating with the disease severity - the soluble IL-2 receptor as well as the neutrophil-to-lymphocyte ratio and the lymphocyte subset imbalance. An immunosuppressive therapy of severe forms of COVID-19, aimed at weakening the inflammatory response, exacerbates immune dysfunction by suppressing the T cell function, mainly due to Th1 lymphocytes involved in recognizing and eliminating intracellular pathogens particularly viruses. Upon that, cell-mediated immunity becomes compromised that relies on cytotoxic T-lymphocytes, natural killer cells and macrophages. Timely and targeted immunocorrection is required to prevent or reduce the immunosuppression that accompanies a severe disease course and leads to serious and prolonged complications, as well as to association of secondary infections. In fight against the cytokine storm, it is important not to miss a time point of developing immunosuppressive condition that transitions into immunoparalysis as follows from recent publications covering the tactics of treating immune-mediated complications of coronavirus infection. The review discusses opportunities for immunosuppressive therapy along with glucocorticosteroids and monoclonal antibodies blocking IL-6 or cognate receptors. Studies using mesenchymal stem cells (MSCs) to reduce systemic inflammatory response at COVID-19 are outlined in the review. The use of antigen-specific Treg and their combinations with antagonists of tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma) as well as low-dose IL-2 in patients with SARS-CoV-2 infection were analyzed. The prognostic perspectives for CAR-T cells and CAR-NK cells technology have been considered as novel therapeutic approaches aimed at "training" effector cells to recognize the surface SARS-CoV-2 virus spike-like (S) protein. The feasibility of a therapeutic approach is also emphasized by comparatively analyzed of efficacy of using IL-7 or IL-15 during lymphopenia in patients with COVID-19. Here, side effects complicating immunocorrection come to the fore. Critical evaluation of corrected immunosuppressive conditions in patients with COVID-19 in the post-COVID-19 period by using low-dose IL-2 therapy revealed its ability to repair cellular immune response. As a result, a low-dose IL-2 therapy is recommended as a cytokine replacement therapy in such patients with COVID-19 during hyper-to-hypo-inflammatory phase transition in immune response.
ABSTRACT
We have recently demonstrated in a double-blind randomized trial the beneficial effects of L-Arginine in patients hospitalized for COVID-19. We hypothesize that one of the mechanisms underlying the favorable effects of L-Arginine is its action on inflammatory cytokines. To verify our hypothesis, we measured longitudinal plasma levels of pro-inflammatory and anti-inflammatory cytokines implied in the pathophysiology of COVID-19 in patients randomized to receive oral L-Arginine or placebo. The study was successfully completed by 169 patients. Patients in the L-Arginine arm had a reduced respiratory support evaluated at 10 and 20 days; moreover, the time to hospital discharge was significantly shorter in the L-Arginine group. The assessment of circulating cytokines revealed that L-Arginine significantly reduced the circulating levels of pro-inflammatory IL-2, IL-6, and IFN-γ and increased the levels of the anti-inflammatory IL-10. Taken together, these findings indicate that adding L-Arginine to standard therapy in COVID-19 patients markedly reduces the need of respiratory support and the duration of in-hospital stay; moreover, L-Arginine significantly regulates circulating levels of pro-inflammatory and anti-inflammatory cytokines.
Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Cytokines , Arginine/therapeutic use , Anti-Inflammatory Agents/adverse effectsABSTRACT
BACKGROUND: Immune dysregulation has been linked to morbidity and mortality in COVID-19 patients. Understanding the immunology of COVID-19 is critical for developing effective therapies, diagnostics, and prophylactic strategies to control the disease. AIM: The aim of this study was to correlate cytokine and chemokine serum levels with COVID-19 disease severity and mortality. SUBJECTS AND METHODS: A total of 60 hospitalized patients from the Tabuk region of Saudi Arabia with confirmed COVID-19 were included in the study. At hospital admission, the IL-1 ß, IL-2, IL-8, IL-10, LT-B4, and CCL-2 serum levels were measured. The cytokine levels in COVID-19 patients were compared to the levels in 30 healthy matched control subjects. RESULTS: The IL-1 ß, IL-2, LTB-4, CCL-2, and IL-8 levels (but not IL-10) were significantly higher in all COVID-19 patients (47 survivors and 13 non-survivors) compared with the levels in the healthy control group. In the non-survivor COVID-19 patients, patients' age, D-dimer, and creatinine kinase were significantly higher, and IL-1 ß, IL-2, and IL-8 were significantly lower compared with the levels in the survivors. CONCLUSION: Mortality rates in COVID-19 patients are associated with increased age and a failure to mount an effective immune response rather than developing a cytokine storm. These results warrant the personalized treatment of COVID-19 patients based on cytokine profiling.
ABSTRACT
The contribution of the cellular immune response to the severity of coronavirus disease 2019 (COVID-19) is still uncertain because most evidence comes from patients receiving multiple drugs able to change immune function. Herein, we conducted a prospective cohort study and obtained blood samples from 128 unvaccinated healthy volunteers to examine the in vitro response pattern of CD4+ and CD8+ T cells and monocyte subsets to polyclonal stimuli, including anti-CD3, anti-CD28, poly I:C, severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) recombinant spike S1 protein, and lipopolysaccharide. Then, we started a six-month follow-up and registered 12 participants who got SARS-CoV-2 infection, from whom we retrospectively analyzed the basal immune response pattern of T cells and monocytes. Of the 12 participants infected, six participants developed mild COVID-19 with self-limiting symptoms such as fever, headache, and anosmia. Conversely, six other participants developed severe COVID-19 with pneumonia, respiratory distress, and hypoxia. Two severe COVID-19 cases required invasive mechanical ventilation. There were no differences between mild and severe cases for demographic, clinical, and biochemical baseline characteristics. In response to polyclonal stimuli, basal production of interleukin-2 (IL-2) and interferon (IFN-) gamma significantly decreased, and the programmed cell death protein 1 (PD-1) increased in CD4+ and CD8+ T cells from participants who posteriorly developed severe COVID-19 compared to mild cases. Likewise, CD14++CD16- classical and CD14+CD16+ non-classical monocytes lost their ability to produce IFN-alpha in response to polyclonal stimuli in participants who developed severe COVID-19 compared to mild cases. Of note, neither the total immunoglobulin G serum titers against the virus nor their neutralizing ability differed between mild and severe cases after a month of clinical recovery. In conclusion, using in vitro polyclonal stimuli, we found a basal immune response pattern associated with a predisposition to developing severe COVID-19, where high PD-1 expression and low IL-2 and IFN-gamma production in CD4+ and CD8+ T cells, and poor IFN-alpha expression in classical and non-classical monocytes are linked to disease worsening. Since antibody titers did not differ between mild and severe cases, these findings suggest cellular immunity may play a more crucial role than humoral immunity in preventing COVID-19 progression.
Subject(s)
COVID-19 , Humans , Immunity, Cellular , Interleukin-2 , Monocytes , Programmed Cell Death 1 Receptor , Prospective Studies , Retrospective Studies , SARS-CoV-2 , T-LymphocytesABSTRACT
A detailed understanding of protective immunity against SARS-CoV-2 is incredibly important in fighting the pandemic. Central to protective immunity is the ability of the immune system to recall previous exposures. Although antibody and T cell immunity have gained considerable attention, the contribution of the NK cell compartment to immune recall and protection from SARS-CoV-2 has not been explored. In this study, we investigate the NK cell responses to stimulation with SARS-CoV-2 in previously exposed and non-exposed individuals. We show that NK cells demonstrate an enhanced CD4+ T cell dependent response when re-exposed to SARS-CoV-2 antigen. The enhanced response is dependent on T cells and correlates with the number of SARS-CoV-2 specific CD4 T cells. We find that IL-2 is a critical mediator of NK cell function. These findings suggest that NK cells contribute to the protective responses against SARS-CoV-2 through a cooperation with antigen-specific CD4 T cells and have significant implications on our understanding of protective immunity in SARS-CoV-2.
Subject(s)
COVID-19 , Interleukin-2 , Killer Cells, Natural , mRNA Vaccines , Adult , Humans , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/prevention & control , Killer Cells, Natural/immunology , SARS-CoV-2 , Vaccination , CD4-Positive T-Lymphocytes , mRNA Vaccines/immunologyABSTRACT
Newcastle Disease (ND) vaccines are being used for more than 7 decades, the disease is still a major challenge for poultry industry both locally and internationally. ND frequently emerges in highly vaccinated flocks causing high economic losses without specific treatment. Mesenchymal stem cells (MSCs) are a group of pluripotent cells with multiple biotechnology applications, including but not limited to tissue genesis, tissue repair, hematopoiesis, and immune modulation. Therapeutic strategies based on the usage of stem cells includes the cells either themselves or their secretions (secretome), which has recently shown ability to inhibit SARS-CoV2 replication in-vitro. In this study, MSCs were prepared from the bone marrow of native Egyptian Fayoumi chicken. The MSC with the surface marker CD105 (CD105+) were magnetically separated and infected with virulent Newcastle disease virus (vNDV). The virusinduced multiple changes at the cellular and ultrastructural level in the infected cells, and it was able to maximize the production of interferon-gamma (IFNγ) and interleukin 2 (IL2), interleukin 6 (IL6) and interleukin 12 (IL12). In conclusion, our data represent a preliminary step in vNDV immunotherapy where MSCs media could be used for the treatment of vNDV in infected flocks © 2022 by the authors. Licensee ResearchersLinks Ltd, England, UK
ABSTRACT
Here, we review thematic publications in available literature sources of the databases PubMed, Scopus, Web of Science, eLibrary, 49 of which were dated of the years 1997–2022. Analysis of such reports is aimed at assessing features of cytokine storm-induced hyperinflammatory reaction with signs of immunosuppression accompanied by pronounced lymphopenia and lowered count of CD4+T helpers during severe COVID-19. The prognostic factor for unfavorable prognosis was based on the marker of systemic inflammatory reaction correlating with the disease severity - the soluble IL-2 receptor as well as the neutrophil-to-lymphocyte ratio and the lymphocyte subset imbalance. An immunosuppressive therapy of severe forms of COVID-19, aimed at weakening the inflammatory response, exacerbates immune dysfunction by suppressing the T cell function, mainly due to Th1 lymphocytes involved in recognizing and eliminating intracellular pathogens particularly viruses. Upon that, cell-mediated immunity becomes compromised that relies on cytotoxic T-lymphocytes, natural killer cells and macrophages. Timely and targeted immunocorrection is required to prevent or reduce the immunosuppression that accompanies a severe disease course and leads to serious and prolonged complications, as well as to association of secondary infections. In fight against the cytokine storm, it is important not to miss a time point of developing immunosuppressive condition that transitions into immunoparalysis as follows from recent publications covering the tactics of treating immune-mediated complications of coronavirus infection. The review discusses opportunities for immunosuppressive therapy along with glucocorticosteroids and monoclonal antibodies blocking IL-6 or cognate receptors. Studies using mesenchymal stem cells (MSCs) to reduce systemic inflammatory response at COVID-19 are outlined in the review. The use of antigen-specific Treg and their combinations with antagonists of tumor necrosis factor-α (TNFα), interferon-γ (IFNγ) as well as low-dose IL-2 in patients with SARS-CoV-2 infection were analyzed. The prognostic perspectives for CAR-T cells and CAR-NK cells technology have been considered as novel therapeutic approaches aimed at “training” effector cells to recognize the surface SARS-CoV-2 virus spike-like (S) protein. The feasibility of a therapeutic approach is also emphasized by comparatively analyzed of efficacy of using IL-7 or IL-15 during lymphopenia in patients with COVID-19. Here, side effects complicating immunocorrection come to the fore. Critical evaluation of corrected immunosuppressive conditions in patients with COVID-19 in the post-COVID-19 period by using low-dose IL-2 therapy revealed its ability to repair cellular immune response. As a result, a low-dose IL-2 therapy is recommended as a cytokine replacement therapy in such patients with COVID-19 during hyper-to-hypo-inflammatory phase transition in immune response. (English) [ FROM AUTHOR] Обзор выполнен поÑредÑтвом поиÑка тематичеÑкой информации Ñреди доÑтупных иÑточников литературы в базах данных Pubmed, Scopus, Web of Science, eLibrary, 49 из которых (1997–2022 гг. изданиÑ) вошли в данный обзор. Ðнализ Ñтих работ направлен на оÑобенноÑти индуцированной цитокиновым штормом гипервоÑпалительной реакции Ñ Ð¿Ñ€Ð¸Ð·Ð½Ð°ÐºÐ°Ð¼Ð¸ иммуноÑупреÑÑии, ÑопровождающейÑÑ Ð²Ñ‹Ñ€Ð°Ð¶ÐµÐ½Ð½Ð¾Ð¹ лимфопенией Ñо Ñнижением количеÑтва CD4+ Т-хелперов при Ñ‚Ñжелом течении COVID-19. ПрогноÑтичеÑким фактором неблагоприÑтного прогноза Ñлужит коррелирующий Ñ Ñ‚ÑжеÑтью Ð·Ð°Ð±Ð¾Ð»ÐµÐ²Ð°Ð½Ð¸Ñ Ð¼Ð°Ñ€ÐºÐµÑ€ ÑиÑтемной воÑпалительной реакции - раÑтворимый рецептор IL-2, а также Ñоотношение нейтрофилов к лимфоцитам и диÑÐ±Ð°Ð»Ð°Ð½Ñ ÑубпопулÑций лимфоцитов. ÐÐ°Ð¿Ñ€Ð°Ð²Ð»ÐµÐ½Ð½Ð°Ñ Ð½Ð° оÑлабление воÑпалительной реакции иммуноÑупреÑÑÐ¸Ð²Ð½Ð°Ñ Ñ‚ÐµÑ€Ð°Ð¿Ð¸Ñ Ñ‚Ñжелых форм COVID-19 уÑугублÑет иммунную диÑфункцию, подавлÑÑ Ð¢-клеточный ответ, в оÑновном, за Ñчет Th1 лимфоцитов, учаÑтвующих в идентификации и Ñлиминации внутриклеточных патогенов, в чаÑтноÑти вируÑов. При Ñтом Ñтрадает клеточно-опоÑредованный иммунитет, который обеÑпечивают цитотокÑичеÑкие Т-лимфоциты, натуральные киллеры и макрофаги. Ð”Ð»Ñ Ð¿Ñ€ÐµÐ´ÑƒÐ¿Ñ€ÐµÐ¶Ð´ÐµÐ½Ð¸Ñ Ð¸Ð»Ð¸ оÑÐ»Ð°Ð±Ð»ÐµÐ½Ð¸Ñ Ð¸Ð¼Ð¼ÑƒÐ½Ð¾ÑупреÑÑии, Ñопровождающей Ñ‚Ñжелое течение и приводÑщей к Ñерьезным и длительным оÑложнениÑм, а также к приÑоединению вторичных инфекций, необходима ÑÐ²Ð¾ÐµÐ²Ñ€ÐµÐ¼ÐµÐ½Ð½Ð°Ñ Ð¸ адреÑÐ½Ð°Ñ Ð¸Ð¼Ð¼ÑƒÐ½Ð¾ÐºÐ¾Ñ€Ñ€ÐµÐºÑ†Ð¸Ñ. Ð’ борьбе Ñ Ñ†Ð¸Ñ‚Ð¾ÐºÐ¸Ð½Ð¾Ð²Ñ‹Ð¼ штормом важно не упуÑтить момент Ñ€Ð°Ð·Ð²Ð¸Ñ‚Ð¸Ñ Ð¸Ð¼Ð¼ÑƒÐ½Ð¾ÑупреÑÑивного ÑоÑтоÑниÑ, переходÑщего в иммунопаралич, что Ñледует из поÑледних публикаций, оÑвещающих тактику Ð»ÐµÑ‡ÐµÐ½Ð¸Ñ Ð¸Ð¼Ð¼ÑƒÐ½Ð¾Ð¾Ð¿Ð¾Ñредованных оÑложнений коронавируÑной инфекции. Ð’ обзоре раÑÑмотрены возможноÑти иммуноÑупреÑÑивной терапии, помимо глюкокортикоÑтероидов и моноклональных антител, блокирующих IL-6 или его рецепторы. Приведены примеры работ Ñ Ð¸Ñпользованием мезенхимальных Ñтволовых клеток (МСК) Ð´Ð»Ñ ÑÐ½Ð¸Ð¶ÐµÐ½Ð¸Ñ ÑиÑтемной воÑпалительной реакции при COVID-19. Подвергнуто анализу применениеантиген-ÑпецифичеÑких Treg и их Ñочетаний Ñ Ð°Ð½Ñ‚Ð°Ð³Ð¾Ð½Ð¸Ñтами фактора некроза опухолей α (TNFα), интерферона γ (IFNγ) и Ñ Ð½Ð¸Ð·ÐºÐ¸Ð¼Ð¸ дозами IL-2 у пациентов Ñ SARS-CoV-2-инфекцией. ПрогноÑтичеÑкие перÑпективы технологии CAR-Т-клеток и CAR-NK-клеток раÑÑмотрены в плане новых терапевтичеÑких подходов, нацеленных на «обучение» Ñффекторных ºÐ»ÐµÑ‚ок раÑпознавать поверхноÑтный шиповидный (S) белок вируÑа SARS-CoV-2. ЦелеÑообразноÑтьиммунокоррегирующей терапии подчеркиваетÑÑ Ñ‚Ð°ÐºÐ¶Ðµ Ñравнительным анализом ÑффективноÑти IL-7 или IL-15 у пациентов Ñ COVID-19 Ñ Ð¸Ð¼Ð¼ÑƒÐ½Ð¾ÑупреÑÑией. КритичеÑÐºÐ°Ñ Ð¾Ñ†ÐµÐ½ÐºÐ° коррекции иммуноÑупреÑÑивных ÑоÑтоÑний у пациентов Ñ COVID-19 в поÑтковидный период Ñ Ð¿Ð¾Ð¼Ð¾Ñ‰ÑŒÑŽ низкодозной терапии препаратами IL-2 позволила выÑвить ее ÑпоÑобноÑÑ‚ÑŒ воÑÑтанавливать клеточный иммунный ответ. Ð’ результате в качеÑтве замеÑтительной цитокиновой терапии у Ñтих пациентов, при переходе от гипервоÑпалительной к гиповоÑпалительной фазе иммунного ответа, может быть рекомендована Ð½Ð¸Ð·ÐºÐ¾Ð´Ð¾Ð·Ð½Ð°Ñ IL-2 терапиÑ. (Russian) [ FROM AUTHOR] Copyright of Russian Journal of Infection & Immunity is the property of National Electronic-Information Consortium and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)
ABSTRACT
BACKGROUND: Cellular immune memory responses post coronavirus disease 2019 (COVID-19) have been difficult to assess due to the risks of contaminating the immune response readout with memory responses stemming from previous exposure to endemic coronaviruses. The work herein presents a large-scale long-term follow-up study investigating the correlation between symptomology and cellular immune responses four to five months post seroconversion based on a unique severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific peptide pool that contains no overlapping peptides with endemic human coronaviruses. METHODS: Peptide stimulated memory T cell responses were assessed with dual interferon-gamma (IFNγ) and interleukin (IL)-2 Fluorospot. Serological analyses were performed using a multiplex antigen bead array. RESULTS: Our work demonstrates that long-term SARS-CoV-2-specific memory T cell responses feature dual IFNγ and IL-2 responses, whereas cross-reactive memory T cell responses primarily generate IFNγ in response to SARS-CoV-2 peptide stimulation. T cell responses correlated to long-term humoral immune responses. Disease severity as well as specific COVID-19 symptoms correlated with the magnitude of the SARS-CoV-2-specific memory T cell response four to five months post seroconversion. CONCLUSION: Using a large cohort and a SARS-CoV-2-specific peptide pool we were able to substantiate that initial disease severity and symptoms correlate with the magnitude of the SARS-CoV-2-specific memory T cell responses.
Subject(s)
COVID-19 , SARS-CoV-2 , CD4-Positive T-Lymphocytes , Follow-Up Studies , Humans , Immunity, Cellular , Severity of Illness IndexABSTRACT
The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide, and the WHO declared it a pandemic on March 11, 2020. Clinical characteristics and epidemiology features of patients infected with SARS-CoV-2 have been explored in the previous study. However, little is known about the combinative association of liver dysfunction and abnormal interleukins (ILs) in severe patients with COVID-19. This study was designed to estimate whether liver dysfunction and abnormal ILs could predict the severity of COVID-19. This study integrated liver function data and ILs data in patients with COVID-19 and found that liver injury and two ILs, interleukin-2 receptor (IL-2R) and interleukin-6 (IL-6), were closely related to the prognosis of patients with COVID-19. This study may give more exact information to clinicians about the prognosis of patients with COVID-19. In addition, this correlational study between liver disorder and ILs may provide a new vision to diagnosis and treatment in patients.
Subject(s)
COVID-19 , Interleukin-6 , Liver/pathology , Receptors, Interleukin-2/blood , COVID-19/diagnosis , Humans , Interleukin-6/blood , PandemicsABSTRACT
A 71-year-old female patient with B-cell depletion due to treatment with an anti-CD20 monoclonal antibody was admitted for worsening COVID-19. Overall, she had persistent viral shedding, worsening respiratory failure, and progressive pneumonia that did not improve despite dexamethasone and antibiotic therapy. After administration of bamlanivimab, a monoclonal antibody with high affinity for the receptor-binding domain of the SARS-CoV-2 spike protein, inflammatory markers rapidly decreased, SARS-CoV2 RT-PCR became negative, and the patient improved clinically and radiologically. In conclusion, we demonstrated successful treatment of prolonged COVID-19 in a patient with severe B-cell aplasia with a virus-neutralizing monoclonal antibody.
ABSTRACT
BACKGROUND: Coronavirus disease 2019 is characterized by the elevation of a broad spectrum of inflammatory mediators associated with poor disease outcomes. We aimed at an in-silico analysis of regulatory microRNA and their transcription factors (TF) for these inflammatory genes that may help to devise potential therapeutic strategies in the future. METHODS: The cytokine regulating immune-expressed genes (CRIEG) were sorted from literature and the GEO microarray dataset. Their co-differentially expressed miRNA and transcription factors were predicted from publicly available databases. Enrichment analysis was done through mienturnet, MiEAA, Gene Ontology, and pathways predicted by KEGG and Reactome pathways. Finally, the functional and regulatory features were analyzed and visualized through Cytoscape. RESULTS: Sixteen CRIEG were observed to have a significant protein-protein interaction network. The ontological analysis revealed significantly enriched pathways for biological processes, molecular functions, and cellular components. The search performed in the miRNA database yielded ten miRNAs that are significantly involved in regulating these genes and their transcription factors. CONCLUSION: An in-silico representation of a network involving miRNAs, CRIEGs, and TF, which take part in the inflammatory response in COVID-19, has been elucidated. Thus, these regulatory factors may have potentially critical roles in the inflammatory response in COVID-19 and may be explored further to develop targeted therapeutic strategies and mechanistic validation.
ABSTRACT
The dysregulation of both the innate and adaptive responses to SARS-CoV-2 have an impact on the course of COVID-19, and play a role in the clinical outcome of the disease. Here, we performed a comprehensive analysis of peripheral blood lymphocyte subpopulations in 82 patients with COVID-19, including 31 patients with a critical course of the disease. In COVID-19 patients who required hospitalization we analyzed T cell subsets, including Treg cells, as well as TCRα/ß and γ/δ, NK cells, and B cells, during the first two weeks after admission to hospital due to the SARS-CoV-2 infection, with marked reductions in leukocytes subpopulations, especially in critically ill COVID-19 patients. We showed decreased levels of Th, Ts cells, Treg cells (both naïve and induced), TCRα/ß and γ/δ cells, as well as CD16+CD56+NK cells in ICU compared to non-ICU COVID-19 patients. We observed impaired function of T and NK cells in critically ill COVID-19 patients with extremely low levels of secreted cytokines. We found that the IL-2/INFγ ratio was the strongest indicator of a critical course of COVID-19, and was associated with fatal outcomes. Our findings showed markedly impaired innate and adaptive responses in critically ill COVID-19 patients, and suggest that the immunosuppressive state in the case of a critical course of SARS-CoV-2 infection might reflect subsequent clinical deterioration and predict a fatal outcome.
Subject(s)
COVID-19/immunology , Immune Tolerance , Lymphocyte Subsets/immunology , SARS-CoV-2/immunology , Severity of Illness Index , Adaptive Immunity , Aged , COVID-19/diagnosis , COVID-19/mortality , COVID-19/virology , Clinical Deterioration , Critical Illness , Female , Hospital Mortality , Hospitalization , Humans , Immunity, Innate , Leukocyte Count , Male , Middle Aged , Poland/epidemiology , Prospective Studies , Risk Assessment/methodsABSTRACT
Most patients with coronavirus disease 2019 (COVID-19) experience asymptomatic disease or mild symptoms, but some have critical symptoms requiring intensive care. It is important to determine how patients with asymptomatic or mild COVID-19 react to severe acute respiratory syndrome coronavirus 2 infection and suppress virus spread. Innate immunity is important for evasion from the first virus attack, and it may play an important role in the pathogenesis in these patients. We measured serum cytokine levels in 95 patients with COVID-19 during the infection's acute phase and report that significantly higher interleukin 12 and 2 levels were induced in patients with asymptomatic or mild disease than in those with moderate or severe disease, indicating the key roles of these cytokines in the pathogenesis of asymptomatic or mild COVID-19.
Subject(s)
COVID-19/immunology , Immunity, Innate , Interleukin-12/blood , Interleukin-2/blood , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Asymptomatic Infections , COVID-19/blood , COVID-19/diagnosis , COVID-19/virology , COVID-19 Nucleic Acid Testing , Case-Control Studies , Female , Healthy Volunteers , Humans , Interleukin-12/immunology , Interleukin-2/immunology , Male , Middle Aged , RNA, Viral/isolation & purification , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Severity of Illness Index , Young AdultABSTRACT
BACKGROUND: Many drugs approved for other indications can control the growth of tumor cells and limit adverse events (AE). DATA SOURCES: Literature searches with keywords 'repurposing and cancer' books, websites: https://clinicaltrials.gov/, for drug structures: https://pubchem.ncbi.nlm.nih.gov/. AREAS OF AGREEMENT: Introducing approved drugs, such as those developed to treat diabetes (Metformin) or inflammation (Thalidomide), identified to have cytostatic activity, can enhance chemotherapy or even replace more cytotoxic drugs. Also, anti-inflammatory compounds, cytokines and inhibitors of proteolysis can be used to control the side effects of chemo- and immuno-therapies or as second-line treatments for tumors resistant to kinase inhibitors (KI). Drugs specifically developed for cancer therapy, such as interferons (IFN), the tyrosine KI abivertinib TKI (tyrosine kinase inhibitor) and interleukin-6 (IL-6) receptor inhibitors, may help control symptoms of Covid-19. AREAS OF CONTROVERSY: Better knowledge of mechanisms of drug activities is essential for repurposing. Chemotherapies induce ER stress and enhance mutation rates and chromosome alterations, leading to resistance that cannot always be related to mutations in the target gene. Metformin, thalidomide and cytokines (IFN, tumor necrosis factor (TNF), interleukin-2 (IL-2) and others) have pleiomorphic activities, some of which can enhance tumorigenesis. The small and fragile patient pools available for clinical trials can cloud the data on the usefulness of cotreatments. GROWING POINTS: Better understanding of drug metabolism and mechanisms should aid in repurposing drugs for primary, adjuvant and adjunct treatments. AREAS TIMELY FOR DEVELOPING RESEARCH: Optimizing drug combinations, reducing cytotoxicity of chemotherapeutics and controlling associated inflammation.
Subject(s)
COVID-19 Drug Treatment , Drug Repositioning , Neoplasms/drug therapy , HumansABSTRACT
Recently an outbreak that emerged in Wuhan, China in December 2019, spread to the whole world in a short time and killed >1,410,000 people. It was determined that a new type of beta coronavirus called severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) was causative agent of this outbreak and the disease caused by the virus was named as coronavirus disease 19 (COVID19). Despite the information obtained from the viral genome structure, many aspects of the virus-host interactions during infection is still unknown. In this study we aimed to identify SARS-CoV-2 encoded microRNAs and their cellular targets. We applied a computational method to predict miRNAs encoded by SARS-CoV-2 along with their putative targets in humans. Targets of predicted miRNAs were clustered into groups based on their biological processes, molecular function, and cellular compartments using GO and PANTHER. By using KEGG pathway enrichment analysis top pathways were identified. Finally, we have constructed an integrative pathway network analysis with target genes. We identified 40 SARS-CoV-2 miRNAs and their regulated targets. Our analysis showed that targeted genes including NFKB1, NFKBIE, JAK1-2, STAT3-4, STAT5B, STAT6, SOCS1-6, IL2, IL8, IL10, IL17, TGFBR1-2, SMAD2-4, HDAC1-6 and JARID1A-C, JARID2 play important roles in NFKB, JAK/STAT and TGFB signaling pathways as well as cells' epigenetic regulation pathways. Our results may help to understand virus-host interaction and the role of viral miRNAs during SARS-CoV-2 infection. As there is no current drug and effective treatment available for COVID19, it may also help to develop new treatment strategies.
ABSTRACT
Effective laboratory markers for the estimation of disease severity and predicting the clinical progression of coronavirus disease-2019 (COVID-19) is urgently needed. Laboratory tests, including blood routine, cytokine profiles and infection markers, were collected from 389 confirmed COVID-19 patients. The included patients were classified into mild (n = 168), severe (n = 169) and critical groups (n = 52). The leukocytes, neutrophils, infection biomarkers [such as C-reactive protein (CRP), procalcitonin (PCT) and ferritin] and the concentrations of cytokines [interleukin (IL)-2R, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α] were significantly increased, while lymphocytes were significantly decreased with increased severity of illness. The amount of IL-2R was positively correlated with the other cytokines and negatively correlated with lymphocyte number. The ratio of IL-2R to lymphocytes was found to be remarkably increased in severe and critical patients. IL-2R/lymphocytes were superior compared with other markers for the identification of COVID-19 with critical illness, not only from mild but also from severe illness. Moreover, the cytokine profiles and IL-2R/lymphocytes were significantly decreased in recovered patients, but further increased in disease-deteriorated patients, which might be correlated with the outcome of COVID-19. Lymphopenia and increased levels of cytokines were closely associated with disease severity. The IL-2R/lymphocyte was a prominent biomarker for early identification of severe COVID-19 and predicting the clinical progression of the disease.