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1.
Redox Biol ; 56: 102465, 2022 10.
Article in English | MEDLINE | ID: covidwho-2105815

ABSTRACT

BACKGROUND: The pathophysiologic significance of redox imbalance is unquestionable as numerous reports and topic reviews indicate alterations in redox parameters during corona virus disease 2019 (COVID-19). However, a more comprehensive understanding of redox-related parameters in the context of COVID-19-mediated inflammation and pathophysiology is required. METHODS: COVID-19 subjects (n = 64) and control subjects (n = 19) were enrolled, and blood was drawn within 72 h of diagnosis. Serum multiplex assays and peripheral blood mRNA sequencing was performed. Oxidant/free radical (electron paramagnetic resonance (EPR) spectroscopy, nitrite-nitrate assay) and antioxidant (ferrous reducing ability of serum assay and high-performance liquid chromatography) were performed. Multivariate analyses were performed to evaluate potential of indicated parameters to predict clinical outcome. RESULTS: Significantly greater levels of multiple inflammatory and vascular markers were quantified in the subjects admitted to the ICU compared to non-ICU subjects. Gene set enrichment analyses indicated significant enhancement of oxidant related pathways and biochemical assays confirmed a significant increase in free radical production and uric acid reduction in COVID-19 subjects. Multivariate analyses confirmed a positive association between serum levels of VCAM-1, ICAM-1 and a negative association between the abundance of one electron oxidants (detected by ascorbate radical formation) and mortality in COVID subjects while IL-17c and TSLP levels predicted need for intensive care in COVID-19 subjects. CONCLUSION: Herein we demonstrate a significant redox imbalance during COVID-19 infection affirming the potential for manipulation of oxidative stress pathways as a new therapeutic strategy COVID-19. However, further work is requisite for detailed identification of oxidants (O2•-, H2O2 and/or circulating transition metals such as Fe or Cu) contributing to this imbalance to avoid the repetition of failures using non-specific antioxidant supplementation.


Subject(s)
COVID-19 , Antioxidants/metabolism , Electron Spin Resonance Spectroscopy , Free Radicals , Humans , Hydrogen Peroxide , Intercellular Adhesion Molecule-1/metabolism , Interleukin-17/metabolism , Nitrates , Nitrites , Oxidants/metabolism , Oxidation-Reduction , Oxidative Stress , RNA, Messenger/metabolism , Uric Acid , Vascular Cell Adhesion Molecule-1/metabolism
2.
Int J Clin Pract ; 2022: 4761631, 2022.
Article in English | MEDLINE | ID: covidwho-2098045

ABSTRACT

Background: Th-17 cells, a proinflammatory subset of CD4 T lymphocytes, have been suggested as a possible cause of coronavirus disease-19 (COVID-19)-related immunological injuries. The aim of this study was to investigate the relationship between IL-17F (rs763780) polymorphism and the susceptibility to and outcomes of COVID-19 infection and to determine the clinical and laboratory predictors of COVID-19 death. Methods: This case-control study included 132 COVID-19 patients and 135 healthy age- and sex-matched controls. The participants were tested for IL-17F rs763780 polymorphism via TaqMan-based genotyping and for the expression of IL-17 by enzyme-linked immunosorbent assay. This study also investigated the predictors for COVID-19 mortality. Results: A non-statistically significant association was observed between IL-17F alleles and genotypes with COVID-19 (P=0.309, P=0.138, respectively). Moreover, no significant difference in the IL-17F genotypes was observed between non-survivors and survivors (P=0.482). In the multivariate analysis, the participants with the following characteristics had 17.7-, 11.2-, 8-, and 17.9-fold higher odds of exhibiting in-hospital mortality, respectively: (1) hypertension, (2) age of >57 years, (3) WBC count of >12.6 × 103/mm3, and (4) D-dimer of >0.9 ng/ml. The ROC curve analysis showed that IL-17 at a cutoff point of >46 pg/ml was a perfect discriminator of COVID-19 patients from control subjects (AUC = 1.0). Conclusion: The findings indicate that the IL-17F H161R variant does not influence the risk of COVID-19. However, the IL-17 level is a perfect discriminator of COVID-19 infection. Hypertension, age of >57 years, white blood cell count of >12.6 × 103/mm3, and D-dimer of >0.9 ng/ml are the independent predictors for death among COVID-19 patients.


Subject(s)
COVID-19 , Hypertension , Humans , Middle Aged , Interleukin-17/genetics , COVID-19/genetics , Genetic Predisposition to Disease , Case-Control Studies , Genotype , Polymorphism, Single Nucleotide
3.
Front Immunol ; 13: 1008438, 2022.
Article in English | MEDLINE | ID: covidwho-2080155

ABSTRACT

Objectives: To determine the profile of cytokines in patients with severe COVID-19 who were enrolled in a trial of COVID-19 convalescent plasma (CCP). Methods: Patients were randomized to receive standard treatment and 3 CCP units or standard treatment alone (CAPSID trial, ClinicalTrials.gov NCT04433910). The primary outcome was a dichotomous composite outcome (survival and no longer severe COVID-19 on day 21). Time to clinical improvement was a key secondary endpoint. The concentrations of 27 cytokines were measured (baseline, day 7). We analyzed the change and the correlation between serum cytokine levels over time in different subgroups and the prediction of outcome in receiver operating characteristics (ROC) analyses and in multivariate models. Results: The majority of cytokines showed significant changes from baseline to day 7. Some were strongly correlated amongst each other (at baseline the cluster IL-1ß, IL-2, IL-6, IL-8, G-CSF, MIP-1α, the cluster PDGF-BB, RANTES or the cluster IL-4, IL-17, Eotaxin, bFGF, TNF-α). The correlation matrix substantially changed from baseline to day 7. The heatmaps of the absolute values of the correlation matrix indicated an association of CCP treatment and clinical outcome with the cytokine pattern. Low levels of IP-10, IFN-γ, MCP-1 and IL-1ß on day 0 were predictive of treatment success in a ROC analysis. In multivariate models, low levels of IL-1ß, IFN-γ and MCP-1 on day 0 were significantly associated with both treatment success and shorter time to clinical improvement. Low levels of IP-10, IL-1RA, IL-6, MCP-1 and IFN-γ on day 7 and high levels of IL-9, PDGF and RANTES on day 7 were predictive of treatment success in ROC analyses. Low levels of IP-10, MCP-1 and high levels of RANTES, on day 7 were associated with both treatment success and shorter time to clinical improvement in multivariate models. Conclusion: This analysis demonstrates a considerable dynamic of cytokines over time, which is influenced by both treatment and clinical course of COVID-19. Levels of IL-1ß and MCP-1 at baseline and MCP-1, IP-10 and RANTES on day 7 were associated with a favorable outcome across several endpoints. These cytokines should be included in future trials for further evaluation as predictive factors.


Subject(s)
COVID-19 , Cytokines , Humans , Interleukin 1 Receptor Antagonist Protein , Interleukin-17 , Chemokine CCL3 , Tumor Necrosis Factor-alpha , Interleukin-6 , Interleukin-4 , Capsid , COVID-19/therapy , Becaplermin , Chemokine CXCL10 , Interleukin-2 , Interleukin-8 , Interleukin-9 , Granulocyte Colony-Stimulating Factor
4.
Front Immunol ; 13: 985433, 2022.
Article in English | MEDLINE | ID: covidwho-2080149

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of COVID-19. A better knowledge of immunological, cellular, and genetic characteristics of MIS-C could help better understand the pathogenesis of the disease and contribute to identifying specific diagnostic biomarkers and develop targeted therapies. We studied 37 MIS-C children at hospital admission and 24 healthy controls analyzing serum cytokines (IFN-α, IFN-ß, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70 and TNF), lymphocyte populations by flow cytometry and 386 genes related to autoimmune diseases, autoinflammation and primary immunodeficiencies by NGS. MIS-C patients showed a significant increase of serum IFNγ (despite a significant reduction of activated Th1) and ILs, even if with a great heterogeneity among patients, revealing different pathways involved in MIS-C pathogenesis and suggesting that serum cytokines at admission may help to select the inflammatory pathways to target in each patient. Flow cytometry demonstrated a relevant reduction of T populations while the percentage of B cell was increased in agreement with an autoimmune pathogenesis of MIS-C. Genetic analysis identified variants in 34 genes and 83.3% of patients had at least one gene variant. Among these, 9 were mutated in more patients. Most genes are related to autoimmune diseases like ATM, NCF1, MCM4, FCN3, and DOCK8 or to autoinflammatory diseases associated to the release of IFNγ like PRF1, NOD2, and MEF. Thus, an incomplete clearance of the Sars-CoV2 during the acute phase may induce tissue damage and self-antigen exposure and genetic variants can predispose to hyper-reactive immune dysregulation events of MIS-C-syndrome. Type II IFN activation and cytokine responses (mainly IL-6 and IL-10) may cause a cytokine storm in some patients with a more severe acute phase of the disease, lymphopenia and multisystemic organ involvement. The timely identification of such patients with an immunocytometric panel might be critical for targeted therapeutic management.


Subject(s)
Autoimmune Diseases , COVID-19 , Immunologic Deficiency Syndromes , Child , Humans , Interleukin-10 , SARS-CoV-2 , Interleukin-17 , Interleukin-6 , RNA, Viral , Cytokines/metabolism , Biomarkers , Autoantigens , Guanine Nucleotide Exchange Factors
5.
Acta Dermatovenerol Croat ; 30(2): 99-105, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-2073256

ABSTRACT

Psoriasis is a chronic inflammatory disease associated with a defective epidermal barrier, in which the immune system is already activated in lesional sites of the skin, and it is thus possible that affected individuals can have different immunologic rates of viral response. This is especially important in the era of the novel coronavirus disease (COVID-19) that is affecting the entire world. Patients with psoriasis are often receiving systemic therapy which includes immunosuppressive and biologic therapy, so this new infectious disease has raised concerns among dermatologists regarding psoriasis treatment. Some of the risk factors of psoriasis are obesity, diabetes mellitus, and hypertension - all of which are diseases linked with negative outcomes and higher severity of COVID-19. Psoriasis is mediated by inflammatory cells and proinflammatory cytokines such as IL-17, IL-23, IFN-γ, and TNF-α, and patients with skin diseases have been shown to be more susceptible to COVID-19 infection, but with a less severe disease course. As an anti-inflammatory agent, vitamin D could play a significant role in the future as a possible treatment for reducing the risk and severity of psoriasis and COVID-19. It has been suggested that patients treated with biologic therapy should continue treatment, as it has not been shown to cause severe complications of the COVID-19 disease. Preventive measures, including vaccination, should be taken to minimize the risk of infection and severity of the clinical outcome.


Subject(s)
COVID-19 , Psoriasis , Cytokines , Humans , Interleukin-17 , Interleukin-23/therapeutic use , Pandemics , Psoriasis/drug therapy , Psoriasis/therapy , Tumor Necrosis Factor-alpha/therapeutic use , Vitamin D
6.
Viruses ; 14(10)2022 09 29.
Article in English | MEDLINE | ID: covidwho-2066547

ABSTRACT

Coronavirus disease 19 (COVID-19) is caused by viral infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Where upregulation of several important biomarkers and multiple organ dysfunction occurs, this study aimed to evaluate the association of cardiac biomarkers and CS induced acute lung damage with disease severity and mortality in survival of COVID-19 patients. A total of 500 COVID-19 patients with elevated cardiac biomarkers were studied for the analysis of myocardial abnormality through cardiac enzymes, inflammatory biomarkers, and the expression analysis of various cytokines, including IL-1, IL-6, IL-10, IL-17, and IL-25 genes. The elevation of various cardiac enzymes including LDH (87%), CK (78.4%), TNI (80.4%), CK-MB (83%), and D-dimer (80.8%) were found correlated (p < 0.001) with COVID-19 infection. Cardiac enzyme elevation was highly associated with an increased level of inflammatory biomarkers such as CRP (14.2%), SAA (11.4%) and erythrocyte sedimentation rate (ESR) (7.8%) (p = 0.001 for all). The quantitative expression analysis of IL-10, 1L-17, and 1L-25 were found to be high, while those of IL-1 and IL-6 were moderately elevated. The death-to-live ratio of COVID-19 patients was 457:43 indicating that the patients having elevated levels of both CKMB, D-dimer, CK and IL-1, IL-6, IL-10 and D-dimer, Troponin, CK and IL-1, IL-10 had high fatality rate (73% and 12% respectively). The current finding concludes that the evaluation of cardiac biomarkers with cytokine storm plays a significant role in COVID-19-associated anatomical organ damage, myocardial injury, and mortality. Physicians should pay special attention to cardiac biomarkers in patients with old age, inflammation, and comorbidities among COVID-19 infections.


Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Interleukin-6 , Interleukin-10 , Interleukin-17/genetics , Pakistan , Biomarkers , Cytokines , Troponin , Interleukin-1
7.
Front Immunol ; 13: 1010808, 2022.
Article in English | MEDLINE | ID: covidwho-2065525

ABSTRACT

Background: Vaccination confers relatively short-term protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), indicating the need for booster doses. Immunocompromised individuals, including those with immune-mediated inflammatory diseases (IMIDs), may have pronounced immune response waning. Vaccine-boosted humoral and T-cell responses minimize poor coronavirus disease 19 (COVID-19) outcome without increasing adverse events (AE). There is limited evidence of third-dose vaccination in axial spondyloarthritis (AxSpA) patients. We investigated immune-response persistence after primary vaccination and immunogenicity and safety after the BNT162b2 booster vaccination. Methods: This prospective observational study enrolled an AxSpA cohort treated with interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNFα) inhibitors. Serum SARS-CoV-2-specific and virus-neutralizing antibodies for humoral response and flow cytometric detection of intracellular cytokines following SARS-CoV-2-specific peptide-based stimulation for T-cell immune responses were assessed, and safety was evaluated via a clinical questionnaire. Results: Fifteen male AxSpA patients treated with TNFα (73·3%) or IL-17 (26·7%) inhibitors were enrolled and had humoral response persistence at 6 months: 905·6 ( ± 186·1 SD) and 409·1 ( ± 335·7) U/mL. Specific antibody concentrations further increased after booster vaccination to 989·7 ( ± 12·62) and 1000 U/mL and T-cell responders from 53·3% to 80%, with no differences between AxSpA (including "vaccination only" and "hybrid immunity" subgroups) and healthy control (HC) cohorts. No severe AE occurred; the AE spectrum was comparable to that of the general population. Conclusion: Immune-response persistence after primary vaccination and immunogenicity after booster vaccination were unaffected by anti-IL17 or anti-TNFα therapy with similar AE as in the general population.


Subject(s)
Axial Spondyloarthritis , Biological Products , COVID-19 , Antibodies, Neutralizing , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , Humans , Interleukin-17 , Male , SARS-CoV-2 , Tumor Necrosis Factor-alpha
8.
Microbiol Spectr ; 10(5): e0307522, 2022 Oct 26.
Article in English | MEDLINE | ID: covidwho-2053143

ABSTRACT

An estimated one-third of the world's population is infected with Mycobacterium tuberculosis, with the majority being vaccinated with Mycobacterium bovis BCG. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a threat, and we must understand how SARS-CoV-2 can modulate both BCG immunity and tuberculosis pathogenesis. Interestingly, neither BCG vaccination nor tuberculosis infection resulted in differences in clinical outcomes associated with SARS-CoV-2 in transgenic mice. Surprisingly, earlier M. tuberculosis infection resulted in lower SARS-CoV-2 viral loads, mediated by the heightened immune microenvironment of the murine lungs, unlike vaccination with BCG, which had no impact. In contrast, M. tuberculosis-infected tissues had increased bacterial loads and decreased histiocytic inflammation in the lungs following SARS-CoV-2 superinfection. SARS-CoV-2 modulated BCG-induced type 17 responses while decreasing type 1 and increasing type 2 cytokines in M. tuberculosis-infected mice. These findings challenge initial findings of BCG's positive impact on SARS-CoV-2 infection and suggest potential ramifications for M. tuberculosis reactivation upon SARS-CoV-2 superinfection. IMPORTANCE Prior to SARS-CoV-2, M. tuberculosis was the leading infectious disease killer, with an estimated one-third of the world's population infected and 1.7 million deaths a year. Here, we show that SARS-CoV-2 superinfection caused increased bacterial dissemination in M. tuberculosis-infected mice along with immune and pathological changes. SARS-CoV-2 also impacted the immunity of BCG-vaccinated mice, resulting in decreased interleukin-17 (IL-17) levels, while offering no protective effect against SARS-CoV-2. These results demonstrate that SARS-CoV-2 may have a deleterious effect on the ongoing M. tuberculosis pandemic and potentially limit BCG's efficacy.


Subject(s)
COVID-19 , Mycobacterium bovis , Mycobacterium tuberculosis , Superinfection , Tuberculosis, Lymph Node , Mice , Animals , Interleukin-17 , SARS-CoV-2 , BCG Vaccine , Cytokines
9.
PLoS Pathog ; 18(9): e1010819, 2022 09.
Article in English | MEDLINE | ID: covidwho-2039445

ABSTRACT

BACKGROUND: Acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions. METHODS AND FINDINGS: In this study, we compared COVID-19 ARDS (n = 43) and bacterial sepsis-induced (non-COVID-19) ARDS (n = 24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within- ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation. CONCLUSION: We present a first comprehensive molecular characterization of differences between two ARDS etiologies-COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions.


Subject(s)
Acute Kidney Injury , COVID-19 , Janus Kinase Inhibitors , Respiratory Distress Syndrome , Sepsis , Thrombocytosis , Arginine , COVID-19/complications , Humans , Interleukin-17 , Lipids , Respiratory Distress Syndrome/etiology , Sepsis/complications , Sphingosine
10.
PLoS One ; 17(9): e0274841, 2022.
Article in English | MEDLINE | ID: covidwho-2039431

ABSTRACT

OBJECTIVES: T-helper 17 cell-mediated response and their effector IL-17 cytokine induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a major cause of COVID-19 disease severity and death. Therefore, the study aimed to determine if IL-17 level in saliva mirrors its circulatory level and hence can be used as a non-invasive biomarker for disease severity. METHODS: Interleukin-17 (IL-17) level was evaluated by ELISA in saliva and blood of 201 adult COVID-19 patients with different levels of severity. The IL-17 saliva level was also associated with COVID-19 disease severity, and need for mechanical ventilation and/or death within 29 days after admission of severe COVID-19 patients. RESULTS: We found that IL-17 level in saliva of COVID-19 patients reflected its circulatory level. High IL-17 level in saliva was associated with COVID-19 severity (P<0.001), need for mechanical ventilation (P = 0.002), and/or death by 29 days (P = 0.002), after adjusting for patients' demographics, comorbidity, and COVID-19 serum severity markers such as D-Dimer, C-reactive protein, and ferritin. CONCLUSION: We propose that saliva IL-17 level could be used as a biomarker to identify patients at risk of developing severe COVID-19.


Subject(s)
COVID-19 , Adult , Biomarkers , C-Reactive Protein , COVID-19/diagnosis , Cytokines , Ferritins , Humans , Interleukin-17 , SARS-CoV-2
11.
ACS Infect Dis ; 8(10): 2119-2132, 2022 Oct 14.
Article in English | MEDLINE | ID: covidwho-2036751

ABSTRACT

The engineering of virus-like particles (VLPs) is a viable strategy for the development of vaccines and for the identification of therapeutic targets without using live viruses. Here, we report the generation and characterization of quadruple-antigen SARS-CoV-2 VLPs. VLPs were generated by transient transfection of two expression cassettes in adherent HEK293T cells─one cassette containing Mpro for processing of three structural proteins (M, E, and N), and the second cassette expressing the Spike protein. Further characterization revealed that the VLPs retain close morphological and antigenic similarity with the native virus and also bind strongly to the SARS-CoV-2 receptor hACE-2 in an in vitro binding assay. Interestingly, the VLPs were found to internalize into U87-MG cells through cholesterol-rich domains in a dynamin-dependent process. Finally, our results showed that mice immunized with VLPs induce robust humoral and cellular immune responses mediated by enhanced levels of IL-4, IL-17, and IFNγ. Taken together, our results demonstrate that VLPs mimic the native virus and induce a strong immune response, indicating the possible use of these particles as an alternative vaccine candidate against SARS-CoV-2. VLPs can also be effective in mapping the initial stages of virus entry and screening inhibitors.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , COVID-19/prevention & control , HEK293 Cells , Humans , Interleukin-17 , Interleukin-4 , Mice , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization
12.
Front Immunol ; 13: 919402, 2022.
Article in English | MEDLINE | ID: covidwho-2022710

ABSTRACT

The present study aimed to evaluate the effects of Nutrition Bio-shield Superfood (NBS) powder on the immune system function and clinical manifestations in patients with COVID-19. We compare the effects of NBS powder on the immune system function and clinical manifestations among two different groups: 1) intervention group receiving standard treatment scheduled according to treatment guidelines plus NBS powder, and 2) control group receiving only the same standard treatment. The serum levels of IL-2, IL-6, IL-17, IFNγ, and TNFα were determined after four weeks of treatment by specific ELISA kits according to the manufacturer's instructions. Finally, the level of immune system stimulation and inflammatory markers were compared at baseline and after intervention in both groups. Data were analyzed using SPSS (version 22). A p-value of ≤ 0.05 was set as significant. A total of 47 patients with COVID-19 (24 patients in the intervention group and 23 patients in the control group) were included in this study. Results showed that the differences in the mean decrease of IL-2, IL-6, and TNF-α in the intervention group in comparison to the control group were 0.93, 10.28, and 8.11 pg/ml, respectively (P<0.001). On the other hand, there was no difference in IL-17, IFNγ, monocytes, eosinophil, and other inflammatory indices between the intervention and control groups. Although NBS powder was able to significantly decrease the levels of some proinflammatory cytokines in patients with COVID-19, however, it is noteworthy that the course of the disease was to large part unaffected by NBS power and there was a reduction independent of treatment. The present study indicates that NBS powder could provide a beneficial anti-inflammatory effect in patients with COVID-19. Hence, NBS in treating patients with COVID-19 shows promise as an adjuvant to the current standard antiviral treatment of such patients. Clinical Trial Registration: https://www.irct.ir, identifier IRCT20200426047206N1.


Subject(s)
COVID-19 , Interleukin-17 , COVID-19/drug therapy , Humans , Interleukin-2 , Interleukin-6 , Monocytes , Powders , Tumor Necrosis Factor-alpha
13.
PLoS One ; 17(9): e0273969, 2022.
Article in English | MEDLINE | ID: covidwho-2021953

ABSTRACT

INTRODUCTION: The rapid spread of COVID-19 has been a global public health problem and it is yet to be put under control. Active COVID-19 is associated with unrestrained secretion of pro-inflammatory cytokines and imbalances in haematological profile including anaemia, leukocytosis and thrombocytopaenia. However, the haematological profile and immune status following recovery from COVID-19 has not been recognized. We evaluated the immunohaematological profile among COVID-19 patients with active infection, recovered cases and unexposed healthy individuals in the Ashanti region of Ghana. METHODOLOGY: A total of 95 adult participants, consisting of 35 positive, 30 recovered and 30 unexposed COVID-19 negative individuals confirmed by RT-PCR were recruited for the study. All the patients had the complete blood count performed using the haematological analyzer Sysmex XN-1500. Their plasma cytokine levels of interleukin (IL)-1ß, IL-6, IL-10, IL-17, tumour necrosis factor-alpha (TNF-α) and interferon gamma (IFN-γ) were analysed using ELISA. Statistical analyses were performed on R statistical software. RESULT: The Patients with COVID-19 active infection had significantly higher levels of IL10 (181±6.14 pg/mL vs 155.00±14.32 pg/mL vs 158.80±11.70 pg/mL, p = 0.038), WBC count (5.5±0.4 x109 /L vs 4.5±0.6 x109 /L vs 3.8±0.5, p < 0.0001) and percentage basophil (1.8±0.1% vs 0.8±0.3% vs 0.7±0.2%, p = 0.0040) but significantly lower levels of IFN-γ (110.10±9.52 pg/mL vs 142.80±5.46 pg/mL vs 140.80±6.39 pg/mL, p = 0.021), haematocrit (24.1±3.7% vs 38.3± 3.0% vs 38.5±2.2%, p < 0.0001), haemoglobin concentration (9.4±0.1g/dl vs 12.5± 5.0g/dl vs 12.7±0.8, p < 0.0001) and MPV (9.8±0.2fL vs 11.1±0.5fL vs 11.6±0.3fL, p < 0.0001) compared to recovered and unexposed controls respectively. There were significant association between IL-1ß & neutrophils (r = 0.42, p<0.05), IL-10 & WBC (r = 0.39, p<0.05), IL-10 & Basophils (r = -0.51, p<0.01), IL-17 & Neutrophil (r = 0.39, p<0.05) in the active COVID-19 cases. CONCLUSION: COVID-19 active infection is associated with increased IL-10 and WBC with a concomitant decrease in IFN-γ and haemoglobin concentration. However, recovery from the disease is associated with immune recovery with appareantly normal haematological profile.


Subject(s)
COVID-19 , Interleukin-10 , Adult , Cytokines , Ghana/epidemiology , Hemoglobins , Humans , Interferon-gamma , Interleukin-17
14.
Microbiol Spectr ; 10(5): e0226322, 2022 Oct 26.
Article in English | MEDLINE | ID: covidwho-2019798

ABSTRACT

We investigated the distribution, virulence, and pathogenic characteristics of mutated SARS-CoV-2 to clarify the association between virulence and the viral spreading ability of current and future circulating strains. Chinese rhesus macaques were infected with ancestral SARS-CoV-2 strain GD108 and Beta variant B.1.351 (B.1.351) and assessed for clinical signs, viral distribution, pathological changes, and pulmonary inflammation. We found that GD108 replicated more efficiently in the upper respiratory tract, whereas B.1.351 replicated more efficiently in the lower respiratory tract and lung tissue, implying a reduced viral shedding and spreading ability of B.1.351 compared with that of GD108. Importantly, B.1.351 caused more severe lung injury and dramatically elevated the level of inflammatory cytokines compared with those observed after infection with GD108. Moreover, both B.1.351 and GD108 induced spike-specific T-cell responses at an early stage of infection, with higher levels of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) in the B.1.351 group and higher levels of interleukin 17 (IL-17) in the GD108 group, indicating a divergent pattern in the T-cell-mediated inflammatory "cytokine storm." This study provides a basis for exploring the pathogenesis of SARS-CoV-2 variants of concern (VOCs) and establishes an applicable animal model for evaluating the efficacy and safety of vaccines and drugs. IMPORTANCE One of the priorities of the current SARS-CoV-2 vaccine and drug research strategy is to determine the changes in transmission ability, virulence, and pathogenic characteristics of SARS-CoV-2 variants. In addition, nonhuman primates (NHPs) are suitable animal models for the study of the pathogenic characteristics of SARS-CoV-2 and could contribute to the understanding of pathogenicity and transmission mechanisms. As SARS-CoV-2 variants continually emerge and the viral biological characteristics change frequently, the establishment of NHP infection models for different VOCs is urgently needed. In the study, the virulence and tissue distribution of B.1.351 and GD108 were comprehensively studied in NHPs. We concluded that the B.1.351 strain was more virulent but exhibited less viral shedding than the latter. This study provides a basis for determining the pathogenic characteristics of SARS-CoV-2 and establishes an applicable animal model for evaluating the efficacy and safety of vaccines and drugs.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Humans , SARS-CoV-2/genetics , Interleukin-17 , Virus Shedding , Virulence , COVID-19 Vaccines , Tumor Necrosis Factor-alpha , Macaca mulatta , Interferon-gamma , Disease Models, Animal
15.
Int J Mol Sci ; 23(18)2022 Sep 07.
Article in English | MEDLINE | ID: covidwho-2010121

ABSTRACT

SARS-CoV-2 is a new coronavirus characterized by a high infection and transmission capacity. A significant number of patients develop inadequate immune responses that produce massive releases of cytokines that compromise their survival. Soluble factors are clinically and pathologically relevant in COVID-19 survival but remain only partially characterized. The objective of this work was to simultaneously study 62 circulating soluble factors, including innate and adaptive cytokines and their soluble receptors, chemokines and growth and wound-healing/repair factors, in severe COVID-19 patients who survived compared to those with fatal outcomes. Serum samples were obtained from 286 COVID-19 patients and 40 healthy controls. The 62 circulating soluble factors were quantified using a Luminex Milliplex assay. Results. The patients who survived had decreased levels of the following 30 soluble factors of the 62 studied compared to those with fatal outcomes, therefore, these decreases were observed for cytokines and receptors predominantly produced by the innate immune system-IL-1α, IL-1α, IL-18, IL-15, IL-12p40, IL-6, IL-27, IL-1Ra, IL-1RI, IL-1RII, TNFα, TGFα, IL-10, sRAGE, sTNF-RI and sTNF-RII-for the chemokines IL-8, IP-10, MCP-1, MCP-3, MIG and fractalkine; for the growth factors M-CSF and the soluble receptor sIL2Ra; for the cytokines involved in the adaptive immune system IFNγ, IL-17 and sIL-4R; and for the wound-repair factor FGF2. On the other hand, the patients who survived had elevated levels of the soluble factors TNFß, sCD40L, MDC, RANTES, G-CSF, GM-CSF, EGF, PDGFAA and PDGFABBB compared to those who died. Conclusions. Increases in the circulating levels of the sCD40L cytokine; MDC and RANTES chemokines; the G-CSF and GM-CSF growth factors, EGF, PDGFAA and PDGFABBB; and tissue-repair factors are strongly associated with survival. By contrast, large increases in IL-15, IL-6, IL-18, IL-27 and IL-10; the sIL-1RI, sIL1RII and sTNF-RII receptors; the MCP3, IL-8, MIG and IP-10 chemokines; the M-CSF and sIL-2Ra growth factors; and the wound-healing factor FGF2 favor fatal outcomes of the disease.


Subject(s)
COVID-19 , Interleukin-27 , Chemokine CCL5 , Chemokine CX3CL1 , Chemokine CXCL10 , Cytokines , Epidermal Growth Factor , Fibroblast Growth Factor 2 , Granulocyte Colony-Stimulating Factor , Granulocyte-Macrophage Colony-Stimulating Factor , Humans , Interleukin 1 Receptor Antagonist Protein , Interleukin-10 , Interleukin-12 Subunit p40 , Interleukin-15 , Interleukin-17 , Interleukin-18 , Interleukin-6 , Interleukin-8 , Macrophage Colony-Stimulating Factor , SARS-CoV-2 , Transforming Growth Factor alpha , Tumor Necrosis Factor-alpha
16.
Medicine (Baltimore) ; 101(35): e29554, 2022 Sep 02.
Article in English | MEDLINE | ID: covidwho-2008659

ABSTRACT

BACKGROUND: Coronavirus (CoV) disease (COVID-19) identified in Wuhan, China, in 2019, is mainly characterized by atypical pneumonia and severe acute respiratory syndrome (SARS) and is caused by SARS CoV-2, which belongs to the Coronaviridae family. Determining the underlying disease mechanisms is central to the identification and development of COVID-19-specific drugs for effective treatment and prevention of human-to-human transmission, disease complications, and deaths. METHODS: Here, next-generation RNA sequencing (RNA Seq) data were obtained using Illumina Next Seq 500 from SARS CoV-infected A549 cells and mock-treated A549 cells from the Gene Expression Omnibus (GEO) (GSE147507), and quality control (QC) was assessed before RNA Seq analysis using CLC Genomics Workbench 20.0. Differentially expressed genes (DEGs) were imported into BioJupies to decipher COVID-19 induced signaling pathways and small molecules derived from chemical synthesis or natural sources to mimic or reverse COVID -19 specific gene signatures. In addition, iPathwayGuide was used to identify COVID-19-specific signaling pathways, as well as drugs and natural products with anti-COVID-19 potential. RESULTS: Here, we identified the potential activation of upstream regulators such as signal transducer and activator of transcription 2 (STAT2), interferon regulatory factor 9 (IRF9), and interferon beta (IFNß), interleukin-1 beta (IL-1ß), and interferon regulatory factor 3 (IRF3). COVID-19 infection activated key infectious disease-specific immune-related signaling pathways such as influenza A, viral protein interaction with cytokine and cytokine receptors, measles, Epstein-Barr virus infection, and IL-17 signaling pathway. Besides, we identified drugs such as prednisolone, methylprednisolone, diclofenac, compound JQ1, and natural products such as Withaferin-A and JinFuKang as candidates for further experimental validation of COVID-19 therapy. CONCLUSIONS: In conclusion, we have used the in silico next-generation knowledge discovery (NGKD) methods to discover COVID-19-associated pathways and specific therapeutics that have the potential to ameliorate the disease pathologies associated with COVID-19.


Subject(s)
Biological Products , COVID-19 , Epstein-Barr Virus Infections , A549 Cells , COVID-19/drug therapy , Cytokines/metabolism , Diclofenac , Herpesvirus 4, Human/genetics , Humans , Interferon Regulatory Factor-3/genetics , Interferon Regulatory Factor-3/metabolism , Interferon-Stimulated Gene Factor 3, gamma Subunit/genetics , Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism , Interferon-beta , Interleukin-17/metabolism , Interleukin-1beta/metabolism , Methylprednisolone , RNA , Receptors, Cytokine/genetics , SARS-CoV-2/genetics , STAT2 Transcription Factor , Sequence Analysis, RNA , Viral Proteins/genetics
17.
Microb Pathog ; 171: 105736, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-1996428

ABSTRACT

From December 2019, the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was started as a cluster of pneumonia cases in Wuhan, Hubei Province, China. The disturbing statistics of SARS-CoV-2 promoted scientists to develop an effective vaccine against this infection. NOM protein is a multi-epitope protein that designed based on Nucleocapsid, ORF3a, and Membrane proteins of SARS-CoV-2. Flagellin is a structural protein that binds to the Toll-like receptor 5 and can enhance the immune response to a particular antigen. In this study, NOM protein as vaccine candidate was linked to the carboxyl and amino terminals of flagellin adjuvant derived from Salmonella enterica subsp. enterica serovar Dublin. Then, informatics evaluations were performed for both NOM protein and NOM protein linked to flagellin (FNOM). The interaction between the NOM and FNOM proteins with the TLR5 were assessed using docking analysis. The FNOM protein, which compared to the NOM protein, had a more suitable 3D structure and a stronger interaction with TLR5, was selected for experimental study. The FNOM and Spike (S) proteins expressed and then purified by Ni-NTA column as vaccine candidates. For analysis of immune response, anti-FNOM and anti-S proteins total IgG and IFN-γ, TNF-α, IL-6, IL-10, IL-22 and IL-17 cytokines were evaluated after vaccination of mice with vaccine candidates. The results indicated that the specific antisera (Total IgG) raised in mice that received FNOM protein formulated with S protein were higher than mice that received FNOM and S proteins alone. Also, IFN-γ and TNF-α levels after the spleen cells stimulation were significantly increased in mice that received the FNOM protein formulated with S protein compared to other groups. Immunogenic evaluations showed that, the FNOM chimeric protein could simultaneously elicit humoral and cell-mediated immune responses. Finally, it could be concluded that the FNOM protein formulated with S protein could be considered as potential vaccine candidate for protection against SARS-CoV-2 in the near future.


Subject(s)
COVID-19 , Viral Vaccines , Adjuvants, Immunologic , Animals , Antibodies, Viral , COVID-19/prevention & control , Epitopes , Flagellin/genetics , Immune Sera , Immunoglobulin G , Interleukin-10 , Interleukin-17 , Interleukin-6 , Mice , Recombinant Fusion Proteins , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Toll-Like Receptor 5 , Tumor Necrosis Factor-alpha
18.
Life Sci ; 307: 120909, 2022 Oct 15.
Article in English | MEDLINE | ID: covidwho-1996410

ABSTRACT

AIMS: The ability of vitamin D (VitD) to modulate immune responses in the clinical setting of COVID-19 infection is not well investigated. This study aimed to evaluate the ability of VitD to attenuate inflammatory responses in patients with severe COVID-19. MATERIALS AND METHODS: Blood samples and nasopharyngeal swabs were obtained from patients with severe COVID-19 who had been treated (20 patients), or not (25 patients), with VitD, during their stay in the intensive care unit. Western blotting was used to evaluate the expressions of STAT3, JNK and AKT signaling pathways and ELISA was used to measure levels of IL-6, IL-17, and IL-1ß in blood of these patients. KEY FINDINGS: Reduced levels of STAT3, JNK and AKT pathways and lower levels of proinflammatory cytokines such as IL-6, IL-17, and IL-1ß were observed in VitD treated patients (50,000 IU of cholecalciferol weekly for 3 weeks), and in vitro following treatment of poly I:C stimulated PBMCs with VitD (50 nM of calcitriol). Moreover, lower circulatory levels of these proinflammatory cytokines following treatment with VitD were associated with lower serum levels of COVID-19-related severity markers such as D-dimer and C-reactive proteins (P < 0.001) which in overall resulted in shorter length of ICU stay for VitD treated compared to untreated patients (18 days for VitD treated vs. 28 days for VitD untreated; P = 0.01). SIGNIFICANCE: This study reveals that VitD plays immunomodulatory role during COVID-19 infection, which further emphasizes the importance of maintaining a normal level of this vitamin for the prevention of hyperinflammatory conditions associated with COVID-19.


Subject(s)
COVID-19 , Vitamin D Deficiency , Calcitriol , Cytokines , Humans , Inflammation , Interleukin-17 , Interleukin-6 , Poly I , Proto-Oncogene Proteins c-akt , Vitamin D/therapeutic use , Vitamin D Deficiency/complications , Vitamin D Deficiency/drug therapy , Vitamins/pharmacology , Vitamins/therapeutic use
19.
PLoS One ; 17(8): e0273186, 2022.
Article in English | MEDLINE | ID: covidwho-1993517

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by a recently identified virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease is a pandemic. Although the hallmarks of severe COVID-19 have been established, the underlying mechanisms that promote severe pathology have not been thoroughly studied. A better understanding of the immune response in severe COVID-19 patients may help guide the development of therapeutic strategies and predict immuno-pathogenicity. This study was set to determine the lymphocyte and cytokine profiles associated with COVID-19 severity. A total of 43 hospitalised COVID-19 patients were recruited for the study and whole blood samples were drawn from each patient. Complete blood counts, lymphocyte subset profiles and C-reactive protein statuses of patients were determined. Cytometric bead array was performed to analyse the cytokine profiles of each patient. The demographic characteristics showed that the median age of the patients was 48.72 years, with an interquartile range from 40 to 60 years, and 69.77% of the patients were male. COVID-19 patients exhibited significantly low CD4+ lymphocyte expansion and leucocytosis augmented by elevated neutrophil and immature granulocytes. Stratification analysis revealed that reduced monocytes and elevated basophils and immature granulocytes are implicated in severe pathology. Additionally, cytokine results were noted to have significant incidences of interleukin 17A (IL-17A) expression associated with severe disease. Results from this study suggest that a systemic neutrophilic environment may preferentially skew CD4+ lymphocytes towards T-helper 17 and IL-17A promotion, thus, aggravating inflammation. Consequently, results from this study suggest broad activity immunomodulation and targeting neutrophils and blocking IL-17 production as therapeutic strategies against severe COVID-19.


Subject(s)
COVID-19 , Adult , CD4-Positive T-Lymphocytes , Cytokines , Female , Humans , Interleukin-17 , Male , Middle Aged , Neutrophil Infiltration , SARS-CoV-2 , Th17 Cells
20.
J Infect Dis ; 226(7): 1215-1223, 2022 09 28.
Article in English | MEDLINE | ID: covidwho-1985078

ABSTRACT

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) presents with inflammation and pathology of multiple organs in the pediatric population in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We characterized the SARS-CoV-2 antigen-specific cytokine and chemokine responses in children with MIS-C, coronavirus disease 2019 (COVID-19), and other infectious diseases. RESULTS: MIS-C is characterized by elevated levels of type 1 (interferon-γ, interleukin [IL] 2), type 2 (IL-4, IL-13), type 17 (IL-17), and other proinflammatory cytokines (IL-1α, IL-6, IL-12p70, IL-18, and granulocyte-macrophage colony-stimulating factor) in comparison to COVID-19 and other infectious diseases following stimulation with SARS-CoV-2-specific antigens. Similarly, upon SARS-CoV-2 antigen stimulation, CCL2, CCL3, and CXCL10 chemokines were significantly elevated in children with MIS-C in comparison to the other 2 groups. Principal component analysis based on these cytokines and chemokines could clearly distinguish MIS-C from both COVID-19 and other infections. In addition, these responses were significantly diminished and normalized 6-9 months after recovery. CONCLUSIONS: Our data suggest that MIS-C is characterized by an enhanced production of cytokines and chemokines that may be associated with disease pathogenesis.


Subject(s)
COVID-19 , Communicable Diseases , Antigens, Viral , COVID-19/complications , Chemokines , Child , Cytokines , Granulocyte-Macrophage Colony-Stimulating Factor , Humans , Immunity , Interferon-gamma , Interleukin-13 , Interleukin-17 , Interleukin-18 , Interleukin-4 , Interleukin-6 , SARS-CoV-2 , Systemic Inflammatory Response Syndrome
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