Immune Response In COVID-19 Patients Research Articles

Cell-free DNA methylation reveals cell-specific tissue injury and correlates with disease severity and patient outcomes in COVID-19

BackgroundThe recently identified methylation patterns specific to cell type allows the tracing of cell death dynamics at the cellular level in health and diseases. This study used COVID-19 as a disease model to investigate the efficacy of cell-specific cell-free DNA (cfDNA) methylation markers in reflecting or predicting disease severity or outcome.MethodsWhole genome methylation sequencing of cfDNA was performed for 20 healthy individuals, 20 cases with non-hospitalized COVID-19 and 12 cases with severe COVID-19 admitted to intensive care unit (ICU). Differentially methylated regions (DMRs) and gene ontology pathway enrichment analyses were performed to explore the locus-specific methylation difference between cohorts. The proportion of cfDNA derived from lung and immune cells to a given sample (i.e. tissue fraction) at cell-type resolution was estimated using a novel algorithm, which reflects lung injuries and immune response in COVID-19 patients and was further used to evaluate clinical severity and patient outcome.ResultsCOVID‑19 patients had globally reduced cfDNA methylation level compared with healthy controls. Compared with non-hospitalized COVID-19 patients, the cfDNA methylation pattern was significantly altered in severe patients with the identification of 11,156 DMRs, which were mainly enriched in pathways related to immune response. Markedly elevated levels of cfDNA derived from lung and more specifically alveolar epithelial cells, bronchial epithelial cells, and lung endothelial cells were observed in COVID-19 patients compared with healthy controls. Compared with non-hospitalized patients or healthy controls, severe COVID-19 had significantly higher cfDNA derived from B cells, T cells and granulocytes and lower cfDNA from natural killer cells. Moreover, cfDNA derived from alveolar epithelial cells had the optimal performance to differentiate COVID-19 with different severities, lung injury levels, SOFA scores and in-hospital deaths, with the area under the receiver operating characteristic curve of 0.958, 0.941, 0.919 and 0.955, respectively.ConclusionSevere COVID-19 has a distinct cfDNA methylation signature compared with non-hospitalized COVID-19 and healthy controls. Cell type-specific cfDNA methylation signature enables the tracing of COVID-19 related cell deaths in lung and immune cells at cell-type resolution, which is correlated with clinical severities and outcomes, and has extensive application prospects to evaluate tissue injuries in diseases with multi-organ dysfunction.

Integrative Molecular Structure Elucidation and Construction of an Extended Metabolic Pathway Associated with an Ancient Innate Immune Response in COVID-19 Patients.

We present compelling evidence for the existence of an extended innate viperin-dependent pathway, which provides crucial evidence for an adaptive response to viral agents, such as SARS-CoV-2. We show the in vivo biosynthesis of a family of novel endogenous cytosine metabolites with potential antiviral activities. Two-dimensional nuclear magnetic resonance (NMR) spectroscopy revealed a characteristic spin-system motif, indicating the presence of an extended panel of urinary metabolites during the acute viral replication phase. Mass spectrometry additionally enabled the characterization and quantification of the most abundant serum metabolites, showing the potential diagnostic value of the compounds for viral infections. In total, we unveiled ten nucleoside (cytosine- and uracil-based) analogue structures, eight of which were previously unknown in humans allowing us to propose a new extended viperin pathway for the innate production of antiviral compounds. The molecular structures of the nucleoside analogues and their correlation with an array of serum cytokines, including IFN-α2, IFN-γ, and IL-10, suggest an association with the viperin enzyme contributing to an ancient endogenous innate immune defense mechanism against viral infection.

Performance Analysis of Serodiagnostic Tests to Characterize the Incline and Decline of the Individual Humoral Immune Response in COVID-19 Patients: Impact on Diagnostic Management.

Serodiagnostic tests for antibody detection to estimate the immunoprotective status regarding SARS-CoV-2 support diagnostic management. This study aimed to investigate the performance of serological assays for COVID-19 and elaborate on test-specific characteristics. Sequential samples (n = 636) of four panels (acute COVID-19, convalescent COVID-19 (partly vaccinated post-infection), pre-pandemic, and cross-reactive) were tested for IgG by indirect immunofluorescence test (IIFT) and EUROIMMUN EUROLINE Anti-SARS-CoV-2 Profile (IgG). Neutralizing antibodies were determined by a virus neutralization test (VNT) and two surrogate neutralization tests (sVNT, GenScript cPass, and EUROIMMUN SARS-CoV-2 NeutraLISA). Analysis of the acute and convalescent panels revealed high positive (78.3% and 91.6%) and negative (91.6%) agreement between IIFT and Profile IgG. The sVNTs revealed differences in their positive (cPass: 89.4% and 97.0%, NeutraLISA: 71.5% and 72.1%) and negative agreement with VNT (cPass: 92.3% and 50.0%, NeutraLISA: 95.1% and 92.5%) at a diagnostic specificity of 100% for all tests. The cPass showed higher inhibition rates than NeutraLISA at VNT titers below 1:640. Cross-reactivities were only found by cPass (57.1%). Serodiagnostic tests, which showed substantial agreement and fast runtime, could provide alternatives for cell-based assays. The findings of this study suggest that careful interpretation of serodiagnostic results obtained at different times after SARS-CoV-2 antigen exposure is crucial to support decision-making in diagnostic management.

Virus-specific humoral immune response in Bulgarian COVID-19 patients with varying disease severity.

Our study aimed to analyze virus-specific humoral immune responses in COVID-19 patients with varying disease severity. A total of 109 serum samples from 87 patients, symptomatic for COVID-19 were studied using anti-SARS-CoV-2 immunoassays detecting different classes of immunoglobulins. Clinical samples were divided into 2 groups - collected up to and more than 2 weeks post-onset of symptoms (PoS). In the first group, the highest percentage of positive samples was found for IgA class virus-specific antibodies (78.1%), followed by IgM (71.9%/59.4%) and IgG (56.3%/53.1%). In the second group, samples positive for virus-specific IgA class antibodies were also the most (97.7%) along with those positive for IgG. A total of 72 IgA and/or IgM and/or IgG positive samples were further tested for SARS-CoV-2 neutralizing antibodies (NAbs) - 89.1% and 100% of samples obtained up to and after 2 weeks PoS, respectively were positive. Serological test results were also analyzed depending on the severity of the disease - SARS-CoV-2 positive samples in mild forms of COVID-19 were fewer than in moderate and severe forms but this difference was not statistically significant. SARS-CoV-2 specific antibodies and a high virus neutralization capacity of these antibodies appear early PoS; Immunoglobulins of IgA class are of most significant diagnostic value for detection of SARS-CoV-2 infection; Timing of testing is the most important factor for positivity rate.

In Vitro and In Vivo Crosstalk between Type I IFN and IL-8 Responses in SARS-CoV-2 Infection.

COVID-19 patients show characteristic over-expression of different cytokines that may interfere with the interferon (IFN) response, delaying its production. Within the overexpressed cytokines, IL-8 plays a key role, and it may impede IFN-I activation. PBMC from eight healthy donors were exposed to 2019-nCoV/Italy-INMI1 isolate and supernatants/cells were collected at different time points; the production of either IFN-alpha or IL-8 was assessed. The same analysis was performed on plasma samples obtained from 87 COVID-19 patients. Antagonism between IFN-alpha and IL-8 was observed, since in those PBMC with medium or high IL-8 levels, IFN-α levels were low. The same scenario was observed in SARS-CoV-2-infected patients that were divided into three groups based on IL-8 low, medium and high levels; the correlation between low levels of IFN-α and high levels of IL-8 was statistically significant in both the IL-8 medium and IL-8 high group. Overall, our results showed a crosstalk/antagonism between IL-8 and IFN-alpha in PBMC from healthy donors challenged with SARS-CoV-2 and inversely proportional IFN-alpha levels to IL-8 concentrations detected in plasma samples from COVID-19 patients, suggesting that the impairment of the innate immune response in COVID-19 patients may be linked to a dysregulated cytokine response, namely through IL-8 production.

Administration of N-Acetylcysteine (NAC) as Adjunctive Therapy for COVID-19 Patients by Improving Oxidative Stress and Inflammation Through Assessment of MDA, IL-6, IL-1β, TNF-α, and TGF-β

INTRODUCTION: Oxidative stress due to COVID-19 will trigger a widespread inflammatory reaction in the lungs. Malondialdehyde (MDA), Interleukin-6 (IL-6), Interleukin-1 β (IL-1β), Tumor Necrosis Factor-α (TNF-α), and Tumor Growth Factor- β (TGF-β) are pro-inflammatory cytokines which levels may rise in the presence of an inflammatory process. N-Acetylcysteine (NAC) is an antioxidant widely considered as adjunctive therapy in COVID-19. We aim to analyze the effect of NAC administration in improving oxidative stress and inflammation in COVID-19 through assessment of MDA, IL-6, IL-1β, TNF-α, and TGF-β. METHOD: This is a quasi-experimental study with pre-post design. MDA, IL-6, IL-1β, TNF-α, and TGF-β levels were measured in admission and day 8 of administration of 5000 mg/72 hours of NAC. RESULT: From 74 samples, between admission and day 8 of NAC therapy, There is a decrease of IL-6 (185.31 ± 181.30 to 97.60 ± 161.86 (p=0.003)), TNF-α (5.83 ± 3.51 to 4.37 ± 3.33 (p=0.019)), IL-1 β (4.65 ± 4.13 to 1.87 ± 0.96 (p<0.001)), and MDA levels (3000.70 ± 2017.98 to 2116.54 ± 1109.58 (p<0.001). However, TGF-β levels were increased from 5.47 ± 2.76 to 7.97 ± 3.24 (p<0.001). DISCUSSION: From our patients we get a significant decrease of pro-inflammatory cytokines (MDA, IL-6, IL-1β, and TNF-α) after administration of NAC. However, we acquired a significant increased level of TGF-β in our patients despite NAC administration which implies the chronic immune response in COVID-19 patients. CONCLUSION: There is an improvement of oxidative stress and inflammation by administration of NAC as adjunctive therapy in COVID-19 patients assessed by decrease of MDA, IL-6, IL-1β, and TNF-α levels. There is no effect of NAC as adjunctive therapy in TGF-β levels in COVID-19 patients. Keywords: NAC, COVID-19, MDA, IL-6, IL-1β, TNF-α, TGF-β

Immune responses in COVID-19 patients during breakthrough infection with SARS-CoV-2 variants Delta, Omicron-BA.1 and Omicron-BA.5.

Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are increasingly observed in vaccinated individuals. Immune responses towards SARS-CoV-2 variants, particularly Omicron-BA.5, are poorly understood. We investigated the humoral and cellular immune responses of hospitalized COVID-19 patients during Delta and Omicron infection waves. The corresponding SARS-CoV-2 variant of the respective patients were identified by whole genome sequencing. Humoral immune responses were analyzed by ELISA and a cell culture-based neutralization assay against SARS-CoV-2 D614G isolate (wildtype), Alpha, Delta (AY.43) and Omicron (BA.1 and BA.5). Cellular immunity was evaluated with an IFN-γ ELISpot assay. On a cellular level, patients showed a minor IFN-γ response after stimulating PBMCs with mutated regions of SARS-CoV-2 variants. Neutralizing antibody titers against Omicron-BA.1 and especially BA.5 were strongly reduced. Double-vaccinated patients with Delta breakthrough infection showed a significantly increased neutralizing antibody response against Delta compared to double-vaccinated uninfected controls (median complete neutralization titer (NT100) 640 versus 80, p<0.05). Omicron-BA.1 infection increased neutralization titers against BA.1 in double-vaccinated patients (median NT100 of 160 in patients versus 20 in controls, p=0.07) and patients that received booster vaccination (median NT100 of 50 in patients versus 20 in controls, p=0.68). For boosted patients with BA.5 breakthrough infection, we found no enhancing effect on humoral immunity against SARS-CoV-2 variants. Neutralizing antibody titers against Omicron-BA.1 and especially BA.5 were strongly reduced in SARS-CoV-2 breakthrough infections. Delta and Omicron-BA.1 but not Omicron-BA.5 infections boosted the humoral immunity in double-vaccinated patients and patients with booster vaccination. Despite BA.5 breakthrough infection, those patients may still be vulnerable for reinfections with BA.5 or other newly emerging variants of concern.

Inflammasome signaling proteins as biomarkers of COVID-19.

One of the main characteristics of COVID-19 is an exacerbated inflammatory response that results in cardiometabolic complications and dysfunction in the nervous system. Moreover, these complications may extend beyond the period of active SARS-CoV2 infection and even extend over a year. Thus, it is important to better understand the contribution of the inflammatory responses in COVID-19 patients, not just in the acute phase but also after the infection has subsided. We measured the protein levels of inflammasome signaling proteins using Simple Plex microfluidics technology in patients with an active SARS-CoV2 infection and in recovered patients to determine their potential use as biomarkers of COVID-19. We carried out statistical analyses to identify which proteins were increased in COVID-19 patients with active infection and in recovered patients. The receiver operating characteristics (ROC) were calculated for each analyte to determine their potential fit as biomarkers. The inflammasome proteins caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), interleukin (IL)-1β and IL-18 were elevated in the plasma of patients with active infection and remained elevated after the infection was resolved for approximately 2 months after. Levels of caspase-1 and ASC continued to increase long after patients had recovered from the infection. Furthermore, when measuring biomarkers of inflammation during active infection, analyses with area under the curve (AUC) values above 0.75 indicated that caspase-1, ASC, IL-1β and IL-18 are reliable biomarkers of the inflammatory response during active COVID-19 infection. Moreover, when measuring biomarkers of inflammation after recovery from active infection, caspase-1 and ASC presented AUC values above 0.9. These findings indicate that inflammasome signaling proteins can be used to reliably monitor the inflammatory innate immune response in COVID-19 patients.

Association between the copper/selenium ratio and the immune response to SARS-CoV-2 infection.

Aim: To assess the association serum levels of selenium (Se) and copper (Cu) with symptoms and IgG immune response to SARS-CoV-2. Patients & methods/materials: Blood samples and nasopharyngealswabs were obtained from 126 COVID-19 patients with mild and severe symptoms. The serum levels of Cu and Se were measured by atomic-absorption spectrophotometry. Results & conclusion: Mean Se was higher in patients with mild symptoms and IgG nonresponders, whereas mean Cu was higher in patients with severe symptoms and IgG responders. The Cu/Se ratio was lower in patients with no IgG responses to infection and mild symptoms versus IgG responders with severe symptoms. These results suggest the Cu/Se ratio as a nutritional biomarker of severity and IgG immune response in COVID-19 patients.

Machine learning of flow cytometry data reveals the delayed innate immune responses correlate with the severity of COVID-19.

The COVID-19 pandemic has posed a major burden on healthcare and economic systems across the globe for over 3 years. Even though vaccines are available, the pathogenesis is still unclear. Multiple studies have indicated heterogeneity of immune responses to SARS-CoV-2, and potentially distinct patient immune types that might be related to disease features. However, those conclusions are mainly inferred by comparing the differences of pathological features between moderate and severe patients, some immunological features may be subjectively overlooked. In this study, the relevance scores(RS), reflecting which features play a more critical role in the decision-making process, between immunological features and the COVID-19 severity are objectively calculated through neural network, where the input features include the immune cell counts and the activation marker concentrations of particular cell, and these quantified characteristic data are robustly generated by processing flow cytometry data sets containing the peripheral blood information of COVID-19 patients through PhenoGraph algorithm. Specifically, the RS between immune cell counts and COVID-19 severity with time indicated that the innate immune responses in severe patients are delayed at the early stage, and the continuous decrease of classical monocytes in peripherial blood is significantly associated with the severity of disease. The RS between activation marker concentrations and COVID-19 severity suggested that the down-regulation of IFN-γ in classical monocytes, Treg, CD8 T cells, and the not down-regulation of IL_17a in classical monocytes, Tregs are highly correlated with the occurrence of severe disease. Finally, a concise dynamic model of immune responses in COVID-19 patients was generalized. These results suggest that the delayed innate immune responses in the early stage, and the abnormal expression of IL-17a and IFN-γ in classical monocytes, Tregs, and CD8 T cells are primarily responsible for the severity of COVID-19.

Therapeutics for the Management of Cytokine Release Syndrome in COVID-19.

Coronavirus disease (COVID-19) is the greatest pandemic of this era and has affected more than 10 million people across 213 nations. However, the etiology, management, and treatment of COVID-19 remain unknown. A better understanding of the novel virus would help in developing accurate diagnostic methods and efficacious drugs for the treatment of patients of all age groups. To control the pandemic urgently, many drugs are being repurposed and several clinical trials are in progress for the same. As cytokine storm has been observed to be one of the common mechanisms of immune response in COVID-19 patients, several drugs are under trials to control the cytokine storm. In this review, we discuss the different categories of drugs in clinical trials for the management of cytokine storms in COVID-19 patients. Hitherto, several promising candidates such as IL-1 and IL-6 inhibitors have failed to display efficacy in the trials. Only corticosteroid therapy has shown benefit so far, albeit limited to patients on ventilator support. Thus, it is crucial to seek novel strategies to combat hyperinflammation and increase survival in COVID-19 afflicted patients.

Diagnostic Performance of Interferon Gamma Release Assay (IGRA) for Cell-Mediated Immune Responses to SARS-CoV-2.

As SARS-CoV-2 infection became a pandemic, much effort has been made to measure both antibody production and T cell response to SARS-CoV-2 to diagnose COVID-19 patients or find out their immune status. Authors tried to determine the optimal cutoff value and evaluate clinical performance of one interferon-γ release assay (IGRA) kit and compared their results with serological antibody assay in COVID-19 patients. Study subjects included 100 patients confirmed as COVID-19 with RT-PCR method and 88 healthy volunteers who were PCR negative. IGRA tests were performed using STANDARDTM E Covi-FERON ELISA. Presence of SARS-CoV-2 antibodies was detected using STANDARD Q COVID-19 IgM/IgG Plus Test. Cutoff value was assessed using receiver operating characteristic (ROC) curve. The cutoff value was 0.24 IU/mL and the area under the curve (AUC) of the ROC curve was 0.973 with 95% confidence interval (CI) of 0.940 - 1.005. At this cutoff value, sensitivity and specificity were 91.7% and 100%, respectively. In addition, when compared with antibody test, concordance rate was 95%. STANDARDTM E Covi-FERON ELISA showed high sensitivity and specificity, when the cutoff value was 0.24 IU/mL. It was also consistent with the antibody test. IGRA test was a good indicator of cellular immune response in COVID-19 patients.

Comorbid Description and Neutrophil Lymphocyte Ratio in COVID-19 Patients (Suspect and Confirmed Patients)

Neutrophil Lymphocyte Ratio (NLR) is a laboratory available as a marker used for the evaluation of systemic inflammation, NLR is a significant predictor and is a critical prognosis for COVID-19 infection and can serve as a useful factor to reflect the intensity of the imbalance of inflammation and immune response in COVID-19 patients. This study aims to determine the difference in NLR values in negative and confirmed COVID-19 patients and description for comorbid for both. This study is an analytic observational study with a cross-sectional design. The study sample was 423 suspected COVID-19 patients at hospitals in Cilacap district for the period in March – October 2020. The data obtained were analyzed descriptively and using the fisher-exact test. In these results from suspected patients with negative COVID-19, lung illness were present 31.8%, viral infections 22.9%, other respiratory disorders 6.1%, diabetes mellitus 4.7%, and anemia 4.7%. Whereas suspected patients with confirmed COVID-19 were, without comorbid diseases (40.2%), lung disease (12.4%), diabetes mellitus (7.7%), hypertension (6.2%), and other respiratory illnesses (5.2%). The mean of NLR in confirmed patients is 3.57 but not any difference between negative and confirmed patients COVID-19, but there’s any a relationship between NLR and ARDS conditions.

Association between SARS-CoV-2 RNAemia and dysregulated immune response in acutely ill hospitalized COVID-19 patients

Severe/critical COVID-19 is associated with immune dysregulation and plasmatic SARS-CoV-2 detection (i.e. RNAemia). We detailed the association of SARS-CoV-2 RNAemia with immune responses in COVID-19 patients at the end of the first week of disease. We enrolled patients hospitalized in acute phase of ascertained SARS-CoV-2 pneumonia, and evaluated SARS-CoV-2 RNAemia, plasmatic cytokines, activated/pro-cytolytic T-cells phenotypes, SARS-CoV-2-specific cytokine-producing T-cells (IL-2, IFN-γ, TNF-α, IL-4, IL-17A), simultaneous Th1-cytokines production (polyfunctionality) and amount (iMFI). The humoral responses were assessed with anti-S1/S2 IgG, anti-RBD total-Ig, IgM, IgA, IgG1 and IgG3, neutralization and antibody-dependent cellular cytotoxicity (ADCC). Out of 54 patients, 27 had detectable viremia (viremic). Albeit comparable age and co-morbidities, viremic more frequently required ventilatory support, with a trend to higher death. Viremic displayed higher pro-inflammatory cytokines (IFN-α, IL-6), lower activated T-cells (HLA-DR+CD38+), lower functional SARS-CoV-2-specific T-cells (IFN-γ+CD4+, TNF-α+CD8+, IL-4+CD8+, IL-2+TNF-α+CD4+, and IL-2+TNF-α+CD4+ iMFI) and SARS-CoV-2-specific Abs (anti-S IgG, anti-RBD total-Ig, IgM, IgG1, IgG3; ID50, %ADCC). These data suggest a link between SARS-CoV-2 RNAemia at the end of the first stage of disease and immune dysregulation. Whether high ab initium viral burden and/or intrinsic host factors contribute to immune dysregulation in severe COVID-19 remains to be elucidated, to further inform strategies of targeted therapeutic interventions.

Early immune markers of clinical, virological, and immunological outcomes in patients with COVID-19: a multi-omics study.

The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients. Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial. We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset. Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models. Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals.

Novel skewed usage of B-cell receptors in COVID-19 patients with various clinical presentations

B cell-mediated immune responses play important roles in controlling SARS-CoV infection. Here, we performed the single-cell B cell receptor sequencing (scBCR-seq) of the PBMC samples from eleven healthy controls, five asymptomatic subjects and 33 symptomatic COVID-19 patients with various clinical presentations, and subsequently analyzed the abundance and diversity of the BCR repertoires in different groups, respectively. We revealed the skewed usage of the IGHV, IGLV and IGKV genes and identified a number of heavy or light chain VDJ gene pairs and combinational preference in each group, such as IGKV3–7 and IGKV2–24 enriched in the asymptomatic subjects, whereas IGHV3–13, IGHV3–23-IGHJ4, IGHV1–18–IGLV3–19, IGHV1–18–IGLV3–21, and IGHV1–18–IGLV3–25 enriched in the recovery patients with severe diseases. We also observed the differential expression of IGHV3–23 in various B cell clusters by analysis of the scRNA-seq data. Additional dock analysis indicated that IGHV3–13 could bind to the spike protein of SARS-CoV-2. These findings may advance our understanding of the humoral immune responses in COVID-19 patients and help develop novel vaccine candidates as well as therapeutical antibodies against SASR-CoV-2 infections.

Neddylation tunes peripheral blood mononuclear cells immune response in COVID-19 patients

Neddylation tunes peripheral blood mononuclear cells immune response in COVID-19 patients

Neddylation tunes peripheral blood mononuclear cells immune response in COVID-19 patients

The COVID-19 pandemic caused by SARS-CoV-2 has reached 5.5 million deaths worldwide, generating a huge impact globally. This highly contagious viral infection produces a severe acute respiratory syndrome that includes cough, mucus, fever and pneumonia. Likewise, many hospitalized patients develop severe pneumonia associated with acute respiratory distress syndrome (ARDS), along an exacerbated and uncontrolled systemic inflammation that in some cases induces a fatal cytokine storm. Although vaccines clearly have had a beneficial effect, there is still a high percentage of unprotected patients that develop the pathology, due to an ineffective immune response. Therefore, a thorough understanding of the modulatory mechanisms that regulate the response to SARS-CoV-2 is crucial to find effective therapeutic alternatives. Previous studies describe the relevance of Neddylation in the activation of the immune system and its implications in viral infection. In this context, the present study postulates Neddylation, a reversible ubiquitin-like post-translational modification of proteins that control their stability, localization and activity, as a key regulator in the immune response against SARS-CoV-2. For the first time, we describe an increase in global neddylation levels in COVID-19 in the serum of patients, which is particularly associated with the early response to infection. In addition, the results showed that overactivation of neddylation controls activation, proliferation, and response of peripheral blood mononuclear cells (PBMCs) isolated from COVID-19 patients. Inhibition of neddylation, and the subsequent avoidance of activated PBMCs, reduces cytokine production, mainly IL-6 and MCP-1 and induce proteome modulation, being a critical mechanism and a potential approach to immunomodulate COVID-19 patients.

High Number and Specific Comorbidities Could Impact the Immune Response in COVID-19 Patients.

BackgroundCellular immunodeficiency and comorbidities are common in COVID-19 patients.AimThe purpose of this study was to investigate comorbidities impacting on the cellular immunity in COVID-19 patients.MethodsThe research objects included 55 healthy controls and 718 COVID-19 patients who divided into the control group and the COVID-19 group, respectively. Those in the COVID-19 group were divided into subgroups on the basis of the number and types of comorbidities present. Lymphocyte itself and its subsets were compared between the control group and the COVID-19 group, the groups with comorbidities based on the different number and types of comorbidities, and the relationship between the lymphocyte counts and subsets with the number and types of comorbidities was investigated.ResultsCompared with the control group, the lymphocyte counts and T cell subsets were significantly increased in the groups with comorbidities, but both B and NK cell subsets were significantly decreased in the no comorbidity group and in most of the groups with comorbidities (all P<0.05). In the three comorbidities group, the lymphocyte counts and T cell subsets were all significantly decreased, but the CD56+ percentage was obviously increased (all P<0.05). The number of comorbidities was negatively correlated with the lymphocyte counts and the T and NK cell subsets. A negative correlation also existed between cancer and both the lymphocyte counts and the T cell subsets, between chronic hepatitis B and the lymphocyte counts, and between chronic kidney disease and the CD3+ counts. A positive correlation existed between nonalcoholic fatty liver disease (NAFLD) disease and both lymphocyte and CD3+ counts. The risk factors were number of comorbidities for the lymphocyte count, CD3+CD4+ and CD3+CD8+ percentages, NAFLD for the lymphocyte and CD3+ counts, cardiovascular diseases for CD3+CD4+ and CD3+CD8+ percentages, diabetes mellitus for the CD3+CD8+ percentage, and cancer for the CD3+ percentage, respectively.ConclusionsHigh numbers of comorbidities and specific comorbidities could impact the immune response of COVID-19 patients. This study provides a reference for clinicians in the identification of suitable and timely immunotherapy for COVID-19 patients.Clinical Trial Registryhttps://www.chictr.org.cn/enindex.aspx, identifier ChiCTR2000034563.

Clinico-epidemiological Profile of COVID-19Associated Invasive Fungal Rhinosinusitis Reported in the Teaching Hospital of Diwaniya,Qadisiya Province, Iraq: A Case Series

Introduction: With the current COVID-19 pandemic, the increasing use of glucocorticoids has resulted in more adverse effects and secondary bacterial or fungal infections. Objective: To find out the clinic-epidemiological profile of patients having COVID-19 associated invasive fungal rhinosinusitis in Diwaniya teaching hospital- Qadisiya province - Iraq.Method: Retrospective case series study of 24 patients with COVID-19 who were admitted to Alshafa centre in Al-Diwaniyah Province from 1st of May 2020 to end of August 2021. Patients were moderate to severe COVID-19 received treatment according to local guidelines. Patients who developed signs and symptoms of nose and paranasal sinuses disorder were seen by otolaryngologists and treated by a multidisciplinary team if invasive mucormycosis and its comorbidities were detected.Results: Out of 24 patients, 8 were female and two patients were excluded because their histopathological examination hasn’t confirmed acute invasive fungal rhinosinusitis. The average age was 54 years old, they all had diabetes, 2 patients had chronic kidney diseases, and 2 patients had malignancy (leukaemia). Furthermore, 19 patients were with severe SARS-COV-2 while 5 patients had moderate symptoms. All patients were confirmed COVID-19 positive by PCR test.Conclusion: Invasive fungal infections of the nose and paranasal sinuses are highly lethal conditions with significant morbidity. Early recognition and high index of suspicion are needed in the case of COVID-19 patients who complain features of sinusitis with careful prescription of drugs that affect immune response in COVID-19 patients.