Pathogenesis of COVID-19 MESHD is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation MESHD is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein PROTEIN potently induces inflammatory cytokines and chemokines including IL-6 HGNC, IL-1b HGNC, TNFa HGNC, CXCL1 HGNC, CXCL2 HGNC, and CCL2 HGNC, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and neucleocapsid ( N) proteins PROTEIN. When stimulated with extracellular S protein PROTEIN, human lung epithelial cells A549 also produce inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein PROTEIN intracellularly are non-inflammatory, but elicit an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein PROTEIN triggers inflammation MESHD via activation of the NF-kB pathway in a MyD88 HGNC-dependent manner. Further, such an activation of the NF-kB pathway is abrogated in Tlr2 HGNC-deficient macrophages. Consistently, administration of S protein PROTEIN induces IL-6, TNF-a, and IL-1b in wild-type, but not Tlr2-deficient mice. Together these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection MESHD and suggest that TLR2 could be a potential therapeutic target for COVID-19 MESHD.

BackgroundCoronavirus Disease MESHD Coronavirus Disease 2019 MESHD ( COVID-19 MESHD) respiratory disease MESHD rapidly caused a global pandemic and social and economic disruption. The combination of Traditional Chinese medicine (TCM) and Conventional Western medicine (CWM) is more effective for COVID-19 MESHD treatment. Moreover, TCM and CWM are important data source for developing new drug targets and promote strategies treat SARS-CoV-2 infection MESHD SARS-CoV-2 infection MESHDs. However, many studies have analyzed the therapeutic mechanism of CWM or TCM alone for COVID-19 MESHD, it is still unclear the interaction mechanism between TCM and CWM on COVID-19 MESHD.MethodsThis paper integrates network pharmacology and GEO database to mine and identify COVID-19 MESHD molecular therapeutic targets, providing potential targets and new ideas for COVID-19 MESHD gene therapy and new drug development. It includes: 1) using TCMSP, TTD, PubChem and CTD databases to analyze drug interactions and associated phenotypes for SARS-CoV-2, to correlate drug and disease interaction mechanisms to screen key drug targets; 2) using GEO database to correlate differential genes and drug targets to screen potential antiviral gene therapy targets, to construct regulatory network and key points of SARS-CoV-2 therapeutic drugs; 3) using computer simulation of molecular docking to screen virus-related proteins for new drugs. ResultsIntegrated analysis of network pharmacology discovered that baicalein, estrone and quercetin are the pivotal active ingredients in TCM and CWM. Combining drug target genes in pharmacology database and virus induced genes in GEO database, the result showed the core hub genes related to COVID-19 MESHD: STAT1 HGNC, IL1B HGNC, IL6 HGNC, IL8 HGNC, PTGS2 HGNC and NFKBIA HGNC, and these genes were significantly downregulated in A549 and NHBE cells by SARS-CoV-2 infection MESHD. Moreover, chemical interaction and molecular docking analysis of hub genes showed that folic acid might as be potential therapeutic drug for COVID-19 MESHD treatment, and SARS-CoV-2 nucleocapsid phosphoprotein was a potential drug target. The network of “drug-target-SARS-CoV-2 related genes” provide noval potential compounds and targets for further studies of SARS-CoV-2.ConclusionsIntegrated analysis of network pharmacology and big data mining provided noval potential compounds and targets for further studies of SARS-CoV-2. Our research implied folic acid and SARS-CoV-2 N as therapeutic target in TCM and CWM. Our research also suggests that targeting SARS-CoV-2 N MESHD N protein PROTEIN is likely to be a common mechanism of TCM and CWM. On the one hand, the identification of pivotal genes provides a target for COVID-19 MESHD molecular therapy, on the other hand, it provides ideas for the analysis of interaction mechanism between virus and host.

The Nucleocapsid Protein (N PROTEIN Protein) of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV2) is located in the viral core. Immunoglobulin G (IgG) targeting N protein PROTEIN is detectable in the serum of infected MESHD patients. The effect of high titers of IgG against N-protein PROTEIN on clinical outcomes of SARS-CoV2 disease MESHD has not been described. We studied 400 RT-PCR confirmed SARS-CoV2 patients to determine independent factors associated with poor outcomes, including MICU admission, prolonged MICU stay and hospital admissions, and in-hospital mortality. We also measured serum IgG against the N protein PROTEIN and correlated its concentrations with clinical outcomes. We found that several factors, including Charlson comorbidity Index (CCI), high levels of IL6 HGNC, and presentation with dyspnea MESHD were associated with poor clinical outcomes. It was shown that higher CCI and higher IL6 HGNC levels were independently associated with in-hospital mortality. Anti- N protein PROTEIN IgG was detected in the serum of 55 (55%) patients at the time of admission. A high concentration of antibodies, defined as signal to cut off ratio (S/Co)> 1.5 (75 percentile of all measurements), was found in 25 (25%) patients. The multivariable logistic regression models showed that between being an African American, higher CCI, lymphocyte counts, and S/Co ratio> 1.5, only S/Co ratio were independently associated with MICU admission and longer length of stay in hospital. This study recommends that titers of IgG targeting N-protein PROTEIN of SARS-CoV2 at admission is a prognostic factor for the clinical course of disease and should be measured in all patients with SARS-CoV2 infection MESHD.

The SARS-CoV-2 pandemic is continuing to impact the global population. This study was designed to assess the interplay of antibodies with the systemic cytokine response in SARS-CoV-2 patients. We demonstrate that significant anti-SARS-CoV-2 antibody production to Receptor Binding Domain (RBD), Nucleocapsid (N PROTEIN), and Spike S1 subunit PROTEIN (S1) of SARS-CoV-2 develops over the first 10 to 20 days of infection. The majority of patients produced antibodies against all three antigens (219/255 SARS-CoV-2 positive patient specimens, 86%) suggesting a broad response to viral proteins. Patient mortality, sex, blood type, and age were all associated with differences in antibody production to SARS-CoV-2 antigens which may help explain variation in immunity between these populations. To better understand the systemic immune response, we analyzed the production of 20 cytokines by SARS-CoV-2 patients over the course of infection. Cytokine analysis of SARS-CoV-2 positive patients exhibited increases in proinflammatory markers ( IL-6 HGNC, IL-8 HGNC, IL-18 HGNC) and chemotactic markers ( IP-10 HGNC, SDF-1 HGNC, MIP-1{beta} HGNC, MCP-1 HGNC, and eotaxin HGNC) relative to healthy individuals. Patients who succumbed to infection produced decreased IL-2 HGNC, IL-4 HGNC, IL-12, IL-13 HGNC, RANTES HGNC, TNF-, GRO-, and MIP-1 HGNC relative to patients who survived infection. We also observed that the chemokine CXCL13 HGNC was particularly elevated in patients that succumbed to infection. CXCL13 HGNC is involved in B cell activation, germinal center development, and antibody maturation, and we observed that CXCL13 HGNC levels in blood trended with anti-SARS-CoV-2 antibody production. Furthermore, patients that succumbed to infection produced high CXCL13 HGNC and also tended to have high ratio of nucleocapsid to RBD antibodies. This study provides insights into SARS-CoV-2 immunity implicating the magnitude and specificity of response in relation to patient outcomes.

Coronavirus disease 2019 MESHD ( COVID-19 MESHD), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and has since become a global pandemic. Pathogen-specific antibodies are typically a major predictor of protective immunity, yet B cell and antibody responses during COVID-19 MESHD are not fully understood. Here, we analyzed antibody-secreting cell (ASC) and antibody responses in twenty hospitalized COVID-19 MESHD patients. The patients exhibited typical symptoms of COVID-19 MESHD, and presented with reduced lymphocyte numbers and increased T cell and B cell activation. Importantly, we detected an expansion of SARS-CoV-2 nucleocapsid protein PROTEIN-specific ASCs in all twenty COVID-19 MESHD patients using a multicolor FluoroSpot assay. Out of the 20 patients, 16 had developed SARS-CoV-2-neutralizing antibodies by the time of inclusion in the study. SARS-CoV-2-specific IgA, IgG and IgM antibody levels positively correlated with SARS-CoV-2-neutralizing antibody titers, suggesting that SARS-CoV-2-specific antibody levels may reflect the titers of neutralizing antibodies in COVID-19 MESHD patients during the acute phase of infection. Lastly, we showed that interleukin 6 HGNC ( IL-6 HGNC) and C-reactive protein HGNC ( CRP HGNC) concentrations were higher in serum of patients who were hospitalized for longer, supporting the recent observations that IL-6 HGNC and CRP HGNC could be used to predict COVID-19 MESHD severity. Altogether, this study constitutes a detailed description of clinical and immunological parameters in twenty COVID-19 MESHD patients, with a focus on B cell and antibody responses, and provides tools to study immune responses to SARS-CoV-2 infection MESHD and vaccination.

Background: To explore the cellular immunity and cytokines status of NCP PROTEIN patients and to predict the correlation between the cellular immunity levels, cytokines and the severity of patients. Methods: 123 NCP PROTEIN patients were divided into mild and severe groups. Peripheral blood was collected, lymphocyte subsets and cytokines were detected. Correlation analysis was performed on the lymphocyte subsets and cytokines, and the differences between the indexes of the two groups were analyzed. Results: 102 mild and 21 severe patients were included. Lymphocyte subsets were reduced in two groups. The proportion of CD8 HGNC + T reduction in the mild and severe group was 28.43% and 61.9%, respectively; The proportion of B cell reduction was 25.49% and 28.57%; The proportion of NK cell reduction was 34.31% and 47.62%; The detection value of IL-6 HGNC was 0 in 55.88% of the mild group, mild group has a significantly lower proportion of patients with IL-6 HGNC higher than normal than severe group; There was no significant linear correlation between the lymphocyte subsets and cytokines, while significant differences were noticed between the two groups in CD4 HGNC + T, CD8 HGNC + T, IL-6 HGNC and IL-10 HGNC. Conclusions: Low levels of CD4 HGNC+T and CD8 HGNC+T are common in severe NCP PROTEIN. IL-6 HGNC and IL-10 HGNC levels were higher in severe patients. T cell subsets and cytokines can be used as one of the basis for predicting the transition from mild to severe. Large number of samples are still needed to confirm the "warning value" of CD4 HGNC + T, CD8 HGNC + T IL-6 HGNC and IL-10 HGNC.