Associations between IL-17A G/A-rs2275913 and IL 23R A/G-rs11209026 gene polymorphisms and severe coronavirus disease 2019 (COVID-19).

Severe COVID-19 disease was linked to a severe proinflammatory response and cytokine storm interleukin 17 (IL-17) is one of these cytokines, was associated with severe acute lung injury and multiorgan dysfunction. Single nucleotide polymorphisms (SNPs) in genes coding IL-17 can affect level of IL-17 hence its role in diseases. Also, SNPs in IL-23 R which control IL-23 is the main activator of IL-17 production. This study aimed to determine whether the IL-17A (G/A-rs2275913), IL-23R (A/G rs11209026) SNPs and serum levels of IL-17 were related to the risk of severe COVID-19. This case-control study included 120 confirmed COVID-19 patients, divided into two categories according to the severity of the disease and 74 normal subjects as controls. COVID-19 patients were SARS-CoV-2 positive by a reverse transcription-polymerase chain reaction and subjected to full clinical examinations, routine laboratory tests, and radiographic evaluations. The IL-17 levels were assessed using ELISA method, and genotyping of IL-17A (197 A/G; rs2275913) and IL-23R rs11209026 (A/G) was performed by the TaqMan Genotyping Assay. There were no differences in the distribution of IL-17A or IL-23R genotypes between COVID-19 groups and the control group (p=0.93 and p=0.84, respectively). Severe COVID-19 patients had significantly higher IL-17 serum levels than non-severe COVID-19 (p=0.0001). The GG genotypes of IL-17A were significantly higher in severe COVID-19 patients (p=0.004). Multivariate logistic regression analysis revealed that AG, GG genotypes of IL-17 and IL-17A were independent predictors of COVID-19 disease severity (p < 0.0001, p=0.06 and p=0.04, respectively). ROC curve analysis for IL-17, as predictor of severe COVID-19 disease revealed a sensitivity of 87.9% and specificity of 66.1% at a cutoff point of 114 pg/ml with AUC = 0.799. In conclusion, these findings indicated that IL-17 may be considered a marker of severe COVID-19. IL-17A SNPs may have a role in COVID-19 severity. IL-23R SNPs had no role in COVID-19.

Investigation of the relationship between IL17A, IL17F and ILR1N polymorphisms and COVID-19 severity: The predictive role of IL17A rs2275913 polymorphism in the clinical course of COVID-19.

Coronavirus disease 2019 (COVID-19) is an infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the mortality rate of the disease has been relatively under control as of 2022, more than 15 million confirmed COVID-19 cases have been detected in Turkey to date, causing more than 100,000 deaths. The clinical manifestation of the disease varies widely, ranging from asymptomatic to acute respiratory distress syndrome causing death. The immune response mechanisms have an important impact on the fine adjustment between healing and enhanced tissue damage. This study aims to investigate the relationship between the variants of the interleukin 1 receptor antagonist (IL1RN), interleukin 17A (IL17A), and interleukin 17F (IL17F) genes and COVID-19 severity. The study population comprised 202 confirmed COVID-19 cases divided into three groups according to severity. The IL1RN variable number of a tandem repeat (VNTR) polymorphism was genotyped by polymerase chain reaction (PCR), and IL17A rs2275913, IL17F rs763780 and rs2397084 polymorphisms were genotyped by the PCR-based restriction fragment length polymorphism method. Statistical analysis revealed a significant association between IL17A rs2275913 variant and COVID-19 severity. The AA genotype and the A allele of IL17A rs2275913 were found significant in the severe group. Additionally, we found a significant relationship between haplotype frequency distributions and severity of COVID-19 for the IL17F rs763780/rs2397084 (p = 0.044) and a combination of IL17F rs763780/rs2397084/ IL17A rs2275913 (p = 0.04). The CG and CGA haplotype frequencies were significantly higher in the severe group. IL17A rs2275913, IL17F rs763780 and rs2397084 variants appear to have important effects on the immune response in COVID-19. In conclusion, variants of IL17A rs2275913, IL17F rs763780 and rs2397084 may be the predictive markers for the clinical course and potential immunomodulatory treatment options in COVID-19, a disease that has placed a significant burden on our country.

Association of Interleukin-17F Polymorphism and Mortality Predictors with the Risk of COVID-19.

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.

Evaluation of Cardiac Biomarkers and Expression Analysis of IL-1, IL-6, IL-10, IL-17, and IL-25 among COVID-19 Patients from Pakistan.

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.

Genetic association of IL17 and the importance of ABO blood group antigens in saliva to COVID-19.

The outbreak of COVID-19 caused by infection with SARS-CoV-2 virus has become a worldwide pandemic, and the number of patients presenting with respiratory failure is rapidly increasing in Japan. An international meta-analysis has been conducted to identify genetic factors associated with the onset and severity of COVID-19, but these factors have yet to be fully clarified. Here, we carried out genomic analysis based on a genome-wide association study (GWAS) in Japanese COVID-19 patients to determine whether genetic factors reported to be associated with the onset or severity of COVID-19 in the international meta-GWAS are replicated in the Japanese population, and whether new genetic factors exist. Although no significant genome-wide association was detected in the Japanese GWAS, an integrated analysis with the international meta-GWAS identified for the first time the involvement of the IL17A/IL17F gene in the severity of COVID-19. Among nine genes reported in the international meta-GWAS as genes involved in the onset of COVID-19, the association of FOXP4-AS1, ABO, and IFNAR2 genes was replicated in the Japanese population. Moreover, combined analysis of ABO and FUT2 genotypes revealed that the presence of oral AB antigens was significantly associated with the onset of COVID-19. FOXP4-AS1 and IFNAR2 were also significantly associated in the integrated analysis of the Japanese GWAS and international meta-GWAS when compared with severe COVID-19 cases and the general population. This made it clear that these two genes were also involved in not only the onset but also the severity of COVID-19. In particular, FOXP4-AS1 was not found to be associated with the severity of COVID-19 in the international meta-GWAS, but an integrated analysis with the Japanese GWAS revealed an association with severity. Individuals with the SNP risk allele found between IL17A and IL17F had significantly lower mRNA expression levels of IL17F, suggesting that activation of the innate immune response by IL17F may play an important role in the severity of SARS-CoV-2 infection.

Viral Mimicry of Interleukin-17A by SARS-CoV-2 ORF8.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers cytokine-mediated inflammation, leading to a myriad of clinical presentations in COVID-19. The SARS-CoV-2 open reading frame 8 (ORF8) is a secreted and rapidly evolving glycoprotein. Patients infected with SARS-CoV-2 variants with ORF8 deleted are associated with mild disease outcomes, but the molecular mechanism behind this is unknown. Here, we report that SARS-CoV-2 ORF8 is a viral cytokine that is similar to but distinct from interleukin 17A (IL-17A) as it induces stronger and broader human IL-17 receptor (hIL-17R) signaling than IL-17A. ORF8 primarily targeted blood monocytes and induced the heterodimerization of hIL-17RA and hIL-17RC, triggering a robust inflammatory response. Transcriptome analysis revealed that besides its activation of the hIL-17R pathway, ORF8 upregulated gene expression for fibrosis signaling and coagulation dysregulation. A naturally occurring ORF8 L84S variant that was highly associated with mild COVID-19 showed reduced hIL-17RA binding and attenuated inflammatory responses. This study reveals how SARS-CoV-2 ORF8 by a viral mimicry of the IL-17 cytokine contributes to COVID-19 severe inflammation. IMPORTANCE Patients infected with SARS-CoV-2 variants lacking open reading frame 8 (ORF8) have been associated with milder infection and disease outcome, but the molecular mechanism behind how this viral accessory protein mediates disease pathogenesis is not yet known. In our study, we revealed that secreted ORF8 protein mimics host IL-17 to activate IL-17 receptors A and C (IL-17RA/C) and induces a significantly stronger inflammatory response than host IL-17A, providing molecular insights into the role of ORF8 in COVID-19 pathogenesis and serving as a potential therapeutic target.

Correlation between interleukin gene polymorphisms and current prevalence and mortality rates due to novel coronavirus disease 2019 (COVID-2019) in 23 countries.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) infection may rely on a potential genetic background for the variations in the inflammatory response. We aimed to investigate the possible correlation between polymorphisms in the IL-6 gene at rs1800796/rs1800795, in IL-6R at rs2228145, in IL-10 at rs1800896 and rs1800871, in IL-17 at rs2275913 and rs763780 loci, and COVID-19 prevalence and mortality rates among populations of 23 countries. METHODS: We searched the literature for polymorphisms in China, Japan, India, Spain, Mexico, Sweden, Turkey, Brazil, Russia, Poland, Italy, South Africa, Netherlands, Greece, Germany, UK, Iran, Finland, Czechia, Tunisia, Norway, Egypt, Croatia. We recorded the prevalence and mortality rates (per million) caused by the Coronavirus infection recorded on 7th September 2020 and 6th December 2020. RESULTS: There was a significant positive correlation between the frequency of AG genotype of rs1800896 and prevalence recorded on 6th December 2020 (r: 0.53, r2 : 0.28, p < .05). There was a significant negative correlation between the mortality rates recorded on 7th September, and the AG genotype of rs2275913 (r: -0.51, r2 : 0.26, p < .05). There was a significant positive correlation between the prevalence recorded on 6th December, and TT genotype at rs763780 (r: 0.65, r2 :0.42, p < .05) while a negative correlation between prevalence and TC genotype at rs763780 (r: -0.66, r2 : 0.43, p < .05). Also, a significant negative correlation was found between mortality rates recorded on 6th December 2020 and CC genotype at rs763780 (r: -0.56, r2 : 0.31, p < .05). CONCLUSION: The variations in prevalence of COVID-19 and its mortality rates among countries may be explained by the polymorphisms at rs1800896 in IL-10, rs2275913 in IL-17A, and rs763780 loci in the IL-17F gene.

A Biological Insight into the Susceptibility to Influenza Infection in Junior Rats by Comprehensive Analysis of lncRNA Profiles.

Long noncoding RNAs (lncRNAs) have been reported to participate in regulating many biological processes, including immune response to influenza A virus (IAV). However, the association between lncRNA expression profiles and influenza infection susceptibility has not been well elucidated. Here, we analyzed the expression profiles of lncRNAs, miRNAs, and mRNAs among IAV-infected adult rat (IAR), normal adult rat (AR), IAV-infected junior rat (IJR), and normal junior rat (JR) by RNA sequencing. Compared with differently expressed lncRNAs (DElncRNAs) between AR and IAR, 24 specific DElncRNAs were found between IJR and JR. Then, based on the fold changes and P value, the top 5 DElncRNAs, including 3 upregulated and 2 downregulated lncRNAs, were chosen to establish a ceRNA network for further disclosing their regulatory mechanisms. To visualize the differentially expressed genes in the ceRNA network, GO and KEGG pathway analysis was performed to further explore their roles in influenza infection of junior rats. The results showed that the downregulated DElncRNA-target genes were mostly enriched in the IL-17 signaling pathway. It indicated that the downregulated lncRNAs conferred the susceptibility of junior rats to IAV via mediating the IL-17 signaling pathway.

SARS-CoV-2 infection initiates interleukin-17-enriched transcriptional response in different cells from multiple organs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a pandemic. Paucity of information concerning the virus and therapeutic interventions have made SARS-CoV-2 infection a genuine threat to global public health. Therefore, there is a growing need for understanding the molecular mechanism of SARS-CoV-2 infection at cellular level. To address this, we undertook a systems biology approach by analyzing publicly available RNA-seq datasets of SARS-CoV-2 infection of different cells and compared with other lung pathogenic infections. Our study identified several key genes and pathways uniquely associated with SARS-CoV-2 infection. Genes such as interleukin (IL)-6, CXCL8, CCL20, CXCL1 and CXCL3 were upregulated, which in particular regulate the cytokine storm and IL-17 signaling pathway. Of note, SARS-CoV-2 infection strongly activated IL-17 signaling pathway compared with other respiratory viruses. Additionally, this transcriptomic signature was also analyzed to predict potential drug repurposing and small molecule inhibitors. In conclusion, our comprehensive data analysis identifies key molecular pathways to reveal underlying pathological etiology and potential therapeutic targets in SARS-CoV-2 infection.

Quercetin for COVID-19 and DENGUE co-infection: a potential therapeutic strategy of targeting critical host signal pathways triggered by SARS-CoV-2 and DENV.

BACKGROUND: The clinical consequences of SARS-CoV-2 and DENGUE virus co-infection are not promising. However, their treatment options are currently unavailable. Current studies have shown that quercetin is both resistant to COVID-19 and DENGUE; this study aimed to evaluate the possible functional roles and underlying mechanisms of action of quercetin as a potential molecular candidate against COVID-19 and DENGUE co-infection. METHODS: We used a series of bioinformatics analyses to understand and characterize the biological functions, pharmacological targets and therapeutic mechanisms of quercetin in COVID-19 and DENGUE co-infection. RESULTS: We revealed the clinical characteristics of COVID-19 and DENGUE, including pathological mechanisms, key inflammatory pathways and possible methods of intervention, 60 overlapping targets related to the co-infection and the drug were identified, the protein-protein interaction (PPI) was constructed and TNFα, CCL-2 and CXCL8 could become potential drug targets. Furthermore, we disclosed the signaling pathways, biological functions and upstream pathway activity of quercetin in COVID-19 and DENGUE. The analysis indicated that quercetin could inhibit cytokines release, alleviate excessive immune responses and eliminate inflammation, through NF-κB, IL-17 and Toll-like receptor signaling pathway. CONCLUSIONS: This study is the first to reveal quercetin as a pharmacological drug for COVID-19 and DENGUE co-infection. COVID-19 and DENGUE co-infection remain a potential threat to the world's public health system. Therefore, we need innovative thinking to provide admissible evidence for quercetin as a potential molecule drug for the treatment of COVID-19 and DENGUE, but the findings have not been verified in actual patients, so further clinical drug trials are needed.

The Effects of Insulin-Like Growth Factor I and BTP-2 on Acute Lung Injury.

Acute lung injury (ALI) afflicts approximately 200,000 patients annually and has a 40% mortality rate. The COVID-19 pandemic has massively increased the rate of ALI incidence. The pathogenesis of ALI involves tissue damage from invading microbes and, in severe cases, the overexpression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). This study aimed to develop a therapy to normalize the excess production of inflammatory cytokines and promote tissue repair in the lipopolysaccharide (LPS)-induced ALI. Based on our previous studies, we tested the insulin-like growth factor I (IGF-I) and BTP-2 therapies. IGF-I was selected, because we and others have shown that elevated inflammatory cytokines suppress the expression of growth hormone receptors in the liver, leading to a decrease in the circulating IGF-I. IGF-I is a growth factor that increases vascular protection, enhances tissue repair, and decreases pro-inflammatory cytokines. It is also required to produce anti-inflammatory 1,25-dihydroxyvitamin D. BTP-2, an inhibitor of cytosolic calcium, was used to suppress the LPS-induced increase in cytosolic calcium, which otherwise leads to an increase in proinflammatory cytokines. We showed that LPS increased the expression of the primary inflammatory mediators such as toll like receptor-4 (TLR-4), IL-1ß, interleukin-17 (IL-17), TNF-α, and interferon-γ (IFN-γ), which were normalized by the IGF-I + BTP-2 dual therapy in the lungs, along with improved vascular gene expression markers. The histologic lung injury score was markedly elevated by LPS and reduced to normal by the combination therapy. In conclusion, the LPS-induced increases in inflammatory cytokines, vascular injuries, and lung injuries were all improved by IGF-I + BTP-2 combination therapy.

Lung Neutrophilic Recruitment and IL-8/IL-17A Tissue Expression in COVID-19.

The new SARS-CoV-2 virus differs from the pandemic Influenza A virus H1N1 subtype (H1N1pmd09) how it induces a pro-inflammatory response in infected patients. This study aims to evaluate the involvement of SNPs and tissue expression of IL-17A and the neutrophils recruitment in post-mortem lung samples from patients who died of severe forms of COVID-19 comparing to those who died by H1N1pdm09. Twenty lung samples from patients SARS-CoV-2 infected (COVID-19 group) and 10 lung samples from adults who died from a severe respiratory H1N1pdm09 infection (H1N1 group) were tested. The tissue expression of IL-8/IL-17A was identified by immunohistochemistry, and hematoxylin and eosin (H&E) stain slides were used for neutrophil scoring. DNA was extracted from paraffin blocks, and genotyping was done in real time-PCR for two IL17A target polymorphisms. Tissue expression increasing of IL-8/IL-17A and a higher number of neutrophils were identified in samples from the H1N1 group compared to the COVID-19 group. The distribution of genotype frequencies in the IL17A gene was not statistically significant between groups. However, the G allele (GG and GA) of rs3819025 was correlated with higher tissue expression of IL-17A in the COVID-19 group. SARS-CoV-2 virus evokes an exacerbated response of the host's immune system but differs from that observed in the H1N1pdm09 infection since the IL-8/IL-17A tissue expression, and lung neutrophilic recruitment may be decreased. In SNP rs3819025 (G/A), the G allele may be considered a risk allele in the patients who died for COVID-19.

"Small" Intestinal Immunopathology Plays a "Big" Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor.

Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as well as staphylococcal superantigens share one common complication, that is T cell-driven cytokine release syndrome (CRS) accompanied by multiple organ dysfunction (MOD). It is not understood whether the failure of a particular organ contributes more significantly to the severity of CRS. Also not known is whether a specific cytokine or signaling pathway plays a more pathogenic role in precipitating MOD compared to others. As a result, there is no specific treatment available to date for CRS, and it is managed only symptomatically to support the deteriorating organ functions and maintain the blood pressure. Therefore, we used the superantigen-induced CRS model in HLA-DR3 transgenic mice, that closely mimics human CRS, to delineate the immunopathogenesis of CRS as well as to validate a novel treatment for CRS. Using this model, we demonstrate that (i) CRS is characterized by a rapid rise in systemic levels of several Th1/Th2/Th17/Th22 type cytokines within a few hours, followed by a quick decline. (ii) Even though multiple organs are affected, small intestinal immunopathology is the major contributor to mortality in CRS. (iii) IFN-γ deficiency significantly protected from lethal CRS by attenuating small bowel pathology, whereas IL-17A deficiency significantly increased mortality by augmenting small bowel pathology. (iv) RNA sequencing of small intestinal tissues indicated that IFN-γ-STAT1-driven inflammatory pathways combined with enhanced expression of pro-apoptotic molecules as well as extracellular matrix degradation contributed to small bowel pathology in CRS. These pathways were further enhanced by IL-17A deficiency and significantly down-regulated in mice lacking IFN-γ. (v) Ruxolitinib, a selective JAK-1/2 inhibitor, attenuated SAg-induced T cell activation, cytokine production, and small bowel pathology, thereby completely protecting from lethal CRS in both WT and IL-17A deficient HLA-DR3 mice. Overall, IFN-γ-JAK-STAT-driven pathways contribute to lethal small intestinal immunopathology in T cell-driven CRS.