ABSTRACT
Tumor necrosis factor (TNF) and interferon-gamma (IFNγ) are important inflammatory mediators in the development of cytokine storm syndrome (CSS). Single nucleotide polymorphisms (SNPs) regulate the expression of these cytokines, making host genetics a key factor in the prognosis of COVID-19. In this study, we investigated the associations of the TNF -308G/A and IFNG +874T/A polymorphisms with COVID-19. We analyzed the frequencies of the two polymorphisms in the control groups (CG: TNF -308G/A, n = 497; IFNG +874T/A, n = 397), a group of patients with COVID-19 (CoV, n = 222) and among the subgroups of patients with nonsevere (n = 150) and severe (n = 72) COVID-19. We found no significant difference between the genotypic and allelic frequencies of TNF -308G/A in the groups analyzed; however, both the frequencies of the high expression genotype (TT) (CoV: 13.51% vs. CG: 6.30%; p = 0.003) and the *T allele (CoV: 33.56% vs. CG: 24. 81%; p = 0.001) of the IFNG +874T/A polymorphism were higher in the COVID-19 group than in the control group, with no differences between the subgroups of patients with nonsevere and severe COVID-19. The *T allele of IFNG +874T/A (rs2430561) is associated with susceptibility to symptomatic COVID-19. These SNPs provided valuables clues about the potential mechanism involved in the susceptibility to developing symptomatic COVID-19.
Subject(s)
COVID-19 , Genetic Predisposition to Disease , Genotype , Interferon-gamma , SARS-CoV-2 , Female , Humans , Male , Alleles , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/genetics , Gene Frequency , Interferon-gamma/genetics , Polymorphism, Single Nucleotide , SARS-CoV-2/pathogenicity , Tumor Necrosis Factor-alpha/geneticsABSTRACT
The cGAS-STING pathway appears to contribute to dysregulated inflammation during coronavirus disease 2019 (COVID-19); however, inflammatory factors related to long COVID are still being investigated. In the present study, we evaluated the association of cGAS and STING gene expression levels and plasma IFN-α, TNF-α and IL-6 levels with COVID-19 severity in acute infection and long COVID, based on analysis of blood samples from 148 individuals, 87 with acute COVID-19 and 61 in the post-COVID-19 period. Quantification of gene expression was performed by real-time PCR, and cytokine levels were quantified by ELISA and flow cytometry. In acute COVID-19, cGAS, STING, IFN-α, TNF-α, and IL-6 levels were higher in patients with severe disease than in those with nonsevere manifestations (p < 0.05). Long COVID was associated with elevated cGAS, STING and IFN-α levels (p < 0.05). Activation of the cGAS-STING pathway may contribute to an intense systemic inflammatory state in severe COVID-19 and, after infection resolution, induce an autoinflammatory disease in some tissues, resulting in long COVID.
Subject(s)
COVID-19 , Post-Acute COVID-19 Syndrome , Humans , Interferon-alpha , Interleukin-6 , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolism , Signal Transduction/genetics , Tumor Necrosis Factor-alpha/geneticsABSTRACT
The Major Histocompatibility Complex (MHC) harbors key genes of the immune response that are likely useful as biomarkers for infectious diseases. However, little is known about their microRNAs and what role they play in infections. The present study aimed to describe the miRNA genes in the MHC (MHC-miRNA), their variability and associations with infectious diseases. Additionally, MHC-miRNA host and target genes were also evaluated in associations with infectious diseases. Surveys in several databases and literature reviews identified 48 MHC-miRNA genes, with high SNP and CNV variability able to disrupt MHC-miRNA expression and putatively under selective pressure. Eight MHC-miRNAs were found inside or close regions of classical MHC rearrangements (RCCX and DRB genome organization). The proportion of MHC-miRNAs associated with infections (23%) was higher than the proportion found for the 1917 hsa-miRNA (4%). Additionally, 35 MHC-miRNAs (57%) have at least one of their target genes associated with infectious diseases, while all nine MHC-miRNA whose host genes were associated with infections have also their target genes associated with infections, being host and target genes of five MHC-miRNAs reported to be associated with the same diseases. This finding may reflect a concerted miRNA-mediated immune response mechanism triggered by infection.
Subject(s)
Communicable Diseases/genetics , Major Histocompatibility Complex/genetics , MicroRNAs/genetics , Databases, Nucleic Acid , Gene Expression Profiling , Genetic Association Studies , Genome , Humans , Immunity/genetics , Polymorphism, Single NucleotideABSTRACT
C-type lectin DC-SIGN receptor, encoded by CD209, plays a key role in the infection of dendritic cells by dengue virus (DENV). Because the -336A/G SNP (rs4804803) polymorphism in the promoter of CD209 modulates DC-SIGN expression, we investigated the putative association of this polymorphism with DENV infection and its pathogenesis. A control sample of 72 individuals, rigorously selected through a clinical investigation for absence of past dengue fever (DF) was compared to a sample of 168 patients (156 classical DF; 12 dengue hemorrhagic fever), all residents from Pará, Brazil. However, the prevalence of symptoms showed a trend higher in the AA genotype (Wilcoxon test; Z=2.02; p=0.04). Hence, our findings indicate that the G allele downregulates the spectrum of symptoms during the early acute phase of DENV infection, putatively decreasing the viremia, as suggested in the literature.
