Abstract
This research aimed to explore the association between the RIG-I-like receptor (RIG-I and MDA5 encoded by DDX58 and IFIH1, respectively) pathways and the risk or severity of hand, foot, and mouth disease caused by enterovirus 71 (EV71-HFMD). In this context, we explored the influence of gene methylation and polymorphism on EV71-HFMD. 60 healthy controls and 120 EV71-HFMD patients, including 60 mild EV71-HFMD and 60 severe EV71-HFMD patients, were enrolled. First, MiSeq was performed to explore the methylation of CpG islands in the DDX58 and IFIH1 promoter regions. Then, DDX58 and IFIH1 expression were detected in PBMCs using RT-qPCR. Finally, imLDR was used to detect DDX58 and IFIH1 single-nucleotide polymorphism (SNP) genotypes. Severe EV71-HFMD patients exhibited higher DDX58 promoter methylation levels than healthy controls and mild EV71-HFMD patients. DDX58 promoter methylation was significantly associated with severe HFMD, sex, vomiting, high fever, neutrophil abundance, and lymphocyte abundance. DDX58 expression levels were significantly lower in mild patients than in healthy controls and lower in severe patients than in mild patients. Binary logistic regression analysis revealed statistically significant differences in the genotype frequencies of DDX58 rs3739674 between the mild and severe groups. GeneMANIA revealed that 19 proteins displayed correlations with DDX58, including DHX58, HERC5, MAVS, RAI14, WRNIP1 and ISG15, and 19 proteins displayed correlations with IFIH1, including TKFC, IDE, MAVS, DHX58, NLRC5, TSPAN6, USP3 and DDX58. DDX58 expression and promoter methylation were associated with EV71 infection progression, especially in severe EV71-HFMD patients. The effect of DDX58 in EV71-HFMD is worth further attention.
Highlights
In recent years, hand, foot and mouth disease (HFMD), a highly infectious digestive tract disease that is mainly caused by enterovirus 71 (EV71) and coxsackievirus A16 (CA16) infection among children and infants, has been prevalent in China [1,2,3]
This research aimed to explore the association between the RIG-I-like receptor (RIG-I and MDA5 encoded by DDX58 and IFIH1, respectively) pathways and the risk or severity of hand, foot, and mouth disease caused by enterovirus 71 (EV71-HFMD)
EV71-HFMD is prevalent in many Asia countries, including China, which caused a lot of death over the last few years
Summary
Hand, foot and mouth disease (HFMD), a highly infectious digestive tract disease that is mainly caused by enterovirus 71 (EV71) and coxsackievirus A16 (CA16) infection among children and infants, has been prevalent in China [1,2,3]. Retinoic acid-inducible gene I (RIG-I, encoded by the DDX58 gene) and melanoma differentiation-associated protein 5 (MDA5, encoded by the IFIH1 gene) are both RIG-I-like pattern recognition receptors (PRRs) that can be activated by double-stranded RNA (dsRNA) and interact with mitochondrial antiviral signaling (MAVS) proteins in cells, resulting in the activation and expression of type I interferon genes [9,10,11]. In other words, they are important receptors of the early immune response after virus infections. We explored the influence of gene methylation and polymorphism on EV71HFMD
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