Polymorphisms of IFN signaling genes and FOXP4 influence the severity of COVID-19.

BACKGROUND: The clinical manifestations of COVID-19 range from asymptomatic, mild to moderate, severe, and critical disease. Host genetic variants were recognized to affect the disease severity. However, the genetic landscape differs among various populations. Therefore, we explored the variants associated with COVID-19 severity in the Guangdong population. METHODS: A total of 314 subjects were selected, of which the severe and critical COVID-19 patients were defined as "cases", and the mild and moderate patients were defined as "control". Twenty-two variants in interferon-related genes and FOXP4 were genotyped using the MassARRAY technology platform. RESULTS: IFN signaling gene MX1 rs17000900 CA + AA genotype was correlated with a reduced risk of severe COVID-19 in males (P = 0.001, OR = 0.050, 95%CI = 0.008-0.316). The AT haplotype comprised of MX1 rs17000900 and rs2071430 was more likely to protect against COVID-19 severity (P = 6.3E-03). FOXP4 rs1886814 CC genotype (P = 0.001, OR = 3.747, 95%CI = 1.746-8.043) and rs2894439 GA + AA genotype (P = 0.001, OR = 5.703, 95% CI = 2.045-15.903) were correlated with increased risk of severe COVID-19. Haplotype CA comprised of rs1886814 and rs2894439 was found to be correlated with adverse outcomes (P = 7.0E-04). FOXP4 rs1886814 CC (P = 0.0004) and rs2894439 GA + AA carriers had higher neutralizing antibody titers (P = 0.0018). The CA + AA genotype of MX1 rs17000900 tended to be correlated with lower neutralizing antibody titers than CC genotype (P = 0.0663), but the difference was not statistically significant. CONCLUSION: Our study found a possible association between MX1 and FOXP4 polymorphisms and the severity of COVID-19. Distinguishing high-risk patients who develop severe COVID-19 will provide clues for early intervention and individual treatment strategies.

The truncated IFITM3 facilitates the humoral immune response in inactivated influenza vaccine-vaccinated mice via interaction with CD81.

A single-nucleotide polymorphism (SNP) rs12252-C of interferon-induced transmembrane protein 3 (IFITM3), resulting in a truncated IFITM3 protein lacking 21 N-terminus amino acids, is associated with severe influenza infection in the Chinese population. However, the effect of IFITM3 rs12252-C on influenza vaccination and the underlying mechanism is poorly understood. Here, we constructed a mouse model with a deletion of 21 amino acids at the N-terminus (NΔ21) of IFITM3 and then compared the antibody response between Quadrivalent influenza vaccine (QIV) immunized wild-type (WT) mice and NΔ21 mice. Significantly higher levels of haemagglutination inhibition (HI) titre, neutralizing antibodies (NAb), and immunoglobulin G (IgG) to H1N1, H3N2, B/Victory, and B/Yamagata viruses were observed in NΔ21 mice compared to WT mice. Correspondingly, the numbers of splenic germinal centre (GC) B cells, plasma cells, memory B cells, QIV-specific IgG+ antibody-secreting cells (ASC), and T follicular helper cells (TFH) in NΔ21 mice were higher compared with WT mice. Moreover, the 21-amino-acid deletion caused IFITM3 translocation from the endocytosis compartment to the periphery of cells, which also prevented the degradation of a co-stimulatory molecule of B cell receptor (BCR) CD81 on the cell surface. More importantly, a more interaction was observed between NΔ21 protein and CD81 compared to the interaction between IFITM3 and CD81. Overall, our study revealed a potential mechanism of NΔ21 protein enhancing humoral immune response by relocation to prevent the degradation of CD81, providing insight into SNP affecting influenza vaccination.

2', 5'-Oligoadenylate Synthetase 2 (OAS2) Inhibits Zika Virus Replication through Activation of Type Ι IFN Signaling Pathway.

BACKGROUND: 2', 5'-oligoadenylate synthetase 2 (OAS2) has been known as an antiviral interferon-stimulated gene (ISG). However, the role of OAS2 on Zika virus (ZIKV) replication is still unknown. In this study, we sought to explore the effect of OAS2 on ZIKV replication and its underlying mechanism. METHODS: We performed RNA-Seq in A549 cells with or without ZIKV infection. OAS2 or RIG-I was overexpressed by plasmid transfection or knocked down by siRNA in A549 cells. Expression levels of mRNA and protein of selected genes were detected by RT-qPCR and Western Blot, respectively. Interferon stimulated response element (ISRE) activity was examined by dual luciferase assay. RESULTS: We found that ZIKV infection induced OAS2 expression through a RIG-I-dependent pathway. OAS2 overexpression inhibited ZIKV replication, while OAS2 knockdown increased ZIKV replication. We observed that OAS2 inhibited ZIKV replication through enhanced IFNß expression, leading to the activation of the Jak/STAT signaling pathway. CONCLUSION: ZIKV infection induced OAS2 expression, which in turn exerted its anti-ZIKV activities through the IFN-activated Jak/STAT signaling pathway.

HBV cccDNA and Its Potential as a Therapeutic Target.

Chronic hepatitis B virus infection continues to be a major health burden worldwide. It can cause various degrees of liver damage and is strongly associated with the development of liver cirrhosis and hepatocellular carcinoma. Covalently closed circular DNA in the nucleus of infected cells cannot be disabled by present therapies which may lead to HBV persistence and relapse. In this review, we summarized the current knowledge on hepatitis B virus covalently closed circular DNA and its potential role as a therapeutic target.

Inactivation of Zika virus in plasma and derivatives by four different methods.

Zika virus (ZIKV) is an emerging arbovirus with increasing prevalence in recent years. To reduce the risk of ZIKV transmission by transfusion, some mitigation strategies were recommended based on pathogen reduction technologies for blood products. In this study, we aimed to study the efficacy of several common pathogen reduction methods in the inactivation of ZIKV. The fresh frozen plasma and derivatives were spiked with a high titer of ZIKV or Sindbis virus (SINV). Viral titers and ZIKV RNA were measured before and after the inactivation treatment by methylene blue (MB), solvent/detergent (S/D), pasteurization, and low pH. The mean ZIKV infectivity titers in plasma and derivatives were 7.08 ± 0.14, 5.17 ± 0.14, 7.08 ± 0.14, and 5.80 ± 0.14 log10 TCID50 /mL, respectively before MB, S/D, pasteurization, and low pH inactivation. We found no detectable ZIKV RNA after five successive passages of inoculation on host cells, indicating there is no infectivity after inactivation. Similar inactivation results were observed for SINV. In conclusion, we achieved robust ZIKV inactivation through the four inactivation procedures in several blood products. These findings suggest that the pathogen reduction technologies commonly applied in plasma and derivatives have the capacity to mitigate the risk of ZIKV transmission by transfusion.

Microrna-130a Downregulates HCV Replication through an atg5-Dependent Autophagy Pathway.

We previously identified that miR-130a downregulates HCV replication through two independent pathways: restoration of host immune responses and regulation of pyruvate metabolism. In this study, we further sought to explore host antiviral target genes regulated by miR-130a. We performed a RT² Profiler™ PCR array to identify the host antiviral genes regulated by miR-130a. The putative binding sites between miR-130a and its downregulated genes were predicted by miRanda. miR-130a and predicted target genes were over-expressed or knocked down by siRNA or CRISPR/Cas9 gRNA. Selected gene mRNAs and their proteins, together with HCV replication in JFH1 HCV-infected Huh7.5.1 cells were monitored by qRT-PCR and Western blot. We identified 32 genes that were significantly differentially expressed more than 1.5-fold following miR-130a overexpression, 28 of which were upregulated and 4 downregulated. We found that ATG5, a target gene for miR-130a, significantly upregulated HCV replication and downregulated interferon stimulated gene expression. miR-130a downregulated ATG5 expression and its conjugation complex with ATG12. ATG5 and ATG5-ATG12 complex affected interferon stimulated gene (ISG) such as MX1 and OAS3 expression and subsequently HCV replication. We concluded that miR-130a regulates host antiviral response and HCV replication through targeting ATG5 via the ATG5-dependent autophagy pathway.