Pralatrexate inhibited the replication of varicella zoster virus and vesicular stomatitis virus: An old dog with new tricks.

Varicella zoster virus (VZV) is associated with herpes zoster (HZ) or herpes zoster ophthalmicus (HZO). All antiviral agents currently licensed for the management of VZV replication via modulating different mechanisms, and the resistance is on the rise. There is a need to develop new antiviral agents with distinct mechanisms of action and adequate safety profiles. Pralatrexate (PDX) is a fourth-generation anti-folate agent with an inhibitory activity on folate (FA) metabolism and has been used as an anti-tumor drug. We observed that PDX possessed potent inhibitory activity against VZV infection. In this study, we reported the antiviral effects and the underlying mechanism of PDX against VZV infection. The results showed that PDX not only inhibited VZV replication in vitro and in mice corneal tissues but also reduced the inflammatory response and apoptosis induced by viral infection. Furthermore, PDX treatment showed a similar anti-VSV inhibitory effect in both in vitro and in vivo models. Mechanistically, PDX inhibited viral replication by interrupting the substrate supply for de novo purine and thymidine synthesis. In conclusion, this study discovered the potent antiviral activity of PDX with a novel mechanism and presented a new strategy for VZV treatment that targets a cellular metabolic mechanism essential for viral replication. The present study provided a new insight into the development of broad-spectrum antiviral agents.

FOLR1-induced folate deficiency reduces viral replication via modulating APOBEC3 family expression.

Folate receptor alpha (FOLR1) is vital for cells ingesting folate (FA). FA plays an indispensable role in cell proliferation and survival. However, it is not clear whether the axis of FOLR1/FA has a similar function in viral replication. In this study, we used vesicular stomatitis virus (VSV) to investigate the relationship between FOLR1-mediated FA deficiency and viral replication, as well as the underlying mechanisms. We discovered that FOLR1 upregulation led to the deficiency of FA in HeLa cells and mice. Meanwhile, VSV replication was notably suppressed by FOLR1 overexpression, and this antiviral activity was related to FA deficiency. Mechanistically, FA deficiency mainly upregulated apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) expression, which suppressed VSV replication in vitro and in vivo. In addition, methotrexate (MTX), an FA metabolism inhibitor, effectively inhibited VSV replication by enhancing the expression of APOBEC3B in vitro and in vivo. Overall, our present study provided a new perspective for the role of FA metabolism in viral infections and highlights the potential of MTX as a broad-spectrum antiviral agent against RNA viruses.

Folate metabolism negatively regulates OAS-mediated antiviral innate immunity via ADAR3/endogenous dsRNA pathway.

BACKGROUND: Folate (FA) is an essential cofactor in the one-carbon (1C) metabolic pathway and participates in amino acid metabolism, purine and thymidylate synthesis, and DNA methylation. FA metabolism has been reported to play an important role in viral replications; however, the roles of FA metabolism in the antiviral innate immune response are unclear. OBJECTIVE: To evaluate the potential regulatory role of FA metabolism in antiviral innate immune response, we establish the model of FA deficiency (FAD) in vitro and in vivo. The molecular and functional effects of FAD on 2'-5'-oligoadenylate synthetases (OAS)-associated antiviral innate immunity pathways were assessed; and the potential relationship between FA metabolism and the axis of adenosine deaminases acting on RNA 3 (ADAR3)/endogenous double-stranded RNA (dsRNA)/OAS was further explored in the present study, as well as the potential translatability of these findings in vivo. METHODS: FA-free RPMI 1640 medium and FA-free feed were used to establish the model of FAD in vitro and in vivo. And FA and homocysteine (Hcy) concentrations in cell culture supernatants and serum were used for FAD model evaluation. Ribonucleoprotein immunoprecipitation assay was used to enrich endogenous dsRNA, and dot-blot was further used for quantitative analysis of endogenous dsRNA. Western-blot assay, RNA isolation and quantitative real-time PCR, immunofluorescence assay, and other molecular biology techniques were used for exploring the potential mechanisms. RESULTS: In this study, we observed that FA metabolism negatively regulated OAS-mediated antiviral innate immune response. Mechanistically, FAD induced ADAR3, which interacted with endogenous dsRNA, to inhibit deaminated adenosine (A) being converted into inosine (I), leading to the cytoplasmic accumulation of dsRNA. Furthermore, endogenous dsRNA accumulated in cytoplasm triggered the host immune activation, thus promoting the expression of OAS2 to suppress the replication of viruses. Additionally, injection of 8-Azaadenosine to experimental animals, an A-to-I editing inhibitor, efficiently enhanced OAS-mediated antiviral innate immune response to reduce the viral burden in vivo. CONCLUSIONS: Taken together, our present study provided a new perspective to illustrate a relationship between FA metabolism and the axis of ADAR3/endogenous dsRNA/OAS, and a new insight for the treatment of RNA viral infectious diseases by targeting the axis of ADAR3/endogenous dsRNA/OAS.

The potential roles of interleukin-25 in infectious diseases.

Interleukin-25 (IL-25), also known as IL-17E, is a recently identified cytokine of the IL-17 family. Numerous studies illustrated that the expression of IL-25 is regulated by multiple pathogens, including parasitic, viral, and bacterial infections. IL-25 has a dual function in infectious diseases. On the one hand, IL-25 activates type 2 immunity via the relevant cytokines, including IL-4, IL-5, and IL-13, which are associated with the development of pathogenic infection-related allergic diseases. On the other hand, IL-25 involves in the recruitment of group 2 innate lymphoid cells (ILC2) to enhanced T helper 2 (Th2) cell differentiation, which are important to the clearance of pathogens. However, the precise roles of IL-25 in infectious diseases remain largely unknown. Thus, the current review will shed light on the pivotal roles of IL-25 in infectious diseases.

Nacre-biomimetic graphene oxide paper intercalated by phytic acid and its ultrafast fire-alarm application.

A novel nacre-like flame-retardant paper based on graphene oxide (GO), and phytic acid (PTA) is fabricated via evaporation-induced self-assembly. This facile method is time saving and low energy consuming. A facile approach is proposed to improve thermal oxidative stability of GO paper by in situ phosphorus doping during flame exposure. Then fire-alarm system is designed based on the high-temperature thermal reduction characteristic of GO. The GO paper functionalized with PTA (GO-PTA) can provide ultrasensitive, reliable and longtime fire early-warning signal. Fire alarm can be triggered at approximately 0.50 s when GO-PTA samples are attacked by fire. Phosphorus atoms are in situ doped into graphene layers during fire exposure, endowing GO-PTA paper with outstanding thermal oxidative stability, and thus alarm duration time of GO is greatly improved. The work develops advanced fire detection and early-warning sensors that provide reliable and continuous signals, which provide more available time for fire evacuation.