Cholesterol 25-hydroxylase Porcine epidemic diarrhea virus 25-hydroxycholesterol Porcine transmissible gastroenteritis virus A B S T R A C TCholesterol 25-hydroxylase (CH25H) has been shown lately to be a host restriction factor that encodes an enzyme, which catalyzes the oxidized form of cholesterol to 25-hydroxycholesterol (25HC). A series of studies have shown that 25HC activity in hosts plays a vital role in inhibiting viral infection. In this study, we explored the antiviral effect of CH25H and 25HC on porcine epidemic diarrhea virus (PEDV), which causes high mortality rates in newborn piglets with severe diarrhea, and considerable financial loss in the swine industry worldwide. Our results showed that PEDV infection downregulated the expression of CH25H in Vero cells. An overexpression and knockdown assay indicated that CH25H has significant antiviral action against PEDV, and a CH25H mutant (CH25H-M) that lacks hydroxylase activity also retains antiviral activity to a lesser extent. Furthermore, 25HC had a broad-spectrum antiviral effect against different PEDV strains by blocking viral entry. In addition, CH25H and 25HC inhibited the replication of porcine transmissible gastroenteritis virus (TGEV). Taken together, CH25H as a natural host restriction factor could inhibit PEDV and TGEV infection.
Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important pathogens affecting many swine-producing regions. Current vaccination strategies and antiviral drugs provide only limited protection. PRRSV infection can cleave mitochondrial antiviral signaling protein (MAVS) and inhibit the induction of type I interferon. The antiviral effector molecules that are involved in host protective responses to PRRSV infection are not fully understood.Here, by using transcriptome sequencing, we found that a zinc finger antiviral protein, ZAP, is upregulated in MAVS-transfected Marc-145 cells and that ZAP suppresses PRRSV infection at the early stage of replication. We also found that the viral protein Nsp9, an RNA-dependent RNA polymerase (RdRp), interacts with ZAP. The interacting locations were mapped to the zinc finger domain of ZAP and N-terminal amino acids 150 to 160 of Nsp9. These findings suggest that ZAP is an effective antiviral factor for suppressing PRRSV infection, and they shed light on virus-host interaction.IMPORTANCE PRRSV continues to adversely impact the global swine industry. It is important to understand the various antiviral factors against PRRSV infection. Here, a zinc finger protein, termed ZAP, was screened from MAVS-induced antiviral genes by transcriptome sequencing, and it was found to remarkably suppress PRRSV replication and interact with PRRSV Nsp9. The zinc finger domain of ZAP and amino acids 150 to 160 of Nsp9 are responsible for the interaction. These findings expand the antiviral spectrum of ZAP and provide a better understanding of ZAP antiviral mechanisms, as well as virus-host interactions.
Porcine reproductive and respiratory syndrome virus (PRRSV) is a prevalent and endemic swine pathogen that causes significant economic losses in the global swine industry. Commercial vaccines provide limited protection against this virus, and no highly effective therapeutic drugs are yet available. In this study, we first screened a library of 386 natural products and found that xanthohumol (Xn), a prenylated flavonoid found in hops, displayed high anti-PRRSV activity by inhibiting PRRSV adsorption onto and internalization into cells. Transcriptome sequencing revealed that Xn treatment stimulates genes associated with the antioxidant response in the nuclear factor-erythroid 2-related factor 2 (Nrf2) signalling pathway. Xn causes increased expression of Nrf2, HMOX1, GCLC, GCLM, and NQO1 in Marc-145 cells. The action of Xn against PRRSV proliferation depends on Nrf2 in Marc-145 cells and porcine alveolar macrophages (PAMs). This finding suggests that Xn significantly inhibits PRRSV proliferation and decreases viral-induced oxidative stress by activating the Nrf2–HMOX1 pathway. This information should be helpful for developing a novel prophylactic and therapeutic strategy against PRRSV infection.
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