Streptococcus suis (S. suis) is a highly virulent zoonotic pathogen and causes severe economic losses to the swine industry worldwide. Public health security is also threatened by the rapidly growing antimicrobial resistance in S. suis. Therefore, there is an urgent need to develop new and safe antibacterial alternatives against S. suis. The green tea polyphenol epigallocatechin gallate (EGCG) with a number of potential health benefits is known for its antibacterial effect; however, the mechanism of its bactericidal action remains unclear. In the present, EGCG at minimal inhibitory concentration (MIC) showed significant inhibitory effects on S. suis growth, hemolytic activity, and biofilm formation, and caused damage to S. suis cells in vitro. EGCG also reduced S. suis pathogenicity in Galleria mellonella larvae in vivo. Metabolomics and proteomics analyses were performed to investigate the underlying mechanism of antibacterial activity of EGCG at MIC. Many differentially expressed proteins involved in DNA replication, synthesis of cell wall, and cell membrane, and virulence were down-regulated after the treatment of S. suis with EGCG. EGCG not only significantly reduced the hemolytic activity of S. suis but also down-regulated the expression of suilysin (Sly). The top three shared KEGG pathways between metabolomics and proteomics analysis were ABC transporters, glycolysis/gluconeogenesis, and aminoacyl-tRNA biosynthesis. Taken together, these data suggest that EGCG could be a potential phytochemical compound for treating S. suis infection.
Japanese encephalitis virus (JEV) infection causes host endoplasmic reticulum stress (ERS) reaction, and then induces cell apoptosis through the UPR pathway, invading the central nervous system and causing an inflammation storm. The endoplasmic reticulum stress inhibitor, 4-phenyl-butyric acid (4-PBA), has an inhibitory effect on the replication of flavivirus. Here, we studied the effect of 4-PBA on JEV infection both in vitro and vivo. The results showed that 4-PBA treatment could significantly decrease the titer of JEV, inhibit the expression of the JEV NS3 protein (in vitro, p < 0.01) and reduce the positive rate of the JEV E protein (in vivo, p < 0.001). Compared to the control group, 4-PBA treatment can restore the weight of JEV-infected mice, decrease the level of IL-1β in serum and alleviate the abnormalities in brain tissue structure. Endoplasmic reticulum stress test found that the expression level of GRP78 was much lower and activation levels of PERK and IRE1 pathways were reduced in the 4-PBA treatment group. Furthermore, 4-PBA inhibited the UPR pathway activated by NS3, NS4b and NS5 RdRp. The above results indicated that 4-PBA could block JEV replication and inhibit ER stress caused by JEV. Interestingly, 4-PBA could reduce the expression of NS5 by inhibiting transcription (p < 0.001), but had no effect on the expression of NS3 and NS4b. This result may indicate that 4-PBA has antiviral activity independent of the UPR pathway. In summary, the effect of 4-PBA on JEV infection is related to the inhibition of ER stress, and it may be a promising drug for the treatment of Japanese encephalitis.
Streptococcus suis (S. suis) is one of the most important zoonotic pathogens that threaten the lives of pigs and humans. Even worse, the increasingly severe antimicrobial resistance in S. suis is becoming a global issue. Therefore, there is an urgent need to discover novel antibacterial alternatives for the treatment of S. suis infection. In this study, we investigated theaflavin (TF1), a benzoaphenone compound extracted from black tea, as a potential phytochemical compound against S. suis. TF1 at MIC showed significant inhibitory effects on S. suis growth, hemolytic activity, and biofilm formation, and caused damage to S. suis cells in vitro. TF1 had no cytotoxicity and decreased adherent activity of S. suis to the epithelial cell Nptr. Furthermore, TF1 not only improved the survival rate of S. suis-infected mice but also reduced the bacterial load and the production of IL-6 and TNF-α. A hemolysis test revealed the direct interaction between TF1 and Sly, while molecular docking showed TF1 had a good binding activity with the Glu198, Lys190, Asp111, and Ser374 of Sly. Moreover, virulence-related genes were downregulated in the TF1-treated group. Collectively, our findings suggested that TF1 can be used as a potential inhibitor for treating S. suis infection in view of its antibacterial and antihemolytic activity.
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