Inhibition of Foot-and-Mouth Disease Virus Replication by Hydro-alcoholic and Aqueous-Acetic Acid Extracts of Alhagi maurorum: Antiviral activity of of Alhagi maurorum against FMDV

Foot-and-mouth disease (FMD) is a major infectious disease of cloven-hoofed animals that is caused by the FMD virus (FMDV). This disease has significantly adverse economic impacts; therefore, rapid control measures are urgent. Hydro-alcoholic and aqueous-acetic acid extracts of A. maurorum were prepared and their anti-FMDV activity was evaluated. Gas Chromatography–Mass Spectrometry (GC-MS) analysis of methanolic and ethanolic extracts was performed to find the likely active compounds of A. maurorum. The cytotoxicity of the extracts was assayed and the antiviral activity of them was evaluated by measuring the percentage of viable FMDV infected-cells via the MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide) assay at different stages of the virus replication cycle. The results indicated that the plant extracts exhibit antiviral activity against FMDV at all stages of the experiment, although the most significant effects were observed in virucidal and pre-treatment assays. GC-MS of the extracts resulted in the separation of 3 and 2 main peaks for the methanolic and ethanolic extracts respectively. The major compound was found to be 1, 2-Benzenedicarboxylic acid, diisooctyl ester. These findings represent the anti-FMDV activities of A. maurorum extracts at several stages of the virus replication cycle; therefore, it could be considered for the potential development of anti-FMDV therapeutics

Oncolytic therapy with recombinant vaccinia viruses targeting the interleukin-15 pathway elicits a synergistic response

We developed recombinant variants of oncolytic vaccinia virus LIVP strain expressing interleukin-15 (IL-15) or its receptor subunit alpha (IL-15Rα) to stimulate IL-15-dependent immune cells. We evaluated their oncolytic activity either alone or in combination with each other in vitro and in vivo using the murine CT26 colon carcinoma and 4T1 breast carcinoma models. We demonstrated that the admixture of these recombinant variants could promote the generation of the IL-15/IL-15Rα complex. In vitro studies indicated that 4T1 breast cancer cells were more susceptible to the developed recombinant viruses. In vivo studies showed significant survival benefits and tumor regression in 4T1 breast cancer syngeneic mice that received a combination of LIVP-IL15-RFP with LIVP-IL15Ra-RFP. Histological analysis showed recruited lymphocytes at the tumor region, while no harmful effects to the liver or spleen of the animals were detected. Evaluating tumor-infiltrated lymphocytes represented profound activation of cytotoxic T cells and macrophages in mice receiving combination therapy. Thus, our experiments showed superior oncolytic effectiveness of simultaneous injection of LIVP-IL15-RFP and LIVP-IL15Ra-RFP in breast cancer-bearing mice. The combined therapy by these recombinant variants represents a potent and versatile approach for developing new immunotherapies for breast cancer

Multiomic Profiling Identified EGF Receptor Signaling as a Potential Inhibitor of Type I Interferon Response in Models of Oncolytic Therapy by Vesicular Stomatitis Virus

Cancer cell lines responded differentially to type I interferon treatment in models of oncolytic therapy using vesicular stomatitis virus (VSV). Two opposite cases were considered in this study, glioblastoma DBTRG-05MG and osteosarcoma HOS cell lines exhibiting resistance and sensitivity to VSV after the treatment, respectively. Type I interferon responses were compared for these cell lines by integrative analysis of the transcriptome, proteome, and RNA editome to identify molecular factors determining differential effects observed. Adenosine-to-inosine RNA editing was equally induced in both cell lines. However, transcriptome analysis showed that the number of differentially expressed genes was much higher in DBTRG-05MG with a specific enrichment in inflammatory proteins. Further, it was found that two genes, EGFR and HER2, were overexpressed in HOS cells compared with DBTRG-05MG, supporting recent reports that EGF receptor signaling attenuates interferon responses via HER2 co-receptor activity. Accordingly, combined treatment of cells with EGF receptor inhibitors such as gefitinib and type I interferon increases the resistance of sensitive cell lines to VSV. Moreover, sensitive cell lines had increased levels of HER2 protein compared with non-sensitive DBTRG-05MG. Presumably, the level of this protein expression in tumor cells might be a predictive biomarker of their resistance to oncolytic viral therapy