Coxsackievirus B3 (CVB3) is a human pathogen that causes acute and chronic infections, but an antiviral drug to treat these diseases has not yet been developed for clinical use. Several intracellular pathways are altered to assist viral transcription, RNA replication, and progeny release. Among these, fatty acid synthase (FAS) expression is increased. In order to test the potential of FAS inhibition as an anti-CVB3 strategy, several experiments were performed, including studies on the correlation of CVB3 replication and FAS expression in human Raji cells and an analysis of the time and dose dependence of the antiviral effect of FAS inhibition due to treatment with amentoflavone. The results demonstrate that CVB3 infection induces an up-regulation of FAS expression already at 1 h postinfection (p.i.). Incubation with increasing concentrations of amentoflavone inhibited CVB3 replication significantly up to 8 h p.i. In addition, suppression of p38 MAP kinase activity by treatment with SB239063 decreased FAS expression as well as viral replication. These data provide evidence that FAS inhibition via amentoflavone administration might present a target for anti-CVB3 therapy.
European swine influenza A viruses donated the matrix protein 2 as well as the neuraminidase (NA) gene to pandemic influenza A (H1N1) viruses that emerged in 2009. As a result, the latter became amantadine resistant and neuraminidase inhibitor (NAI) susceptible. These recent developments reflecting the close connection between influenza A virus infection chains in humans and pigs urge an antiviral surveillance within swine influenza A viruses. Here, NAI susceptibility of 204 serologically typed swine influenza A viruses of subtypes H1N1, H1N2, and H3N2 circulating in Germany between 1981 and 2008 was analyzed in chemiluminescence-based NA inhibition assays. Mean 50% inhibitory concentrations of oseltamivir and zanamivir indicate a good drug susceptibility of tested viruses. As found for human isolates, the oseltamivir and zanamivir susceptibility was subtype-specific. So, swine influenza A (H1N1) viruses were just as susceptible to oseltamivir as to zanamivir. In contrast, swine H1N2 and H3N2 influenza A viruses were more sensitive to oseltamivir than to zanamivir. Furthermore, reduction in plaque size and virus spread by both drugs was tested with selected H1N1 and H1N2 isolates in MDCK cells expressing similar amounts of α2.3- and α2.6-linked sialic acid receptors. Data obtained in cell culture-based assays for H1N1 isolates correlated with that from enzyme inhibition assays. But, H1N2 isolates that are additionally glycosylated at Asn158 and Asn163 near the receptor-binding site of hemagglutinin (HA) were resistant to both NAI in MDCK cells. Possibly, these additional HA glycosylations cause a misbalance between HA and NA function that hampers or abolishes NAI activity in cells.
The search for new antiviral strategies to treat influenza A virus (IAV) infections is one major international health care activity. Hereby, the IAV-caused misuse of cellular nuclear factor kappa B (NF-κB) signaling pathways in infected cells represents one target for antiviral therapy. In the present study, pyrrolidine dithiocarbamate (PDTC), which is known as an antioxidant and as an inhibitor of IAV-induced NF-κB activation, was studied in vivo. After the antiviral activity of PDTC was confirmed in MDCK cells, mice-infected with the mouse-adapted strain of IAV A/PR/8/34 (H1N1)-were treated intraperitoneally simultaneously with PDTC (75, 150, 200 mg/kg body weight). The influence of PDTC administrations was evaluated on viral replication and inflammatory reactions in lung tissue up to 14 days postinfection (p. i.). This therapy increased survival up to 80% and reduced IAV-caused weight loss and viral replication in lung tissue in a dose-dependent manner. Protective effects were less pronounced, if the therapy started later on during an ongoing IAV infection. In addition, simultaneous PDTC treatment also limited IAV-caused infiltration of immune cells as well as local interferon-γ expression in lung tissue. These results imply that PDTC decreases IAV-caused disease in mice significantly. Therefore, the development of drugs like PDTC that interfere with NF-κB signaling may represent a modern focus of anti-IAV therapy.
Coxsackievirus B3 (CVB3) is associated with several different acute and chronic forms of human disease, including myocarditis, aseptic meningitis, and pancreatitis. Moreover, CVB3 also infects immune cells like CD19+ B lymphocytes, but the viral uptake mechanism into these cells is not well understood. Therefore, primary murine and human CD19+ B cells were isolated by magnetic-activated cell separation technology and analyzed for virus receptor expression, antibody-dependent enhancement of viral infection, and different cellular surface proteins, that might be involved in mechanisms of viral uptake. Western blot analysis of these cells revealed no significant expression of the coxsackievirus-adenovirus receptor CAR. But incubation of CVB3 with serum dilutions, which exhibited binding but not neutralizing characteristics, increased viral uptake and replication significantly in a dose-dependent manner. Viral entry was reduced when Fc portions of immunoglobulins were blocked by protein A treatment. Moreover, the classical complement system rather than Fc-gamma-receptor-mediated mechanisms could be involved in viral uptake. Taken together, these data suggest an antibody-dependent enhancement of CVB3 infection of primary murine and human CD19+ B cells.
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