Browsing by Author "Thapa, Simrika"
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- ItemOpen AccessInduction of Antiviral Response Against Avian Infectious Laryngotracheitis Virus Infection(2015-06-09) Thapa, Simrika; Careem, Faizal; Czub, MarkusToll-like receptors (TLRs) recognize pathogen associated molecular patterns (PAMPs). The PAMPs that act as ligands for TLRs prompt downstream signalling leading to antimicrobial effects. However, the details of antiviral responses of lipotechoic acid (LTA) and CpG DNA, which act as ligands for TLR-2 and -21 respectively, elicited against avian viruses are scarce. We investigated whether in ovo delivery of LTA and CpG DNA induces antiviral responses against infectious laryngotracheitis virus (ILTV) infection in chickens. We found that in ovo delivery of these two ligands reduces ILTV infections in lungs pre- and post-hatch. However, only CpG DNA could reduce mortality and morbidity due to ILTV infection encountered post-hatch. The expression of IL-1β mRNA and increase of macrophage numbers in lungs were found to be correlates of observed antiviral responses. Thus, LTA and CpG DNA can be candidate TLR ligands worthy of further investigation for the control of ILTV infection in chickens.
- ItemOpen AccessNovel Approaches to Fight Prion Diseases(2020-04-29) Thapa, Simrika; Schaetzl, Hermann M.; Gilch, Sabine; Trang, Tuan; van Marle, Guido; Coffin, Carla S.; Telling, Glenn C.Prion diseases are fatal neurodegenerative disorders caused by PrPSc, the misfolded and infectious isoform of the cellular prion protein (PrPC). Currently, no preventive or therapeutic measures are available. In this work, we focused on therapeutic and prophylactic strategies against prion infections. In the therapeutic approach, we targeted cellular pathways and investigated the role of the quality control (QC) proteins, ERp57 and VIP36, on prion propagation. We found that the overexpression of ERp57 or VIP36 significantly reduced PrPSc levels in persistently prion-infected cells and decreased the susceptibility of uninfected cells to de novo prion infection. Moreover, lentiviral-mediated overexpression of ERp57 prolonged the survival of prion-infected mice. Mechanistically, we found that ERp57 overexpression reduced endoplasmic reticulum (ER) stress. To translate this proof-of-concept into potential drug therapy, we investigated the anti-prion effect of Sephin1, shown to prolong the phosphorylation of eIF2α and lower ER stress in the cells. In persistently prion-infected neuronal cells, we found that treatment with Sephin1 markedly reduced PrPSc levels. Moreover, Sephin1 reduced ER stress-induced PrP aggregates in cells and significantly extended the survival of prion-infected mice. These data provide the basis for targeting these cellular pathways as novel anti-prion therapy. In our prophylactic approach, we hypothesized that active vaccination is useful to contain chronic wasting disease (CWD), a contagious and expanding prion disease of cervids. Here, we vaccinated transgenic mice expressing elk prion protein with adjuvant CpG alone, or one of four recombinant PrP (rPrP) immunogens: deer dimer (Ddi), deer monomer (Dmo), mouse dimer (Mdi), and mouse monomer (Mmo). After challenging the animals with CWD prions intraperitoneally, we found that all vaccinated groups had longer survival times than the CpG control group. Interestingly, the Mmo-immunized group revealed that survival was extended by 60%. We also observed 28.4% and 24.1% prolongation in Dmo and Ddi groups, respectively. Our preliminary study in reindeer showed substantial humoral immune response induced by Mdi and Ddi, and the sera from the Ddi-vaccinated reindeer significantly reduced CWD prions in a cell culture model. Taken together, this study describes potential vaccine candidates against CWD. However, their protective effect in the natural cervid host needs further investigation.