Induction of resistance to viral infections in the domestic cat by stimulation of the immune system

[摘要] Broadening the understanding of mechanisms linked to innate immunity is of primordial importance in a time of continuous emergence of rapidly spreading viral diseases. The domestic cat represents an ideal model for the study of host-virus interactions, as it is an outbred species naturally susceptible to many viruses sharing biological properties with those affecting humans. Additionally, due to their acquisition of infallible transmission strategies, rapid propagation of feline viruses within a group is particularly difficult to inhibit, reflecting the challenges linked to the prevention of pandemics. The present work was designed to gain insights on the innate immune responses of the domestic cat to viruses, and to determine whether early antiviral mechanisms can be manipulated to enhance resistance to viral infection in this species. In a first phase, real-time polymerase chain reaction (PCR) systems were developed, enabling to measure the expression of feline genes considered to be hallmarks of innate responses to viral infection, including various interferon (IFN) ? and IFN? subtypes, IFN?, intracellular antiviral Myxovirus resistance (Mx) factor, natural killer (NK) cell stimulator IL-15 and effectors perforin and granzyme B, as well as Toll-like receptors (TLRs) 3, 7, 8 and 9. These tools could then be employed to evaluate innate immune parameters in both in vitro and in vivo models of infection, conferring valuable information not only regarding strength, breadth and kinetics of antiviral defences in feline cells, but also possible biological properties of important viruses affecting the cat. In a further step, the newly developed PCR assays were utilized to assess the immunomodulatory potential of various immune response modifiers (IRMs) in feline cells in vitro. The IRMs mimicking natural viral components were selected, namely Poly IC and Resiquimod (R-848), artificial models of viral dsRNA and ssRNA, as well as dSLIM? and ODN 2216, synthetic oligonucleotides containing several unmethylated CpG motifs. Although all analysed IRMs positively modulated the innate immune state of treated peripheral mononuclear cells (PBMCs), ODN 2216 induced by far the most potent response: this molecule not only altered the gene expression profile of feline PBMCs in an antiviral orientation, but also significantly enhanced the proliferation of these immune cells and increased the presence on their surface of co-stimulatory molecules necessary for the diffusion of immunological defence signals. Moreover, when incubated in vitro with target cells of epithelial and fibroblastic origin, the supernatants of ODN 2216-stimulated PBMCs not only induced high production of intracellular antiviral proteins in these cells but also inhibited the replication of five feline viruses, namely the feline calici- (FCV), herpes- (FHV), parvo- (FPV), corona- (FCoV) and leukemia (FeLV) viruses. Altogether, this study procures a better understanding of innate antiviral mechanisms in an outbred species and highlights the promising potential of CpG-containing molecules such as ODN 2216 to protect domestic cats against a broad range of virus infections. Further in vitro and in vivo investigations will determine the feasibility of stimulation of the innate immune system by such molecules to prevent viral propagation in humans, cats and other species.

[发布机构] University of Zurich

[效力级别] 570 Life sciences

[关键词] Department of Farm Animals;570 Life sciences;biology;630 Agriculture