Abstract
Domestic cats are commonly affected by viral pathogens that induce lengthy infections with fatal outcomes. Prevention of viral propagation is of primordial importance in shelters and catteries, where cats from different backgrounds have narrow contacts. Oligonucleotides (ODN) containing cytosine-phosphate-guanosine motifs of class A (CpG-A) are highly potent synthetic inducers of innate antiviral mechanisms. The aim of this study was to test their ability to modulate innate immune responses and prevent viral replication as stand-alone agents in the domestic cat. CpG-A stimulation of feline peripheral blood mononuclear cells (PBMCs) enhanced their proliferation, increased the presence of co-stimulatory molecules on their surface and influenced their gene expression profiles in an antiviral orientation. Incubation of the supernatants of CpG-A stimulated PBMCs with feline cell lines of epithelial and fibroblastic origin induced expression of the antiviral myxovirus resistance (Mx) gene in these target cells, which also showed enhanced resistance to feline viruses from five distinct families, namely Coronaviridae, Herpesviridae, Caliciviridae, Parvoviridae, and Retroviridae. Most importantly, subcutaneous administration of CpG-A in domestic cats systemically increased the expression of Mx, reaching maximal levels within 24 h. Plasma from treated cats could furthermore inhibit viral replication in vitro. Altogether, our data highlight the promising potential of CpG-A to induce a preventive antiviral state in the cat and to protect feline populations against a broad range of virus infections.
Highlights
Alarmed TLR9 is the initial instigator of gene expression profiles that strongly support antiviral mechanisms: upregulation of costimulatory molecules major histocompatibility complex (MHC) II, B7.1 and B7.2 on the surface of stimulated cells provides them with a stronger antigen presenting potential [8,9] and production of cytokines such as type I interferon (IFN), interleukin (IL)-12, IFNγ, IL-6 and tumor necrosis factor (TNF)α, contribute to providing an optimal immune environment for the development of innate and adaptive responses against intracellular pathogens [10,11]
With the objective to test whether ODN 2216 could exert such properties in feline immune cells, the expression of B7.1 and MHCII was measured by flow cytometry in stimulated peripheral blood mononuclear cells (PBMCs) of the same eight cats as above
We show that ODN 2216, the first described CpG-A [12], can upregulate the expression of a series of genes in feline immune cells that play important roles in early responses to viruses
Summary
Feline viruses are of opportunistic character. In order to adapt to the solitary way of life of ancestral felids, these pathogens have acquired elaborate means to persist within their host population over the course of time. Innate pathogen recognition relies on a set of sensory molecules, the Toll-like receptors (TLRs), which enable the immediate reaction of specific immune cells to pathogen “danger signals”, the so-called pathogen-associated molecular patterns (PAMPs) [4]. Due to their abundance in all bacterial as well as some viral genomes, oligodeoxynucleotides (ODN) containing unmethylated cytosine–phosphate–guanosine (CpG) motifs are effectively recognized as PAMPs by the vertebrate innate immune system [5]. This enzyme is known to be directly regulated by the type I IFN, and its detection is readily used as marker for upregulation and biological activity of this cytokine family [19]
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