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


Robert-Tissot, C. Induction of resistance to viral infections in the domestic cat by stimulation of the immune system. 2011, University of Zurich, Vetsuisse Faculty.

Abstract

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.

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.

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Additional indexing

Item Type:Dissertation
Referees:Lutz H, Hübscher U, Hengartner H, Ackermann M, Sonderegger P
Communities & Collections:05 Vetsuisse Faculty > Veterinary Clinic > Department of Farm Animals
Dewey Decimal Classification:570 Life sciences; biology
630 Agriculture
Language:English
Date:2011
Deposited On:15 Mar 2012 21:44
Last Modified:05 Apr 2016 15:39
Number of Pages:163
Related URLs:http://opac.nebis.ch/F/?local_base=NEBIS&CON_LNG=GER&func=find-b&find_code=SYS&request=006955434
Permanent URL: https://doi.org/10.5167/uzh-59752

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