Abstract
X-linked severe combined immunodeficiency (XSCID) is caused by a genetic mutation within the common gamma chain (γc), an essential component of the cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. XSCID patients are most commonly treated with bone marrow transplants (BMT) to restore systemic immune function. However, BMT-XSCID humans and dogs remain at an increased risk for development of cutaneous papillomavirus (PV) infections and their associated neoplasms, most typically cutaneous papillomas. Since basal keratinocytes are the target cell for the initial PV infection, we wanted to determine if canine XSCID keratinocytes have a diminished antiviral cytokine response to poly(dA:dT) and canine papillomavirus-2 (CPV-2) upon initial infection. We performed quantitative RT-PCR for antiviral cytokines and downstream interferon stimulated genes (ISG) on poly(dA:dT) stimulated and CPV-2 infected monolayer keratinocyte cultures derived from XSCID and normal control dogs. We found that XSCID keratinocytes responded similarly to poly(dA:dT) as normal keratinocytes by upregulating antiviral cytokines and ISGs. CPV-2 infection of both XSCID and normal keratinocytes did not result in upregulation of antiviral cytokines or ISGs at 2, 4, or 6 days post infection. These data suggest that the antiviral response to initial PV infection of basal keratinocytes is similar between XSCID and normal patients, and is not the likely source for the remaining immunodeficiency in XSCID patients.
Highlights
Severe combined immunodeficiency (SCID) represents a diverse group of genetic diseases that results in either absent or nonfunctional B and T lymphocytes
Primary keratinocyte cultures used in this study were established from 3 normal dogs and 2 bone marrow transplants (BMT)-X-linked SCID (XSCID) dogs
Primers for interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), cc, IL-2Ra, IL-4Ra, IL-7Ra, IL-9Ra, IL15Ra, and IL-21Ra were designed based upon the reference mRNA sequence listed in the NCBI database using commercially available primer design software (Oligo Primer Analysis Software, Molecular Biology Insights, Inc., West Cascade, CO, USA)
Summary
Severe combined immunodeficiency (SCID) represents a diverse group of genetic diseases that results in either absent or nonfunctional B and T lymphocytes. A similar increase in risk for cutaneous PV infections and development of associated papillomas has been observed in a research colony of dogs with a genetic mutation within cc [5] Their similar clinical and immunological phenotype to human patients has made them a successful animal model to study XSCID [6,7]. We first examined the response to a synthetic analog of viral dsDNA [poly(dA:dT)] and to CPV-2, looking at cytokines and interferon stimulated genes (ISG) that our laboratory has previously shown to be upregulated in normal keratinocytes in response to poly(dA:dT) [16] These included several of the cytosolic nucleic acid sensing pattern recognition receptors (PRRs): melanoma differentiation associated gene 5 (MDA5), retinoic acid-inducible gene I (RIG-I), and IFI16 (interferon inducible gene 16) [17]. We still wanted to investigate the response of CPV-2 infection in XSCID kerationcytes based upon the clinical observations of the seemingly increased susceptibility to PV infections in these XSCID patients
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