Gamma Interferon (IFN-γ) Receptor Null-Mutant Mice Are More Susceptible to Herpes Simplex Virus Type 1 Infection than IFN-γ Ligand Null-Mutant Mice

Abstract

Mouse strains with null mutations in the gamma interferon gene (Ifng) or the gamma interferon receptor gene (Ifngr) have been engineered. The use of these strains as animal models of viral and bacterial infections has enhanced our understanding of the role of gamma interferon (IFN-γ) in the host immune response. However, direct comparisons between Ifng−/− (GKO) and Ifngr−/− (RGKO) mice have been problematic because previously available strains of these mice have had different genetic backgrounds (i.e., C57BL/6 and BALB/c for GKO mice and 129/Sv//Ev for RGKO mice). To enable direct comparison of herpes simplex virus type 1 (HSV-1) infections in GKO and RGKO mice, we introduced the IFN-γ null mutation into the 129/Sv//Ev background. We report that, after HSV-1 inoculation, mortality was significantly greater in RGKO mice than in GKO mice (38 versus 23%,P = 0.0001). Similarly, the mortality from vaccinia virus challenge was significantly greater in RGKO mice than in GKO mice. With differences in genetic background excluded as a confounding issue, these results are consistent with the existence of an alternative ligand(s) for the IFN-γ receptor that is also capable of mediating protection against viral challenge.

The role of IL-12, IL-23 and IFN-γ in immunity to viruses

“…f An abnormal immune defense refers to a more severe disease or in vitro immune response in mice with impaired IFN␥-or IL-12-and IL-23-mediated response; GKO: IFN-␥ and IFN-␥R1KO mice; aG: anti-IFN␥ antibody-treated mice; 12KO: IL-12p40 and IL-12R␤1 mice; a12: anti-IL-12 antibody-treated mice. Infection routes: intranasal [43,61,67,68,69]; corneal [46,[49][50][51]55]; intradermal [47,52]; intraperitoneal [43,45,53,[54][55][56][57][58][59][60][61][62][63][64]66]. References for each experimental infection are indicated.…”

“…References for each experimental infection are indicated. The genetic backgrounds were: IFN-␥KO mice: Balb/C [46][47][48][49]57,65,66]; C57BL/6 [56]; 129/SV/E [50,51]; IFN-␥R1KO mice: 129/SV/E [44,45,[47][48][49][50][51][55][56][57]64,[66][67][68]; anti-IFN␥ antibody-treated mice: Balb/C [52,53,59,60,65] clinical outcomes were compared with those observed after administration of natural human tropic viruses permissive in mice, or their murine-tropic counterparts, to mice KO for the genes of several components of IL-12/IL-23 signaling (IL-12p40, IL-12R␤1 = 12KO) or IFN-␥ (IFN-␥, IFN-␥R1 = GKO), or treated with neutralizing mAb to IFN-␥ (aG) or IL-12 (a12).…”

“…Immune response was not compromised in the lungs of adenovirus-infected 12KO mice [43]. HSV experimental infection has been extensively described as pathogenic in both GKO [44][45][46][47][48][49][50][51] and anti-IFN-␥-treated mice [52][53][54], although viral replication of attenuated form of HSV in GKO mice was not different from congenic controls [55]. Experimental infections with murine cytomegalovirus (MCMV), a mouse-permissive (human nontropic) DNA virus, exacerbated infection in GKO [56][57][58], aG [54,59,60], 12KO [61,62] and a12 [63] mice (Table 1).…”

Critical role of the endogenous interferon ligand–receptors in type I and type II interferons response

“…In contrast to IFNGR1-deficient mice, 57 T lymphocytes isolated from IFN-c-58 or IFNGR2-59 deficient mice are not able to generate type 1 T helper (Th1) cells. Since the genetic background of mice may not be the sole cause for the functional disparity in the type II IFN system (IFN-c, IFNGR1 and IFNGR2), 60 we hypothesize that specific interactions between the members of the type I and type II IFN systems may in part explain those differences in T cells. A specific interaction between IFNGR2 and IFNAR1 has been reported.…”

Genomic structure and characterization of mRNA expression pattern of porcine interferon gamma receptor 1 gene

“…In human, deficiency in IFNGR1 gene is closely associated with severe susceptibility to poorly virulent mycobacteria (Dö ffinger et al, 2000;Jouanguy et al, 1999Jouanguy et al, , 1997Pierre-Audigier et al, 1997;Dorman et al, 1999), and polymorphisms in IFNGR1 promoter region have relevance to post kala-azar dermal leishmaniasis (Salih et al, 2007), and is a genetic aetiology of Mendelian susceptibility to mycobacterial diseases (Kong et al, 2009). Mice lacking IFNGR1 showed deficiencies in natural resistance to bacterial, parasitic, and viral infections Pearl et al, 2001;Van den Broek et al, 1995;Kamijo et al, 1993) and are more susceptible to herpes simplex virus infection than IFN-c ligand null-mutant mice (Cantin et al, 1999).…”