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PubMed1994

Involvement of the IRF-1 transcription factor in antiviral responses to interferons.

The mechanisms underlying interferon (IFN)-induced antiviral states are not well understood. Interferon regulatory factor-1 (IRF-1) is an IFN-inducible transcriptional activator, whereas IRF-2 suppresses IRF-1 action. The inhibition of encephalomyocarditis virus (EMCV) replication by IFN-alpha and especially by IFN-gamma was impaired in cells from mice with a null mutation in the IRF-1 gene (IRF-1-/- mice). The IRF-1-/- mice were less resistant than normal mice to EMCV infection, as revealed by accelerated mortality and a larger virus titer in target organs. The absence of IRF-1 did not clearly affect replication of two other types of viruses. Thus, IRF-1 is necessary for the antiviral action of IFNs against some viruses, but IFNs activate multiple activation pathways through diverse target genes to induce the antiviral state.

Animals↗
PubMed1974

Effects of some antiviral isatinisothiosemicarbazones on cellular and viral ribonucleic acid synthesis in Mengovirus-infected FL cells.

Three antiviral isatinisothiosemicarbazones strongly inhibited the incorporation of [(3)H]uridine into the ribonucleic acid (RNA) of FL cells as a consequence of the inhibition of uridine transport. After prelabeling of cells at a low temperature (1 h at 16 C) with uptake of [(3)H]uridine into the acid-soluble nucleotide pool, the later addition of the test compounds revealed only a small or negligible influence on host-directed RNA synthesis. The pulse-labeled soluble nucleotide pool of FL cells was sufficient to give a gradual increase in incorporation into RNA over a period of 7 h. With the same method of prelabeling at the beginning of the experiment, it was also possible to detect virus-induced RNA synthesis in the presence of actinomycin D. In this way the specific inhibitory action of the three isatinisothiosemicarbazones on viral RNA synthesis could be demonstrated.

Animals↗
PubMed2004

Theiler's virus infection: a model for multiple sclerosis.

Both genetic background and environmental factors, very probably viruses, appear to play a role in the etiology of multiple sclerosis (MS). Lessons from viral experimental models suggest that many different viruses may trigger inflammatory demyelinating diseases resembling MS. Theiler's virus, a picornavirus, induces in susceptible strains of mice early acute disease resembling encephalomyelitis followed by late chronic demyelinating disease, which is one of the best, if not the best, animal model for MS. During early acute disease the virus replicates in gray matter of the central nervous system but is eliminated to very low titers 2 weeks postinfection. Late chronic demyelinating disease becomes clinically apparent approximately 2 weeks later and is characterized by extensive demyelinating lesions and mononuclear cell infiltrates, progressive spinal cord atrophy, and axonal loss. Myelin damage is immunologically mediated, but it is not clear whether it is due to molecular mimicry or epitope spreading. Cytokines, nitric oxide/reactive nitrogen species, and costimulatory molecules are involved in the pathogenesis of both diseases. Close similarities between Theiler's virus-induced demyelinating disease in mice and MS in humans, include the following: major histocompatibility complex-dependent susceptibility; substantial similarities in neuropathology, including axonal damage and remyelination; and paucity of T-cell apoptosis in demyelinating disease. Both diseases are immunologically mediated. These common features emphasize the close similarities of Theiler's virus-induced demyelinating disease in mice and MS in humans.

Animals↗
PubMed2006

The gamma interferon (IFN-gamma) mimetic peptide IFN-gamma (95-133) prevents encephalomyocarditis virus infection both in tissue culture and in mice.

We have demonstrated previously that the C-terminal gamma interferon (IFN-gamma) mimetic peptide consisting of residues 95 to 133 [IFN-gamma(95-133)], which contains the crucial IFN-gamma nuclear localization sequence (NLS), has antiviral activity in tissue culture. Here we evaluate the efficacy of this peptide and its derivatives first in vitro and then in an animal model of lethal viral infection with the encephalomyocarditis (EMC) virus. Deletion of the NLS region from the IFN-gamma mimetic peptide IFN-gamma(95-133) resulted in loss of antiviral activity. However, the NLS region does not have antiviral activity in itself. Replacing the NLS region of IFN-gamma(95-133) with the NLS region of the simian virus 40 large T antigen retains the antiviral activity in tissue culture. IFN-gamma(95-133) prevented EMC virus-induced lethality in mice in a dose-dependent manner compared to controls. Mice treated with IFN-gamma(95-133) had no or low EMC virus titers in their internal organs, whereas control mice had consistently high viral titers, especially in the heart tissues. Injection of B8R protein, which is encoded by poxviruses as a defense mechanism to neutralize host IFN-gamma, did not inhibit IFN-gamma(95-133) protection against a lethal dose of EMC virus, whereas mice treated with rat IFN-gamma were not protected. The data presented here show that the IFN-gamma mimetic peptide IFN-gamma(95-133) prevents EMC virus infection in vivo and in vitro and may have potential against other lethal viruses, such as the smallpox virus, which encodes the B8R protein.

Amino Acid Sequence↗
PubMed2003

Major histocompatibility complex heterozygote superiority during coinfection.

Genes of the major histocompatibility complex (MHC) play a critical role in immune recognition, and many alleles confer susceptibility to infectious and autoimmune diseases. How these deleterious alleles persist in populations is controversial. One hypothesis postulates that MHC heterozygote superiority emerges over multiple infections because MHC-mediated resistance is generally dominant and many allele-specific susceptibilities to pathogens will be masked by the resistant allele in heterozygotes. We tested this hypothesis by using experimental coinfections with Salmonella enterica (serovar Typhimurium C5TS) and Theiler's murine encephalomyelitis virus (TMEV) in MHC-congenic mouse strains where one haplotype was resistant to Salmonella and the other was resistant to TMEV. MHC heterozygotes were superior to both homozygotes in 7 out of 8 comparisons (P = 0.0024), and the mean standardized pathogen load of heterozygotes was reduced by 41% over that of homozygotes (P = 0.01). In contrast, no heterozygote superiority was observed when the MHC haplotype combinations had similar susceptibility profiles to the two pathogens. This is the first experimental evidence for MHC heterozygote superiority against multiple pathogens, a mechanism that would contribute to the evolution of MHC diversity and explain the persistence of alleles conferring susceptibility to disease.

Alleles↗
PubMed2006

Infectious RNA isolated from the spinal cords of mice chronically infected with Theiler's murine encephalomyelitis virus.

The DA strain of Theiler's murine encephalomyelitis virus (TMEV) persistently infects cells of the spinal cord during the chronic phase of infection. Although in situ hybridization and reverse transcription-PCR have demonstrated the presence of viral RNA in the spinal cord, it has not been determined whether this RNA is infectious and, if so, how many PFU equivalents of virus the RNA can yield. In this study, we demonstrated that TMEV RNA isolated from the spinal cords of chronically infected mice is infectious and that there is at least 30-fold more infectious RNA than infectious virus in the spinal cords of these mice.

Animals↗
PubMed2006

CD1d mediates T-cell-dependent resistance to secondary infection with encephalomyocarditis virus (EMCV) in vitro and immune response to EMCV infection in vivo.

The innate and adaptive immune responses have evolved distinct strategies for controlling different viral pathogens. Encephalomyocarditis virus (EMCV) is a picornavirus that can cause paralysis, diabetes, and myocarditis within days of infection. The optimal innate immune response against EMCV in vivo requires CD1d. Interaction of antigen-presenting cell CD1d with distinct natural killer T-cell ("NKT") populations can induce rapid gamma interferon (IFN-gamma) production and NK-cell activation. The T-cell response of CD1d-deficient mice (lacking all NKT cells) against acute EMCV infection was further studied in vitro and in vivo. EMCV persisted at higher levels in CD1d-knockout (KO) splenocyte cultures infected in vitro. Furthermore, optimal resistance to repeat cycles of EMCV infection in vitro was also shown to depend on CD1d. However, this was not reflected in the relative levels of NK-cell activation but rather by the responses of both CD4(+) and CD8(+) T-cell populations. Repeated EMCV infection in vitro induced less IFN-gamma and alpha interferon (IFN-alpha) from CD1d-deficient splenocytes than with the wild type. Furthermore, the level of EMCV replication in wild-type splenocytes was markedly and specifically increased by addition of blocking anti-CD1d antibody. Depletion experiments demonstrated that dendritic cells contributed less than the combination of NK and NKT cells to anti-EMCV responses and that none of these cell types was the main source of IFN-alpha. Finally, EMCV infection in vivo produced higher levels of viremia in CD1d-KO mice than in wild-type animals, coupled with significantly less lymphocyte activation and IFN-alpha production. These results point to the existence of a previously unrecognized mechanism of rapid CD1d-dependent stimulation of the antiviral adaptive cellular immune response.

Acute Disease↗
PubMed1994

VCAM-1 is a receptor for encephalomyocarditis virus on murine vascular endothelial cells.

Murine VCAM-1 has been identified as a receptor for the D variant of encephalomyocarditis (EMC-D) virus on vascular endothelial cells from the heart. Monoclonal antibodies to VCAM-1 inhibited infection and lysis of endothelial cells with EMC-D virus. CHO cells transfected with the VCAM-1 gene were susceptible to EMC-D virus lysis, while control CHO cells transfected with the ELAM-1 gene were resistant. Similarly, 35S-labeled EMC-D virus bound to CHO-VCAM cells, and binding was inhibited with anti-VCAM-1 antibodies. Little or no radiolabeled virus bound to CHO-ELAM-1 cells.

Animals↗
PubMed1995

The in vivo antiviral activity of interleukin-12 is mediated by gamma interferon.

The injection of 20 ng of mouse interleukin-12 (IL-12) protects mice from a lethal infection with encephalomyocarditis virus. In vitro, an anti-gamma interferon (anti-IFN-gamma) monoclonal antibody but not an anti-IL-12 monoclonal antibody neutralizes the antiviral activity present in the supernatants of splenocytes stimulated with IL-12. Finally, IL-12 fails to protect 129 Sv/Ev IFN-gamma R0/0 mice against encephalomyocarditis virus infection. These results demonstrate that IL-12 exerts its antiviral activity through the induction of endogenous IFN-gamma.

Animals↗
PubMed1996

Mutational analysis of the mengovirus poly(C) tract and surrounding heteropolymeric sequences.

Previously, we described three mengovirus mutants derived from cDNA plasmids, containing shortened poly(C) tracts (C8, C12, and C13UC10), that exhibited strong attenuation for virulence in mice yet grew like wild-type virus in HeLa cells. Thirteen additional mutants hav now been constructed and characterized. Five of these differ only in poly(C) length, including one with a precise deletion of the tract. The other mutants bear deletions into the regions juxtaposing poly(C). Studies with HeLa cells confirm the essential dispensability of mengovirus's poly(C) tract but reveal a subtle, measurable correlation between poly(C) length and plaque diameter. Virulence studies with mice also revealed a strong correlation between poly(C) length and virulence. For the poly(C)-flanking mutations, the 15 bases directly 5' of the tract proved dispensable for virus viability, whereas the 20 to 30 bases 3' of poly(C) were critical for growth, thus implicating this region in the basal replication of the virus.

Animals↗
PubMed1997

Gain or loss of diabetogenicity resulting from a single point mutation in recombinant encephalomyocarditis virus.

Molecular pathogenic mechanisms for virus-induced disease have received considerable attention. Encephalomyocarditis (EMC) virus-induced diabetes in mice has been extensively studied to elucidate the cellular and molecular mechanisms involved in the development of this disease. In this study, we report for the first time that a single point mutation at nucleotide position 3155 or 3156 of the recombinant EMC viral genome, located on the major capsid protein VP1, which causes an amino acid change, results in the gain or loss of viral diabetogenicity. A G base at nucleotide position 3155 (alanine at amino acid position 776 of the EMC virus polyprotein [Ala776]; GCC) results in viral diabetogenicity, whereas the substitution of other bases at the same or next position results in a loss of viral diabetogenicity. This finding provides clear evidence that a point mutation at a critical site in a viral genome affects the ability of the virus to cause a cell-specific disease.

Alanine↗
PubMed1997

Possible role of macrophage-derived soluble mediators in the pathogenesis of encephalomyocarditis virus-induced diabetes in mice.

Pancreatic islets from DBA/2 mice infected with the D variant of encephalomyocarditis (EMC-D) virus revealed lymphocytic infiltration with moderate to severe destruction of pancreatic beta cells. Our previous studies showed that the major population of infiltrating cells at the early stages of infection is macrophages. The inactivation of macrophages prior to viral infection resulted in the prevention of diabetes, whereas activation of macrophages prior to viral infection resulted in the enhancement of beta-cell destruction. This investigation was initiated to determine whether macrophage-produced soluble mediators play a role in the destruction of pancreatic beta cells in mice infected with a low dose of EMC-D virus. When we examined the expression of the soluble mediators interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS) in the pancreatic islets, we found that these mediators were clearly expressed at an early stage of insulitis and that this expression was evident until the development of diabetes. We confirmed the expression of these mediators by in situ hybridization with digoxigenin-labelled RNA probes or immunohistochemistry in the pancreatic islets. Mice treated with antibody against IL-1beta or TNF-alpha or with the iNOS inhibitor aminoguanidine exhibited a significant decrease in the incidence of diabetes. Mice treated with a combination of anti-IL-1beta antibody, anti-TNF-alpha antibody, and aminoguanidine exhibited a greater decrease in the incidence of disease than did mice treated with one of the antibodies or aminoguanidine. On the basis of these observations, we conclude that macrophage-produced soluble mediators play an important role in the destruction of pancreatic beta cells, resulting in the development of diabetes in mice infected with a low dose of EMC-D virus.

Animals↗
PubMed1997

The shiverer mutation affects the persistence of Theiler's virus in the central nervous system.

Theiler's virus persists in the white matter of the spinal cord of genetically susceptible mice and causes primary demyelination. The virus persists in macrophages/microglial cells, but also in oligodendrocytes, the myelin-forming cells. Susceptibility/resistance to this chronic infection has been mapped to several loci including one tentatively located in the telomeric region of chromosome 18, close to the myelin basic protein locus (Mbp locus). To determine if the MBP gene influences viral persistence, we inoculated C3H mice bearing the shiverer mutation, a 20-kb deletion in the gene. Whereas control C3H mice were of intermediate susceptibility, C3H mice heterozygous for the mutation were very susceptible, and those homozygous for the mutation were completely resistant. This resistance was not immune mediated. Furthermore, C3H/101H mice homozygous for a point mutation in the gene coding for the proteolipid protein of myelin, the rumpshaker mutation, were resistant. These results strongly support the view that oligodendrocytes are a necessary viral target for the establishment of a persistent infection by Theiler's virus.

Animals↗
PubMed1998

NF-kappaB-mediated inhibition of apoptosis is required for encephalomyocarditis virus virulence: a mechanism of resistance in p50 knockout mice.

Apoptosis is a central host defense mechanism to eliminate virus-infected cells. Activation of NF-kappaB suppresses apoptosis following some types of stimulation in vitro. To test the physiological importance of this pathway in vivo, we studied murine encephalomyocarditis virus (EMCV) infection in mice and cell lines defective in NF-kappaB1 (p50) signaling. As previously reported, we find that all p50 knockout (p50 -/-) mice survive an EMCV infection that readily kills normal mice. By introducing the p50 mutation into interferon (IFN) type I receptor knockout (IFNRI -/-) mice, we find that this resistance is not mediated by IFN-beta as previously thought. While no IFNRI -/- mice survive, the double-knockout mice survive 60% of the time. The survival is tightly linked to the animals' ability to clear the virus from the heart in vivo. Using murine embryonic fibroblasts (MEF) derived from wild-type, p50 -/-, and p65 -/- embryos, we found that NF-kappaB is not required for the replication cycle of EMCV. However, during these experiments we observed that p50 -/- and p65 -/- MEF infected with EMCV undergo enhanced, premature cytotoxicity. Upon examination of this cell death, we found that EMCV infection induced both plasma membrane and nuclear changes typical of apoptosis in all cell lines. These apoptotic processes occurred in an accelerated and pronounced way in the NF-kappaB-defective cells, as soon as 6 h after infection, when virus is beginning to be released. Previously, only the RelA (p65) subunit of NF-kappaB has been shown to play a role in suppressing apoptosis. In our studies, we find that p50 is equally important in suppressing apoptosis during EMCV infection. Additionally, we show that suppression of apoptosis by NF-kappaB1 is required for EMCV virulence in vivo. The attenuation in p50 -/- mice can be explained by rapid apoptosis of infected cells which allows host phagocytes to clear infected cells before the viral burst leading to a reduction of the viral burden and survival of the mice.

Animals↗
PubMed1999

Viral load and a locus on chromosome 11 affect the late clinical disease caused by Theiler's virus.

Theiler's virus causes a persistent infection and a demyelinating disease of mice which is a model for multiple sclerosis. Susceptibility to viral persistence maps to several loci, including the interferon gamma locus. Inactivating the gene coding for the interferon gamma receptor makes 129/Sv mice susceptible to persistent infection and clinical disease, whereas inactivating the interferon gamma gene makes C57BL/6 mice susceptible to persistent infection but not to clinical disease. This difference in phenotype is due to the difference in genetic background. Clinical disease depends on high viral load and Tmevd5, a locus on chromosome 11. These results have consequences for the identification of viruses which might be implicated in multiple sclerosis.

Animals↗
PubMed1999

Prevention of encephalomyocarditis virus-induced diabetes in mice by inhibition of the tyrosine kinase signalling pathway and subsequent suppression of nitric oxide production in macrophages.

Macrophages comprise the major population of cells infiltrating pancreatic islets during the early stages of infection in DBA/2 mice by the D variant of encephalomyocarditis virus (EMC-D virus). Inactivation of macrophages prior to viral infection almost completely prevents EMC-D virus-induced diabetes. This investigation was initiated to determine whether a tyrosine kinase signalling pathway might be involved in the activation of macrophages by EMC-D virus infection and whether tyrosine kinase inhibitors might, therefore, abrogate EMC-D virus-induced diabetes in vivo. When isolated macrophages were infected with EMC-D virus, inducible nitric oxide synthase mRNA was expressed and nitric oxide was subsequently produced. Treatment of macrophages with the tyrosine kinase inhibitor tyrphostin AG126, but not tyrphostin AG556, prior to EMC-D virus infection blocked the production of nitric oxide. The infection of macrophages with EMC-D virus also resulted in the activation of the mitogen-activated protein kinases (MAPKs) p42(MAPK/ERK2)/p44(MAPK/ERK1), p38(MAPK), and p46/p54(JNK). In accord with the greater potency of AG126 than of AG556 in blocking EMC-D virus-mediated macrophage activation, the incidence of diabetes in EMC-D virus-infected mice treated with AG126 (25%) was much lower than that in AG556-treated (75%) or vehicle-treated (88%) control mice. We conclude that EMC-D virus-induced activation of macrophages resulting in macrophage-mediated beta-cell destruction can be prevented by the inhibition of a tyrosine kinase signalling pathway involved in macrophage activation.

Animals↗
PubMed1999

Baculovirus stimulates antiviral effects in mammalian cells.

Herein, we report that Autographa californica nucleopolyhedrovirus, a member of the Baculoviridae family, is capable of stimulating antiviral activity in mammalian cells. Baculoviruses are not pathogenic to mammalian cells. Nevertheless, live baculovirus is shown here to induce interferons (IFN) from murine and human cell lines and induces in vivo protection of mice from encephalomyocarditis virus infection. Monoclonal antibodies specific for the baculovirus envelope gp67 neutralize baculovirus-dependent IFN production. Moreover, UV treatment of baculovirus eliminates both infectivity and IFN-inducing activity. In contrast, the IFN-inducing activity of the baculovirus was unaffected by DNase or RNase treatment. These data demonstrate that IFN production can be induced in mammalian cells by baculovirus even though the cells fail to serve as a natural host for an active viral infection. Baculoviruses, therefore, provide a novel model in which to study at least one alternative mechanism for IFN induction in mammalian cells.

Animals↗