Modeling subacute sclerosing panencephalitis in a transgenic mouse system: uncoding pathogenesis of disease and illuminating components of immune control.

Subacute sclerosing panencephalitis (SSPE) is a chronic neurodegenerative disease of the central nervous system (CNS) that afflicts eight to 20 individuals per one million of those who become infected with measles virus (MV). The six cardinal elements of SSPE are: (1) progressive fatal CNS disease developing several years after MV infection begins; (2) replication of MV in neurons; (3) defective nonreplicating MV in the CNS that is recoverable by co-cultivation with permissive tissue culture cells; (4) biased hypermutation of the MV recovered from the CNS with massive A to G (U to C) base changes primarily in the M gene of the virus; (5) high titers of antibody to MV; and (6) infiltration of B and T cells into the CNS. All these parameters can be mimicked in a transgenic (tg) mouse model that expresses the MV receptor, thus enabling infection of a usually uninfectable mouse in which the immune system is or is not manipulated. Utilization and analysis of such mice have illuminated how chronic measles virus infection of neurons can be initiated and maintained, leading to the SSPE phenotype. Further, an active role in prolonging MV replication while inhibiting its spread in the CNS can be mapped to a direct affect of the biased hypermutations (A to G changes) of the MV M gene in vivo.

Type I interferon during viral infections: multiple triggers for a multifunctional mediator.

Type I interferons (IFN-I) orchestrate numerous biological and cellular processes and are essential elements during host antiviral defense. After recognition of highly conserved virus signatures, a complex network of signaling events is rapidly initiated and leads to IFN-I synthesis. These cytokines directly induce a strong antiviral state and exert several immune-regulatory actions aimed at preventing virus spread. On the other hand, viruses evolved to evade or subvert the IFN-I system for their own benefit. In the present article, we review selective aspects of IFN-I induction and functions during several viral infections and discuss the beneficial and detrimental roles of IFN-I illustrated during lymphocytic choriomeningitis virus (LCMV) infection in its natural host, the mouse.

Molecular mimicry, microbial infection, and autoimmune disease: evolution of the concept.

Molecular mimicry is defined as similar structures shared by molecules from dissimilar genes or by their protein products. Either several linear amino acids or their conformational fit may be shared, even though their origins are separate. Hence, during a viral or microbe infection, if that organism shares cross-reactive epitopes for B or T cells with the host, then the response to the infecting agent will also attack the host, causing autoimmune disease. A variation on this theme is when a second, third, or repeated infection(s) shares cross-reactive B or T cell epitopes with the first (initiating) virus but not necessarily the host. In this instance, the secondary infectious agents increase the number of antiviral/antihost effector antibodies or T cells that potentiate or precipitate the autoimmune assault. The formation of this concept initially via study of monoclonal antibody or clone T cell cross-recognition in vitro through its evolution to in vivo animal models and to selected human diseases is explored in this mini-review.

Molecular and cellular mechanisms, pathogenesis, and treatment of insulin-dependent diabetes obtained through study of a transgenic model of molecular mimicry.

The portrait of autoimmune diabetes mellitus or type I diabetes can be copied by a transgenic model in which either the nucleoprotein (NP) or glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) is expressed in beta cells of the islets of Langerhans. In the absence of further environmental insult, diabetes does not occur. However, when LCMV or a dissimilar virus that shares cross-reactive T cell epitopes with LCMV initiates infection, diabetes ensues. If the self "viral" transgene is expressed only in the beta cells, then diabetes occurs acutely within 8 to 12 days. Specific antiviral (self) CD8 T cells are mandatory for disease, but CD4 T cells are not. In this instance, diabetes can occur in the absence of infection if interferon gamma or B7.1 molecules are also expressed in the islets but not when IL-2, IL-4, IL-10, or IL-12 is similarly expressed. In contrast, both CD8 and CD4 antiviral (self) specific T cells are required when the self "viral" transgene is expressed concomitantly in beta cells and in the thymus. In this instance, infection by LCMV or cross-reacting virus is essential to cause diabetes. Further, the time from onset of infection until disease depends, in part, on the host's MHC background and its quantitative influence on negative selection of high-avidity antiviral (self) T cells. Knowledge of the cells, their numbers, and the molecules required to cause diabetes allows the design of successful strategies to treat and prevent the autoimmune disease.

Infection of dendritic cells by lymphocytic choriomeningitis virus.

Dendritic cells (DCs) comprise the major antigen-presenting cells (APCs) of the host, uniquely programmed to stimulate immunologically naïve T lymphocytes. Viruses that can target and disorder the function of these cells enjoy a selective advantage. The cellular receptor for lymphocytic choriomeningitis virus (LCMV), Lassa fever virus (LFV), and several other arenaviruses is alpha-dystroglycan (alpha-DG). Among cells of the immune system, CD11c+ and DEC-205+ DCs primarily and preferentially express alpha-DG. By selection, strains and variants of LCMV generated as quasi-species that bind alpha-DG with high affinity replicate in the majority of CD11c+ and DEC-205+ (>75%) DCs, causing a generalized immunosuppression, and establish a persistent infection. In contrast, viral strains and variants that bind with low affinity to alpha-DG display minimal replication in CD11c+ and DEC-205+ DCs (<10%), rarely replicate in the white pulp, and generate a robust anti-LCMV CTL response that clears the virus infection. Hence, receptor-virus interaction on DCs in vivo is an essential step in the initiation of virus-induced immunosuppression and viral persistence. Investigation into the mechanism of how virus-infected DCs cause immunosuppression reveals loss of MHC class II surface expression and costimulatory molecules on surface of such DCs. As a consequence DCs are unable to act as APCs, initiate immune responses, and have a defect in migration into the T cell area. These data indicate that LCMV infection influences DC maturation and migration, leading to decreased T cell stimulatory capacity of DCs, events essential for the initiation of immune responses. Because several other viruses known to cause immunosuppression (HIV, measles) interact with DCs, the observations noted here are likely a common selective mechanism by which viruses also are able to evade the host's immune system.