Factors that Control Susceptibility to Theiler's Murine Encephalomyelitis Virus

M ultiple sclerosis is an inflammatory disease that is characterized by immune damage to the myelin sheath surrounding axons in the brain and spinal cord. Accumulating damage to the myelin sheath results in demyelination of the axons and a broad array of symptoms. While the symptoms and pathology are well documented, the underlying immunological mechanisms are poorly understood. Theiler's murine encephalomyelitis virus (TMEV) induces a demyelinating disease in susceptible mice that has similarities to multiple sclerosis in humans and serves as a useful animal model to study the disease. In the current issue of Viral Immunology, Bowen and Olson have used this model to address the role of IFNγ in regulating the immune response during demyelination. Building on earlier studies demonstrating that the innate immune response affects development of TMEV-induced demyelinating disease, the authors now show that IFNγ-deficient mice have an altered innate immune response to TMEV-infection characterized by reduced expression of innate immune cytokines, especially type I interferons. Interestingly, administration of type I interferons, IFNα, and IFNβ, to TMEV-infected IFNγ- deficient mice during the innate immune response restored innate immune cytokine expression. These findings suggest that IFNγ plays an important role in the innate immune response to TMEV and directly affects the development of demyelinating disease. These and other breakthroughs will enhance our understanding of the immune mechanisms that underlie multiple sclerosis and help promote the development of more effective treatments in the future.

Several articles in this issue of Viral Immunology focus on our understanding of adaptive immunity and how it can be harnessed for vaccine development. Patch and colleagues have investigated the cellular immune response to foot-and-mouth disease virus (FMDV), an economically important disease of cloven-hoofed animals. The authors had previously reported that a modified adenovirus-vectored FMDV vaccine could induce FDMV-specific CTL activity in swine. They now show that these CTL are also induced following FMDV infection. Importantly, vaccinated animals showed delayed clinical disease and significantly suppressed viremia after FMDV infection. These results offer important new insights showing induction of CTL responses and demonstrate the potential to improving vaccine performance by targeting cellular immunity. Another significant livestock virus is infectious bronchitis virus (IBV) of chickens. Okino and colleagues have evaluated the antibody and cellular immune responses to IBV at mucosal sites of chickens following immunization with an attenuated vaccine. Their data indicate that mucosal IgG, IgA, and CD8+ T cell responses developed after vaccination and correlated with protection.

In addition to livestock infections, two articles in this issue address viruses of high clinical significance. Influenza virus is a major pathogen of humans for which we have only inadequate vaccines. The challenge posed by this virus is its variability that necessitates regular reformulation of the vaccine and yearly re-administration. Thus, there has been considerable emphasis on developing vaccines that target relatively invariable parts of the virus. In this regard, Kaminaka et al. present data on a universal influenza virus vaccine comprised of conserved matrix protein 2 (M2e) peptides and additional cysteine residues. Mice immunized with these peptides displayed enhanced antibody titers to M2e and protected mice against a lethal influenza virus challenge.

Another clinically significant virus in humans is respiratory syncytial virus (RSV), which causes severe lower respiratory tract infections in infants and the elderly. Noh et al. use a mouse model to show that intranasal administration of RSV glycoprotein core fragment to neonatal mice induces systemic humoral immune responses and protective immunity against RSV without causing damaging lung eosinophilia. This was true even when the vaccine was administered in the presence of high levels of RSV-specific maternal antibodies. The data suggest that this is a safe and effective vaccine strategy for the control of RSV in neonates.

Three additional articles in this issue of Viral Immunology discuss the development of antibodies in the context of infection, therapeutics, and diagnostics. Masrinoul and colleagues have tested human monoclonal antibodies specific for the viral nonstructural protein 1 (NS1) of Dengue virus (DENV). The authors show that high concentrations of one of the antibodies enhanced DENV infection in human monocytes, indicating that serotype-specific anti-NS1 antibodies are potentially involved in virus production.

Shimoni et al. have described a procedure to screen antibody-presenting phage libraries against native cell-surface proteins and used the method to isolate antibodies that selectively recognize the CCR5, which is the major co-receptor for human immunodeficiency virus entry. They argue that their procedure is applicable to screen antibody-presenting phage libraries against any cell-surface expressed proteins. Highly specific anti-CCR5 antibodies could be used for diagnostic or therapeutic purposes.

On the diagnostic front, Hassan et al. note that there is huge variation in the sensitivity of cytomegalovirus (CMV) DNA detection in dried blood spots. This is a problem for the detection of congenital cytomegalovirus in newborns and has prompted the authors to recommend additional testing of CMV IgM, to improve the retrospective laboratory diagnosis of congenital CMV.

Viral immunology continues to be the only journal that focuses exclusively on all aspects of this rapidly growing field. As illustrated by the current issue, the Journal provides an important forum for leading investigators worldwide and serves as a vehicle to highlight cutting-edge research on a wide range of viruses from a clinical, translational, or basic science perspective.