Thomas E. Lane

Coxsackievirus B3-Induced Myocarditis : Perforin Exacerbates Disease, But Plays No Detectable Role in Virus Clearance

Viral myocarditis is remarkably common, being detected in approximately 1% of unselected asymptomatic individuals. Many cases are attributable to enteroviral infection, and in particular to coxsackievirus B3. The underlying pathogenesis is controversial, but most studies admit the important immunopathological role of infiltrating CD8+ (cytotoxic) T lymphocytes (CTLs). We have previously shown that CTLs play conflicting roles in coxsackievirus B (CVB) myocarditis; they assist in controlling virus replication, but also are instrumental in causing the extensive inflammatory disease, which often results in severe myocardial scarring. A role for perforin, the major CTL cytolytic protein, in CVB myocarditis has been suggested, but never proven. In the present study we use perforin knockout (PKO) mice to show that perforin plays a major role in CVB infection; in broad terms, perforin is important in immunopathology, but not in CVB clearance. For example, PKO mice are better able to withstand a normally lethal dose of CVB (100% survival of PKO mice compared with 90% death in +/+ littermates). In addition, PKO mice given a nonlethal dose of CVB develop only a mild myocarditis, whereas their perforin+ littermates have extensive myocardial lesions. The myocarditis in PKO mice resolves more quickly, and these mice show minimal histological sequelae; in contrast, late in disease the perforin+ mice develop severe myocardial fibrosis. PKO mice, despite lacking this major CTL effector function, can control the infection and eradicate the virus; growth kinetics and peak CVB titers are indistinguishable in PKO and perforin+ mice. Therefore, the immunopathological and antiviral effects of CTLs can be uncoupled by ablation of perforin; this offers a promising target for therapy of myocarditis. Furthermore, we evaluate the possible roles of apoptosis, and of chemokine expression, in CVB infection. In perforin+ mice, apoptotic cells are detected within the inflammatory infiltrate, whereas in their PKO counterparts, apoptotic myocyte nuclei are seen. Chemokine expression in both PKO and perforin+ mice precedes and parallels the course of myocarditis. Several chemokines are detectable earlier in PKO mice than in perforin+ mice, but PKO mice show reduced peak levels, and chemokine expression decays sooner. In particular, MIP-1alpha expression is barely detectable at any time point in PKO mice, but it is readily identified in perforin+ animals, peaking just before the time of maximal myocarditis; this is particularly interesting, given that MIP-1alpha knockout mice are resistant to CVB myocarditis, but remain able to control viral infection. Thus, the chemokine pathway offers a second route of intervention to diminish myocarditis and its sequelae, while permitting the host to eradicate the virus.

Cutting Edge: Inhibition of Hepatitis B Virus Replication by Activated NK T Cells Does Not Require Inflammatory Cell Recruitment to the Liver

We have previously reported that intrahepatic NK T cells activated by α-galactosylceramide inhibit hepatitis B virus replication noncytopathically in the liver of transgenic mice. This effect is mediated by antiviral cytokines directly produced by activated NK T cells and/or by other cytokine-producing inflammatory cells that are recruited into the liver. In this study, we demonstrated that IFN-γ produced by activated NK T cells induced parenchymal and nonparenchymal cells of the liver to produce high levels of CXC chemokine ligands 9 and 10, which mediated the intrahepatic recruitment of lymphomononuclear inflammatory cells. Recruitment of these cells was not necessary for the antiviral activity, indicating that direct activation of the intrahepatic resident NK T cell is sufficient to control viral replication in this model.

Murine coronavirus infection: a paradigm for virus-induced demyelinating disease.

A variety of neurological diseases in humans, including multiple sclerosis (MS), have been postulated to have a viral etiology. The use of animal models provides insights into potential mechanism(s) involved in the disease process. The murine coronavirus-induced demyelinating disease in rodents is one such model for demyelinating disease in humans.

Chemokine Responses in Virus-Induced Neurologic Disease

Publisher Summary This chapter focuses on the chemokine response to viral infection of the central nervous system (CNS) with an emphasis on the functional significance of chemokine expression as it relates to both host defense and neuropathology. Available evidence demonstrates clearly that viral infection of the CNS results in a dramatic increase in chemokine gene expression. Moreover, production of chemokines in response to infection is highly focused within areas of viral replication early in the disease process and areas of viral RNA persistence during the chronic stages of disease. Resident glial cells are capable of generating a robust chemokine response following viral infection in the absence of inflammatory cells suggesting that this response may reflect an innate CNS response against viral infection analogous to the response of phagocytic cells in the periphery. Differences in virus and cellular tropism are likely explanations for the slight differences in chemokine profiles and duration of expression observed in the different models. The non-ELR CXC chemokine CXCL10 is often the predominant chemokine expressed early following viral infection suggesting an important role as a sentinel molecule in initiating neuroinflammation. Based on the studies presented in this chapter, it is clear that targeting chemokines during either acute or chronic viral-induced CNS disease may offer exciting new insights into potentially novel interventional mechanisms in treating human neuroinflammatory diseases. Publisher Summary This chapter focuses on the chemokine response to viral infection of the central nervous system (CNS) with an emphasis on the functional significance of chemokine expression as it relates to both host defense and neuropathology. Available evidence demonstrates clearly that viral infection of the CNS results in a dramatic increase in chemokine gene expression. Moreover, production of chemokines in response to infection is highly focused within areas of viral replication early in the disease process and areas of viral RNA persistence during the chronic stages of disease. Resident glial cells are capable of generating a robust chemokine response following viral infection in the absence of inflammatory cells suggesting that this response may reflect an innate CNS response against viral infection analogous to the response of phagocytic cells in the periphery. Differences in virus and cellular tropism are likely explanations for the slight differences in chemokine profiles and duration of expression observed in the different models. The non-ELR CXC chemokine CXCL10 is often the predominant chemokine expressed early following viral infection suggesting an important role as a sentinel molecule in initiating neuroinflammation. Based on the studies presented in this chapter, it is clear that targeting chemokines during either acute or chronic viral-induced CNS disease may offer exciting new insights into potentially novel interventional mechanisms in treating human neuroinflammatory diseases.