Age-Dependent Pathogenesis of Murine Gammaherpesvirus 68 Infection of the Central Nervous System

Abstract

Gammaherpesvirus infection of the central nervous system (CNS) has been linked to various neurological diseases, including meningitis, encephalitis, and multiple sclerosis. However, little is known about the interactions between the virus and the CNS in vitro or in vivo. Murine gammaherpesvirus 68 (MHV-68 or (gamma)HV-68) is genetically related and biologically similar to human gammaherpesviruses, thereby providing a tractable animal model system in which to study both viral pathogenesis and replication. In the present study, we show the successful infection of cultured neuronal cells, microglia, and astrocytes with MHV-68 to various extents. Upon intracerebroventricular injection of a recombinant virus (MHV-68/LacZ) into 4-5-week-old and 9-10-week-old mice, the 4-5-week-old mice displayed high mortality within 5-7 days, while the majority of the 9-10-week-old mice survived until the end of the experimental period. Until a peak at 3-4 days post-infection, viral DNA replication and gene expression were similar in the brains of both mouse groups, but only the 9-10-week-old mice were able to subdue viral DNA replication and gene expression after 5 days post-infection. Pro-inflammatory cytokine mRNAs of tumor necrosis factor-alpha, interleukin 1beta, and interleukin 6 were highly induced in the brains of the 4-5-week-old mice, suggesting their possible contributions as neurotoxic factors in the agedependent control of MHV-68 replication of the CNS.

The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system

“…Both over-stimulation and attenuated expression of pro-inflammatory cytokines in suckling or weanling mice have been associated with poor disease outcome [10,29,177]. Likewise, differences in the function of immune cells between animals of different ages can influence the development of viral disease [59].…”

A Gammaherpesvirus Establishes Persistent Infection in Neuroblastoma Cells

“…Lytic gene expression, DNA replication, and virion production were concomitantly induced after treatment with TPA and sodium butyrate, but they were blocked after treatment with GCV. Taken together, these results suggest that both productive and latent infections may be established in neuroblastoma cells, which may account for persistent infection in the brain of infected mice (Cho et al, 2009;Kang et al, 2012). Because only few cell lines are available to study persistent infection of MHV-68 áå= îáíêç following ÇÉ= åçîç infection, MHV-68 infection in neuroblastoma cells may provide a valuable experimental system to investigate the various aspects of γHV latency by using functional genomics.…”

“…EBV infection has been linked to various neurological diseases such as aseptic meningitis, encephalitis, human immunodeficiency virus (HIV)-related primary central nervous system (CNS) lymphoma, and multiple sclerosis (MS) (Bossolasco et al, 2006;Said et al, 1997;Serafini et al, 2007). Consistent with the neurological pathogenesis of human gammaherpesvirus (γHV), murine gammaherpesvirus-68 (MHV-68 or also called γHV-68; a murine homolog of EBV) has also been reported to infect the brain and replicate in it as well as in various cell types derived from the CNS (Cho et al, 2009;Terry et al, 2000). Furthermore, our recent studies by noninvasive bioluminescence imaging of a Virus-Host Interactions Laboratory, Division of Biotechnology, Department of Biosystems and Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Korea *Correspondence: moonsong@korea.ac.kr recombinant MHV-68 expressing the firefly luciferase (M3FL) suggested that MHV-68 may persist in the brain following cerebral infection .…”

“…In contrast, cultured endothelial cells have been reported to sustain persistent ongoing productive infection with the extended viability of the infected cells, but not viral latency (Suarez and van Dyk, 2008). The brain is a potential site of viral persistency áå=îáîç ; therefore, it is notable that MHV-68 infection of murine neuroblastoma cells resulted in productive replication of MHV-68, but did not manifest any apparent signs of cell deaths during the course of infection (Cho et al, 2009). Here, we further characterized a unique pattern of MHV-68 infection in both murine and human neuroblastoma cells.…”

“…In our previous study, we showed that MHV-68 productively replicated in Neuro2A cells without inducing severe CPEs (Cho et al, 2009). To validate this observation, we conducted a kinetic study of MHV-68 infection in Neuro2A cells for 5 days using a recombinant virus expressing the enhanced green fluorescence protein (MHV-68/EGFP) in this study (Fig.…”