The influence of macrophage growth factors on Theiler’s Murine Encephalomyelitis Virus (TMEV) infection and activation of macrophages

Abstract

Macrophages are common targets for infection and innate immune activation by many pathogenic viruses including the neurotropic Theiler's Murine Encephalomyelitis Virus (TMEV). As both infection and innate activation of macrophages are key determinants of viral pathogenesis especially in the central nervous system (CNS), an analysis of macrophage growth factors on these events was performed. C3H mouse bone-marrow cells were differentiated in culture using either recombinant macrophage colony stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), inoculated with TMEV (BeAn) and analyzed at various times thereafter. Cytokine RNA and protein analysis, virus titers, and flow cytometry were performed to characterize virological parameters under these culture conditions. GM-CSF-differentiated macrophages showed higher levels of TMEV viral RNA and proinflammatory molecules compared to infected M-CSF-differentiated cells. Thus, GM-CSF increases both TMEV infection and TMEV-induced activation of macrophages compared to that seen with M-CSF. Moreover, while infectious viral particles decreased from a peak at 12h to undetectable levels at 48h post infection, TMEV viral RNA remained higher in GM-CSF- compared to M-CSF-differentiated macrophages in concert with increased proinflammatory gene expression. Analysis of a possible basis for these differences determined that glycolytic rates contributed to heightened virus replication and proinflammatory cytokine secretion in GM-CSF compared to M-CSF-differentiated macrophages. In conclusion, we provide evidence implicating a role for GM-CSF in promoting virus replication and proinflammatory cytokine expression in macrophages, indicating that GM-CSF may be a key factor for TMEV infection and the induction of chronic TMEV-induced immunopathogenesis in the CNS.

Facets of Theiler’s Murine Encephalomyelitis Virus-Induced Diseases: An Update

“…Microglia and macrophages play a crucial role in the initiation and progression of TMEV-induced demyelination as effector cells and a source of immunomodulatory mediators [21,54,185,186]. The onset of virus-induced demyelination is associated with a dominating polarization of macrophages into pro-inflammatory M1 subtypes, while mounting M2 polarization together with continuous high M1-related gene expression can be found during the chronic-progressive phase [185].…”

Impact of Astrocyte Depletion upon Inflammation and Demyelination in a Murine Animal Model of Multiple Sclerosis

“…After intracerebral infection of susceptible mice with a low neurovirulent TME virus (TMEV) strain (like BeAn), animals develop a biphasic disease that consists of an acute polioencephalitis, followed by a progressive demyelinating leukomyelitis with astrogliosis [25,29,31,32,33]. During the acute phase of TME, virus replication takes place in neurons, whereas the virus resides in oligodendrocytes and microglia/macrophages during the chronic phase [25,29,31,32,33,34]. Mechanisms leading to demyelination in the chronic phase of TME include delayed-type hypersensitivity, bystander demyelination, as well as virus mediated oligodendrocyte death [35,36,37].…”

The Role of Granulocyte-Macrophage Colony-Stimulating Factor in Murine Models of Multiple Sclerosis

“…The role of GM-CSF in less commonly used models of MS has not been well elucidated. One model that may depend on GM-CSF signaling is the Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) [77]. Theiler's murine virus is an enteric commensal in most mouse stains; however, when injected via intracranial injection into susceptible mice, such as SJL/J mice, the result is a chronic and progressive demyelinating disease [78,79].…”

“…One study suggested that GM-CSF may play a role in promoting pathology in this model. Bone marrow cells stimulated with GM-CSF were infected with TMEV, and the presence of GM-CSF was found to promote virus replication and the production of proinflammatory cytokines, indicating that GM-CSF is important in inducing TMEV-IDD [77]. The importance of GM-CSF in this model further highlights the important role of GM-CSF in promoting neuroinflammation associated with immune cell infiltration into the CNS parenchyma, although additional in vivo studies need to be performed to further characterize the role of GM-CSF in this model of demyelinating disease.…”