Abstract
Neurotropic viruses target the brain and contribute to neurologic diseases. C-type lectin receptors (CLRs) are pattern recognition receptors that recognize carbohydrate structures on endogenous molecules and pathogens. The myeloid CLR dendritic cell immunoreceptor (DCIR) is expressed by antigen presenting cells and mediates inhibitory intracellular signalling. To investigate the effect of DCIR on neurotropic virus infection, mice were infected experimentally with Theiler’s murine encephalomyelitis virus (TMEV). Brain tissue of TMEV-infected C57BL/6 mice and DCIR−/− mice were analysed by histology, immunohistochemistry and RT-qPCR, and spleen tissue by flow cytometry. To determine the impact of DCIR deficiency on T cell responses upon TMEV infection in vitro, antigen presentation assays were utilised. Genetic DCIR ablation in C57BL/6 mice was associated with an ameliorated hippocampal integrity together with reduced cerebral cytokine responses and reduced TMEV loads in the brain. Additionally, absence of DCIR favoured increased peripheral cytotoxic CD8+ T cell responses following TMEV infection. Co-culture experiments revealed that DCIR deficiency enhances the activation of antigen-specific CD8+ T cells by virus-exposed dendritic cells (DCs), indicated by increased release of interleukin-2 and interferon-γ. Results suggest that DCIR deficiency has a supportive influence on antiviral immune mechanisms, facilitating virus control in the brain and ameliorates neuropathology during acute neurotropic virus infection.
Highlights
Neurotropic viruses target the brain and can cause asymptomatic or acute and fatal diseases[1,2]
Two-way analysis of variance (ANOVA) yielded a significant effect of dendritic cell immunoreceptor (DCIR) deficiency on neuronal integrity determined by histology (HE score; p = 0.0008) and immunohistochemistry (NeuN+ area/mm[2], p = 0.0006), as well as on Theiler’s murine encephalomyelitis virus (TMEV) load (TMEV+ cells/mm[2], p = 0.0257)
The accelerated TMEV elimination observed in the brain of DCIR−/− mice suggests an enhanced antiviral immune response
Summary
Neurotropic viruses target the brain and can cause asymptomatic or acute and fatal diseases[1,2]. C57BL/6 mice mount early robust antiviral immune responses, but are prone to develop hippocampal injury with neuronal loss during the acute infection p hase[1,9]. Innate immune responses during the initial phase significantly contribute to the development of antiviral T cell responses and virus elimination in TMEV-infected m ice[13,14,15]. Surveillance of virus infection and initiation of innate immune responses are mediated by pattern recognition receptors (PRRs) on professional antigen presenting cells (APCs), such as dendritic cells (DCs). The aim of the present study was to investigate DCIR-mediated effects on the balance of immune responses, virus load and neuropathology in Theiler’s murine encephalomyelitis (TME). Genetic ablation of DCIR indicates that receptor signalling contributes to neuroinflammation and brain injury in C57BL/6 mice following TMEV infection. In vitro studies reveal that DCIR deficiency enhanced T cell activation in a dendritic cell/T cell co-culture system
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