Electronic Poster | Session 2

016 – Key role of the mCSF/CSF1R axis on microglia in the control of herpes simplex virus encephalitis

Olus Uyar (1) – Nataly Laflamme (2) – Marie-Christine Venable (1) – Karima Zarrouk (1) – Jocelyne Piret (1) – Serge Rivest (2) – Guy Boivin (1)
CHU de Québec, Université Laval, Axe Microbiologie-Immunologie et Infectiologie, Québec, Canada (1) – CHU de Québec, Université Laval, Axe Neurosciences, Québec, Canada (2)

Herpes simplex virus encephalitis (HSE) is the most common fatal sporadic viral encephalitis in Western countries. Despite antiviral therapy, most surviving patients suffer from significant neuronal damage caused by both viral replication and exaggerated immune response. However, the role of immune cells in the pathogenesis of HSE is not clearly established. Our hypothesis is that the immune response mediated by microglia in the early phase of HSE is a key factor for a better control of the infection. Firstly, we evaluated the effect of microglial activation by a colony stimulating factor (mCSF) treatment prior to herpes simplex virus 1 (HSV-1) infection. mCSF (40 µg/kg, IP) was administered to BALB/c mice on days 2 and 4 prior to intranasal infection with 2,500 PFUs of HSV-1. Our results showed that mCSF treatment increased significantly the survival rate of mice compared to saline (50% versus 10%). Viral titers and inflammatory cytokines (e.g., IL-6) were also significantly decreased in brain homogenates from mice treated with mCSF compared to saline on day 6 post-infection (p.i). A semi-quantitative analysis of the colocalization of Tmem-119 (marker of microglia) and CD68 (marker of phagocytosis) signals on brain sections indicated that mCSF increased the number of CD68+ microglial cells in the hypothalamic region compared to saline. Secondly, the receptor of mCSF (CSF1R) was conditionally depleted on microglial cells of CSF1R-loxP-CX3CR1-cre/ERT2 mice through induction by tamoxifen. Mice were then infected intranasally with 600,000 PFUs of HSV-1. The survival rates of CSF1R KO mice was significantly lower than that of wild type (WT; 100% versus 58%). Viral titers and inflammatory cytokines were significantly higher in mice depleted in CSF1R than in WT animals on day 6 p.i. Moreover, flow cytometry analysis revealed an important microgliosis in WT compared to CSF1R KO mice on day 4 p.i. with a lack of microglial proliferation. In conclusion, our results suggest that the proliferative signal mediated by mCSF/CSF1R axis on microglial cells in early stage of HSE is needed for a better control of the disease.