Abstract
The kinetics and distribution of infiltrating blood monocytes into the central nervous system and their involvement in the cerebral immune response together with resident macrophages, namely microglia, were evaluated in experimental herpes simplex virus 1 (HSV-1) encephalitis (HSE). To distinguish microglia from blood monocyte-derived macrophages, chimeras were generated by conditioning C57BL/6 recipient mice with chemotherapy regimen followed by transplantation of bone morrow-derived cells that expressed the green fluorescent protein. Mice were infected intranasally with a sub-lethal dose of HSV-1 (1.2x106 plaque forming units). Brains were harvested prior to and on days 4, 6, 8 and 10 post-infection for flow cytometry and immunohistochemistry analysis. The amounts of neutrophils (P<0.05) and «Ly6Chi» inflammatory monocytes (P<0.001) significantly increased in the CNS compared to non-infected controls on day 6 post-infection, which corresponded to more severe clinical signs of HSE. Levels decreased on day 8 for both leukocytes subpopulations (P<0.05 for inflammatory monocytes compared to non-infected controls) to reach baseline levels on day 10 following infection. The percentage of «Ly6Clow» patrolling monocytes significantly increased (P<0.01) at a later time point (day 8), which correlated with the resolution phase of HSE. Histological analysis demonstrated that blood leukocytes colonized mostly the olfactory bulb and the brainstem, which corresponded to regions where HSV-1 particles were detected. Furthermore, infiltrating cells from the monocytic lineage could differentiate into activated local tissue macrophages that express the microglia marker, ionized calcium-binding adaptor molecule 1. The lack of albumin detection in the brain parenchyma of infected mice showed that the infiltration of blood leukocytes was not necessarily related to a breakdown of the blood-brain barrier but could be the result of a functional recruitment. Thus, our findings suggest that blood monocyte-derived macrophages infiltrate the central nervous system and may contribute, with resident microglia, to the innate immune response seen during experimental HSE.
Highlights
Herpes simplex virus 1 (HSV-1) encephalitis (HSE) constitutes the most frequent sporadic and potentially fatal form of viral encephalitis in Western countries [1]
Chemotherapy regimen induces a strong peripheral chimerism following bone marrow transplantation Chimeras were generated by subjecting WT C57BL/6 mice to a myeloablative chemotherapy regimen and transplantation of bone marrow-derived cells harvested from green fluorescent protein (GFP)+/- transgenic
Chemotherapy regimen consisting in the alkylating agent busulfan and the immunosuppressive drug cyclophosphamide was used to generate chimeric mice by transplantation of blood mononuclear cells that expressed the GFP from donor mice without affecting the pool of resident microglia in the central nervous system (CNS)
Summary
Herpes simplex virus 1 (HSV-1) encephalitis (HSE) constitutes the most frequent sporadic and potentially fatal form of viral encephalitis in Western countries [1]. This devastating disease affects 2 to 4 individuals per million per year, the virus infects a high percentage of the population [2]. Despite the use of intravenous acyclovir that aimed at blocking virus replication, the mortality rate associated with HSE is still high (i.e., 20–30%), with the majority of surviving patients developing severe neurological sequelae [2, 4]. It is believed that the high mortality rate attributable to HSE could involve both virally- and immune-induced brain damages [5,6,7,8,9]
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