Inflammatory monocytes damage the hippocampus during acute picornavirus infection of the brain

Charles L Howe,Stephanie J Lafrance,Reghann G Lafrance-Corey,Rhianna S Sundsbak

doi:10.1186/1742-2094-9-50

Charles L Howe, Stephanie J Lafrance + Show 2 more

Open Access

https://doi.org/10.1186/1742-2094-9-50

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Abstract

BackgroundNeuropathology caused by acute viral infection of the brain is associated with the development of persistent neurological deficits. Identification of the immune effectors responsible for injuring the brain during acute infection is necessary for the development of therapeutic strategies that reduce neuropathology but maintain immune control of the virus.MethodsThe identity of brain-infiltrating leukocytes was determined using microscopy and flow cytometry at several acute time points following intracranial infection of mice with the Theiler's murine encephalomyelitis virus. Behavioral consequences of immune cell depletion were assessed by Morris water maze.ResultsInflammatory monocytes, defined as CD45hiCD11b++F4/80+Gr1+1A8-, and neutrophils, defined as CD45hiCD11b+++F4/80-Gr1+1A8+, were found in the brain at 12 h after infection. Flow cytometry of brain-infiltrating leukocytes collected from LysM: GFP reporter mice confirmed the identification of neutrophils and inflammatory monocytes in the brain. Microscopy of sections from infected LysM:GFP mice showed that infiltrating cells were concentrated in the hippocampal formation. Immunostaining confirmed that neutrophils and inflammatory monocytes were localized to the hippocampal formation at 12 h after infection. Immunodepletion of inflammatory monocytes and neutrophils but not of neutrophils only resulted in preservation of hippocampal neurons. Immunodepletion of inflammatory monocytes also preserved cognitive function as assessed by the Morris water maze.ConclusionsNeutrophils and inflammatory monocytes rapidly and robustly responded to Theiler's virus infection by infiltrating the brain. Inflammatory monocytes preceded neutrophils, but both cell types were present in the hippocampal formation at a timepoint that is consistent with a role in triggering hippocampal pathology. Depletion of inflammatory monocytes and neutrophils with the Gr1 antibody resulted in hippocampal neuroprotection and preservation of cognitive function. Specific depletion of neutrophils with the 1A8 antibody failed to preserve neurons, suggesting that inflammatory monocytes are the key effectors of brain injury during acute picornavirus infection of the brain. These effector cells may be important therapeutic targets for immunomodulatory or immunosuppressive therapies aimed at reducing or preventing central nervous system pathology associated with acute viral infection.

Highlights

Neuropathology caused by acute viral infection of the brain is associated with the development of persistent neurological deficits
We further confirmed the presence of neutrophils and inflammatory monocytes in the brain following infection using LysM:green fluorescent protein (GFP) reporter mice
In contrast to other viral models in which neutrophils apparently do not infiltrate the central nervous system (CNS) until recruited by other immune populations such as lymphocytes [2], our findings suggest that neutrophils are one of the earliest responders in the Theiler’s murine encephalomyelitis virus (TMEV) model

Summary

Introduction

Neuropathology caused by acute viral infection of the brain is associated with the development of persistent neurological deficits. The relationship between the delayed adaptive antigen-specific T and B cell-mediated response that eventually controls and eliminates the viral pathogen and the rapid but largely non-specific innate immune system response is poorly understood. Bergmann and colleagues observed that neutrophils and inflammatory monocytes were the first leukocytes to infiltrate the brain in mice infected with the non-lethal neurotropic JHM strain of mouse hepatitis virus (JHMV) [3], and depletion or blockade of monocytes impaired subsequent T cell infiltration into the brain parenchyma [4]. Lokensgard and colleagues observed an early neutrophil and inflammatory monocyte response in the brain following infection with herpes simplex virus 1 and this response preceded lymphocyte infiltration by a week [6]. The common denominator in all of these studies was the ensuing neuropathology triggered by infiltrating neutrophils and inflammatory monocytes

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