The CSF1R-Microglia Axis Has Protective Host-Specific Roles During Neurotropic Picornavirus Infection

Abstract

Viral encephalitis is a major cause of morbidity and mortality, but the manifestation of disease varies greatly between individuals even in response to the same virus. Microglia are professional antigen presenting cells that reside in the central nervous system (CNS) parenchyma that are poised to respond to viral insults. However, the role of microglia in initiating and coordinating the antiviral response is not completely understood. Utilizing Theiler’s murine encephalomyelitis virus (TMEV), a neurotropic picornavirus, and PLX5622, a small molecule inhibitor of colony-stimulating factor 1 receptor (CSF1R) signaling that can deplete microglia in the CNS; we investigated the role of the CSF1R-microglia axis in neurotropic picornavirus infection of C57BL/6J and SJL/J mice. These mouse strains differ in their ability to clear TMEV and exhibit different neurological disease in response to TMEV infection. CSF1R antagonism in C57BL/6J mice, which normally clear TMEV in the CNS, led to acute fatal encephalitis. In contrast, CSF1R antagonism in SJL/J mice, which normally develop a chronic CNS TMEV infection, did not result in acute encephalitis, but exacerbated TMEV-induced demyelination. Immunologically, inhibition of CSF1R in C57BL/6J mice reduced major histocompatibility complex II expression in microglia, decreased the proportion of regulatory T cells in the CNS, and upregulated proinflammatory pathways in CNS T cells. Acute CSF1R inhibition in SJL/J mice had no effect on microglial MHC-II expression and upregulated anti-inflammatory pathways in CNS T cells, however chronic CSF1R inhibition resulted in broad immunosuppression. Our results demonstrate strain-specific effects of the CSF1R-microglia axis in the context of neurotropic viral infection as well as inherent differences in microglial antigen presentation and subsequent T cell crosstalk that contribute to susceptibility to neurotropic picornavirus infection.

Microglia Reduce Herpes Simplex Virus 1 Lethality of Mice with Decreased T Cell and Interferon Responses in Brains

“…More importantly, we employed PLX5622 to efficiently deplete microglia before and during the entire period of infection and found that depletion of microglia by this way increased HSV-1 lethality of mice with elevated brain levels of viral loads, infected neurons, neuron loss, CD4 T cells, CD8 T cells, neutrophils, IFN-β, and IFN-γ. Our results showing that microglia depletion increases many types of immune responses in HSV-1-infected mice are different from the previous HSV-1 report [23] and are rarely seen in other virus infections [2,[7][8][9][10].…”

“…Our eye results suggest that the elevated immune responses in brains of infected mice with PLX5622 treatment are due to increases in local viral titer/inflammation and unlikely due to altered induction of the immune response. In the mouse brain, PLX5622 increases CD4 and CD8 T cells in HSV-1-infected mice, macrophages in MHV-infected mice [8], and CD8 T cells in mice infected with TMEV or WNV [9,10]. These studies provide a better understanding that PLX5622 fails to reduce the infiltration of macrophages and T cells into brains of infected mice.…”

“…Collectively, microglia depletion provokes an inflammatory environment in brains of infected mice. Microglia regulate T cell activities in brains of mice infected with TMEV, MHV, or WNV [7][8][9][10]. As T cells are important anti-HSV-1 effectors [18,19], we studied the effect of microglia depletion on the brain levels of infiltrating T (CD45 hi CD3 + ) cells, which were low on day 5 p.i.…”

“…Microglia depletion diminishes the numbers and activation of CD4 T cells, fails to affect the number of CD8 T cells, and increases IFN-γ, interleukin (IL)-6, and IL-10 mRNA in Theiler's murine encephalomyelitis virus (TMEV)-infected mice [7]. However, another report showed that microglia depletion decreases regulatory T cells but increases CD8 T cells in TMEV-infected mice [10]. Microglia depletion reduces the levels of major histocompatibility complex class II (MHC-II), CD4 T cells, CD4 T cells expressing IFN-γ, regulatory T cells, and CD8 cells, but increases macrophages and mRNA levels of IFN-α, IFN-β, and IL-6, in mouse hepatitis virus (MHV)-infected mice [8].…”

MAVS mediates a protective immune response in the brain to Rift Valley fever virus

“…Such early responses in the brain are critical for direct control of viral replication, as well as for recruitment of adaptive immune cells that participate in viral clearance [ 17 , 18 ]. Microglia, the resident immune cells of the brain, play a key role in bridging innate and adaptive immune responses in the brain [ 19 – 21 ], and depletion of microglia increases susceptibility to multiple viral infections [ 18 , 22 , 23 ]. Although potent immune responses are required for viral control in the brain, limiting inflammation presents a unique immunoregulatory challenge as excessive inflammation can be especially deleterious and promote neurodegenerative diseases such as Parkinson’s [ 24 ] and Alzheimer’s [ 25 ] disease.…”