Abstract
Infection with Influenza A virus can lead to the development of encephalitis and subsequent neurological deficits ranging from headaches to neurodegeneration. Post-encephalitic parkinsonism has been reported in surviving patients of H1N1 infections, but not all cases of encephalitic H1N1 infection present with these neurological symptoms, suggesting that interactions with an environmental neurotoxin could promote more severe neurological damage. The heavy metal, manganese (Mn), is a potential interacting factor with H1N1 because excessive exposure early in life can induce long-lasting effects on neurological function through inflammatory activation of glial cells. In the current study, we used a two-hit model of neurotoxin-pathogen exposure to examine whether exposure to Mn during juvenile development would induce a more severe neuropathological response following infection with H1N1 in adulthood. To test this hypothesis, C57BL/6 mice were exposed to MnCl2 in drinking water (50 mg/kg/day) for 30 days from days 21-51 postnatal, then infected intranasally with H1N1 three weeks later. Analyses of dopaminergic neurons, microglia and astrocytes in basal ganglia indicated that although there was no significant loss of dopaminergic neurons within the substantia nigra pars compacta, there was more pronounced activation of microglia and astrocytes in animals sequentially exposed to Mn and H1N1, as well as altered patterns of histone acetylation. Whole transcriptome Next Generation Sequencing (RNASeq) analysis was performed on the substantia nigra and revealed unique patterns of gene expression in the dual-exposed group, including genes involved in antioxidant activation, mitophagy and neurodegeneration. Taken together, these results suggest that exposure to elevated levels of Mn during juvenile development could sensitize glial cells to more severe neuro-immune responses to influenza infection later in life through persistent epigenetic changes.
Highlights
Parkinson’s disease (PD) is characterized by the loss of voluntary motor control due to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) with associated α-synuclein protein-aggregation, neuroinflammatory activation of glial cells, mitochondrial dysfunction and oxidative stress [1]
Stereological determination of tyrosine hydroxylase (TH)+ dopaminergic neurons and morphological analysis of Iba1 + microglia at 21 DPI revealed that pre-treatment with MnCl2 during juvenile development induced persistent morphological changes in microglia consistent with an activated phenotype and increased their reactivity to a subsequent infection with H1N1, characterized by retraction of cytoplasmic processes and adoption of an amoeboid phenotype (Fig 1B–1I)
Given the increased number of reactive microglia in the substantia nigra and previous work showing that astrocytes play a significant role in microglial activation through glial-glial communication [7, 22, 23, 33, 34], we examined the extent and severity of astrocyte activation in the basal ganglia following treatment with MnCl2 (50mg/kg/day) and intranasal infection with H1N1 at 21 DPI (Fig 2)
Summary
Parkinson’s disease (PD) is characterized by the loss of voluntary motor control due to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) with associated α-synuclein protein-aggregation, neuroinflammatory activation of glial cells, mitochondrial dysfunction and oxidative stress [1]. Our lab and others have recently shown that exposure to certain classes of enveloped RNA viruses, Western equine encephalitis virus (WEEV) and H5N1 (strain, A/VN/1203/04) via intranasal infection can induce loss of dopaminergic neurons in the SNpc [7, 8]. Infection with viruses such as H5N1 avian influenza virus, WEEV and H1N1 induce neuronal loss in part through the activation of microglia and astrocytes and subsequent release of glial-derived neurotoxic inflammatory mediators [7,8,9]. Astrocytes and microglia have innate immunological memory in the brain to facilitate a rapid inflammatory response to recurrent inflammatory stressors, and it has been postulated that this acute and exacerbated inflammatory response from glia may have the capacity to exacerbate neuronal injury following secondary insults [12]
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