Abstract
BackgroundGenetically polymorphic Superoxide Dismutase 1 G93A (SOD1-G93A) underlies one form of familial Amyotrophic Lateral Sclerosis (ALS). Exposures from viruses may also contribute to ALS, possibly by stimulating immune factors, such as IL-6, Interferon Stimulated Genes, and Nitric Oxide. Recently, chlorovirus ATCV-1, which encodes a SOD1, was shown to replicate in macrophages and induce inflammatory factors.ObjectiveThis study aimed to determine if ATCV-1 influences development of motor degeneration in an ALS mouse model and to assess whether SOD1 of ATCV-1 influences production of inflammatory factors from macrophages.MethodsSera from sporadic ALS patients were screened for antibody to ATCV-1. Active or inactivated ATCV-1, saline, or a viral mimetic, polyinosinic:polycytidylic acid (poly I:C) were injected intracranially into transgenic mice expressing human SOD1-G93A- or C57Bl/6 mice. RAW264.7 mouse macrophage cells were transfected with a plasmid vector expressing ATCV-1 SOD1 or an empty vector prior to stimulation with poly I:C with or without Interferon-gamma (IFN-γ).ResultsSerum from sporadic ALS patients had significantly more IgG1 antibody directed against ATCV-1 than healthy controls. Infection of SOD1-G93A mice with active ATCV-1 significantly accelerated onset of motor loss, as measured by tail paralysis, hind limb tucking, righting reflex, and latency to fall in a hanging cage-lid test, but did not significantly affect mortality when compared to saline-treated transgenics. By contrast, poly I:C treatment significantly lengthened survival time but only minimally slowed onset of motor loss, while heat-inactivated ATCV-1 did not affect motor loss or survival. ATCV-1 SOD1 significantly increased expression of IL-6, IL-10, ISG promoter activity, and production of Nitric Oxide from RAW264.7 cells.ConclusionATCV-1 chlorovirus encoding an endogenous SOD1 accelerates pathogenesis but not mortality, while poly I:C that stimulates antiviral immune responses delays mortality in an ALS mouse model. ATCV-1 SOD1 enhances induction of inflammatory factors from macrophages.
Highlights
Infectious agents, such as viruses, have been postulated as contributors to motor neuron diseases (MND) [1]
The results reveal that Acanthocystis turfacea chlorella virus 1 (ATCV-1) infection significantly accelerated onset and progression of MND in superoxide dismutase 1 (SOD1)-G93A-transgenic mice starting at day 141, compared to the phosphate buffered saline (PBS)-treated transgenic mice, which developed symptoms of MND starting at 150 days (Figure 2A)
Greater motor deterioration of ATCV-1-infected mice was detected for the 14 days, after which the MND in ATCV-1-inoculated SOD1G93A-transgenic mice approached that of the PBS-treated transgenic mice
Summary
Infectious agents, such as viruses, have been postulated as contributors to motor neuron diseases (MND) [1]. ATCV-1 SOD1 is predicted to lower the concentration of reactive oxygen species in cells early during viral infection, thereby evading that aspect of innate anti-viral resistance [9]. This is of clinical interest given that one of the most common genetic forms of amyotrophic lateral sclerosis (ALS) is due to polymorphisms in the human SOD1 gene, with mouse models recapitulating these findings [10]. Polymorphic Superoxide Dismutase 1 G93A (SOD1-G93A) underlies one form of familial Amyotrophic Lateral Sclerosis (ALS). Chlorovirus ATCV-1, which encodes a SOD1, was shown to replicate in macrophages and induce inflammatory factors
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