Background: Genetically 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.
Objective: This 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.
Methods: Sera from sporadic ALS patients were screened for antibody to ATCV-1.
Active or inactivated ATCV-1, saline, or a viralmimetic, 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-g).
Results: Serum 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.
Conclusion: ATCV-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. |
