Exposure to, and or infection with CVs in both humans and SOD1G93A transgenic mice, may contribute to the development of MND by the induction of inflammatory cytokines via macrophages.

  Infectious agents such as viruses may contribute to MND or ALS, through the induction of inflammatory cytokines from macrophages. Chloroviruses (CVs) are large dsDNA viruses, located ubiquitously in fresh-water environments worldwide, and recently shown to slowly replicate in macrophages inducing inflammatory cytokines. Of note, ATCV-1, a common CV subtype encodes its own functional Cu-Zn superoxide dismutase (SOD).

  CV ATCV-1, heat-killed ATCV-1, poly I:C, or saline were injected intracranially into both SOD1G93A-transgenic and C57Bl/6 wild-type mice at 5 weeks of age. Poly I:C was injected as a control of innate anti-viral immune responses without infection. RAW264.7 macrophage cell line was transfected with expression vectors of SOD1 G93A, ATCV-1 SOD1, or wild-type (wt) human SOD1 prior to stimulation with poly I:C, with or without Interferon-gamma. 

   ATCV-1 infection of SOD1G93A transgenic mice significantly accelerated the onset and progression of motor loss, as compared to saline-treated transgenics. By contrast, heat-killed ATCV-1 did not accelerate motor loss, while poly I:C significantly delayed mortality in transgenics.  Overexpression of wtSOD1, G93A SOD1, or ATCV-1 SOD1 increased production of inflammatory cytokine IL-6 while wtSOD1 or G93A SOD1 decreased production of anti-inflammatory cytokine IL-10 from RAW264.7 cells.

  Exposure to ATCV-1 significantly accelerates onset and progression of ALS-like MND in a transgenic mouse model.  Injection of poly I:C, had a significant beneficial motor effect and overexpression of SOD1 in macrophages increases inflammatory cytokine and decreases anti-inflammatory cytokine expression.  Our cumulative research findings indicate that components of the innate antiviral immune response appear protective against MND while infection with ATCV-1 may contribute to ALS/MND pathogenesis by encoding a viral SOD1, which potentially contributes to disease propagation.