Chlorovirus Acceleration of Motor Neuron Disease in SOD1G93A Transgenic Mice may Clarify some of the Augmented anti-Chlorovirus Serology in Amyotrophic Lateral Sclerosis Patients

Abstract

Abstract Infections and inflammatory responses may contribute to motor neuron diseases (MND), such as Amyotrophic Lateral Sclerosis (ALS). A portion of familial ALS is caused by polymorphic Superoxide Dismutase (SOD)1 gene (SOD1G93A). As chloroviruses (CV) infect macrophages inducing inflammatory cytokines, they may contribute to ALS. Moreover, ATCV-1 is one of several chlorovirus types that encodes its own SOD1. Thus we evaluated serum from human ALS patients compared with controls for antibody against ATCV-1. In addition, we i.c. injected saline or ATCV-1 into SOD1G93A-transgenic and C57Bl/6 control mice and assessed development of ALS-like MND. Sera from ALS patients and controls had antibody to ATCV-1. However, ALS patients had significantly greater IgG1 anti-ATCV-1 compared with controls. This was accompanied by elevated IL-6, IFN-γ, and anti-Tetanus toxin antibody, but not IL-17. SOD1G93A mice inoculated with ATCV-1 had significantly accelerated development of MND, including tail paralysis, hindlimb tucking, decreased righting reflex, and latency to fall in a hanging cage lid test, compared with saline injected SOD1G93A mice. Splenic T cells of SOD1G93A and control mice showed similar IFN-γ and IL-17 responses to anti-CD3/-CD28, while Foxp3 expression overall was significantly higher in T cells of SOD1G93A compared with control mice. Inoculation with ATCV-1 decreased Foxp3 expression in SOD1G93A T cells compared with mice not given ATCV-1. These results indicate that chloroviruses, ubiquitous in fresh waters worldwide, induce antibody responses in humans that are elevated in ALS and may accelerate MND in the SOD1G93A type of familial ALS. Funding was generously provided by the Stuart Nichols ALS Research Foundation.