Macrophage responses to and elevated antibody levels against Chlorovirus ATCV-1 in ALS patients.

Acanthocystis turfacea chlorella virus 1 (ATCV-1) is a giant virus that is part of the human oral microvirome. Previously we showed that ATCV-1 infects mouse macrophages, stimulates production of inflammatory cytokines, and accelerates motor neuron disease in the Amyotrophic Lateral Sclerosis (ALS) model SOD1-G93A transgenic mice. This, coupled with significantly elevated levels of serum IgG1 antibody to ATCV-1 in ALS patients compared with healthy controls, suggests involvement of ATCV-1 in ALS. Herein, using serum and CSF from a different ALS cohort we again show elevated antibodies to ATCV-1 in ALS patients compared with healthy controls. To assess ATCV-1 in human macrophages, we challenged immature (IMM), M0, M1, and M2 human THP-1 macrophage cells containing an Interferon Stimulated Response Element (ISRE) promoter-reporter with ATCV-1 or its Major Capsid protein (MCP) glycans. ATCV-1 infected M1 THP-1 to a greater degree than IMM, M0, or M2 THP-1. The initial high ISRE-promoter activity of M1 THP-1 was suppressed by the MCP-Glycans of ATCV-1. M0, but not IMM or M2 THP-1 produced IL-6 in response to ATCV-1 or its MCP-glycan, while high levels of IL-6 from unchallenged M1 THP-1 increased further by ATCV-1 or its MCP glycan. In contrast, ATCV-1 or its MCP-Glycan significantly reduced the high levels of IL-10 produced by M2 THP-1. Thus, antibody to ATCV-1 in ALS patients and the susceptibility of human M1 macrophages to ATCV-1 infection with boosted inflammatory cytokine and diminished anti-inflammatory cytokine production suggest that ATCV-1 may contribute to ALS motor neuron disease.