Pattern recognition channels in anti-viral host defense in humans and an insect vector

Abstract

Abstract A novel mechanism of innate immune signaling is proposed. The central hypothesis is that viral-associated molecular patterns directly activate intracellular splice variants of voltage-gated sodium channels to increase transcription of anti-viral genes. Past work revealed that splice variants of human voltage-gated sodium channels are expressed intracellularly on endosomes and contain exon deletions that alter channel kinetics. Here it is shown that intracellular dsRNA activates the human macrophage SCN5A variant to initiate a signaling cascade that leads to increased transcription of type I interferons and SP100-related genes. This pathway is regulated by sequential downstream activation of a calcium-dependent adenylate cyclase, adcy8, and the cyclic AMP-dependent transcription factor ATF-2. Knockdown of channel expression in human macrophages reduces the host response to HSV-1. Additional work reveals expression of an evolutionarily related sodium channel gene, AAEL006019, in Aedes aegypti, the yellow fever mosquito. This intracellular channel contains an alternative exon deletion that reduces peak current but does not alter ion selectivity. In contrast to human macrophage SCN5A, the AAEL006019 channel is activated by mimics of virally-derived ssRNA, but not dsRNA. Channel activation increases transcription of mediators of insect innate immunity, RelA and Ago2. These data suggest that channel variants initiate anti-viral responses independently of other pattern recognition receptor pathways. It is postulated that pattern recognition by channel variants are an evolutionarily conserved mechanism of innate immune signaling that reflect a complex interplay between human host, vector, and virus.