Targeting Host Store-Operated Ca2+ Release to Attenuate Viral Infections

Kevin   B.   Clark; E.   M.   Eisenstein

doi:10.2174/15680266113139990128

Abstract

Viruses coopt host intracellular Ca²⁺ signaling pathways to optimize timing and effectiveness of infection stages against barriers to invasion, pathogenesis, replication, and release. Virus-induced changes in free cytosolic Ca²⁺ levels facilitate virus adsorption, uncoating, catalysis, toxin production, structural assembly and stabilization, trafficking, and fusion and budding. Ca²⁺-associated alterations in virus status also selectively precipitate host cytopathologies through, among other events, retardation or induction of apoptosis, elevation of metabolic stress and reactive oxygen species production, and promotion of proinflammatory cytokine and chemokine synthesis and release. Viral particles and proteins tune spatiotemporal dynamics of host free cytosolic Ca²⁺ concentrations by modulating Ca²⁺ entry from the extracellular environment, upstream first or second messengers, ion- and ATP-dependent Ca2+ pumps that sequester or extrude free cytosolic Ca²⁺, store-operated Ca²⁺ mobilization and leakage, and viral capsid/envelope and downstream host Ca²⁺ binding proteins and sensors. Each of these major viral mechanisms, briefly reviewed in this article, presents a suitable drug target capable of mitigating the severity and incidence of viral infections. Given its pivotal role in cellular response regulation, bioenergetics, posttranslational protein and lipid modification and transport, homeostasis, cell motility and morphogenesis, and T lymphocyte proliferation, targeting virally stimulated inositol 1,4,5-trisphoshate (IP₃)-mediated store-operated Ca²⁺ release especially offers unique, predictable benefits for augmenting immunoprotection in vertebrate clinical populations. We appraise possibilities of modulating this system with experimental proteins that gate activation kinetics of endoplasmic-reticulum-localized Ca²⁺-conducting IP₃ receptors via allosteric protein-protein interactions. Such compounds are expected to be valuable in treating primary disease symptoms and sequelae, including virus-associated dementia.