Host Calcium Channels and Pumps in Viral Infections

Abstract

Ca²⁺ is essential for virus entry, viral gene replication, virion maturation, and release. The alteration of host cells Ca²⁺ homeostasis is one of the strategies that viruses use to modulate host cells signal transduction mechanisms in their favor. Host calcium-permeable channels and pumps (including voltage-gated calcium channels, store-operated channels, receptor-operated channels, transient receptor potential ion channels, and Ca²⁺-ATPase) mediate Ca²⁺ across the plasma membrane or subcellular organelles, modulating intracellular free Ca²⁺. Therefore, these Ca²⁺ channels or pumps present important aspects of viral pathogenesis and virus-host interaction. It has been reported that viruses hijack host calcium channels or pumps, disturbing the cellular homeostatic balance of Ca²⁺. Such a disturbance benefits virus lifecycles while inducing host cells' morbidity. Evidence has emerged that pharmacologically targeting the calcium channel or calcium release from the endoplasmic reticulum (ER) can obstruct virus lifecycles. Impeding virus-induced abnormal intracellular Ca²⁺ homeostasis is becoming a useful strategy in the development of potent antiviral drugs. In this present review, the recent identified cellular calcium channels and pumps as targets for virus attack are emphasized.

Keywords: antiviral; calcium channels; calcium pumps; virus; virus–host interaction.

Figure 1

Schematics of host cell elevated cytosolic calcium concentration induced by a virus. Calcium channels (voltage-gated calcium channels (VGCCs), receptor-operated channels (ROC), store-operated Ca²⁺ (SOC), channels and transient receptor potential (TRP) channels) mediate the entry of Ca²⁺ from extracellular medium (black arrows). The IP₃ receptor (IP₃R) and the ryanodine receptors (RyR) on the endoplasmic reticulum (ER) mediate the release of Ca²⁺ from internal stores (black arrows). Calcium pumps (the plasma membrane Ca²⁺-ATPase (PMCA), sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA)) and the Na⁺/Ca²⁺ exchanger (NCX) are responsible for transporting Ca²⁺ from the cytosol to external medium or into cellular calcium stores (red arrows). Viruses utilize these calcium components to elevate cytosolic calcium concentration to activate Ca²⁺-dependent/sensitive enzymes and transcriptional factors to promote virus replication (right panel).

Figure 2

Examples of viruses interplaying with host calcium channels or pumps to achieve viral entry (A) and release (B). VGCCs are important for influenza A virus (IAV) and severe fever with thrombocytopenia syndrome virus (SFTSV) entry into the host cell as well as TPC1/2 for EBOV (A). RSV, Zika virus (ZIKA), dengue virus (DENV) and West Nile virus (WNV) hijack SPCA1 to facilitate their release as well as Ebola virus (EBOV), MARV, LASV, JUNV, HIV-1 and DENV manipulates STIM1/ORAI1 (B). For a complete list of definitions, see Table 1.