Dysregulation of host cell calcium signaling during viral infections: Emerging paradigm with high clinical relevance

Abstract

Viral infections are one of the leading causes of human illness. Viruses take over host cell signaling cascades for their replication and infection. Calcium (Ca²⁺) is a versatile and ubiquitous second messenger that modulates plethora of cellular functions. In last two decades, a critical role of host cell Ca²⁺ signaling in modulating viral infections has emerged. Furthermore, recent literature clearly implicates a vital role for the organellar Ca²⁺ dynamics (influx and efflux across organelles) in regulating virus entry, replication and severity of the infection. Therefore, it is not surprising that a number of viral infections including current SARS-CoV-2 driven COVID-19 pandemic are associated with dysregulated Ca²⁺ homeostasis. The focus of this review is to first discuss the role of host cell Ca²⁺ signaling in viral entry, replication and egress. We further deliberate on emerging literature demonstrating hijacking of the host cell Ca²⁺ dynamics by viruses. In particular, a variety of viruses including SARS-CoV-2 modulate lysosomal and cytosolic Ca²⁺ signaling for host cell entry and replication. Moreover, we delve into the recent studies, which have demonstrated the potential of several FDA-approved drugs targeting Ca²⁺ handling machinery in inhibiting viral infections. Importantly, we discuss the prospective of targeting intracellular Ca²⁺ signaling for better management and treatment of viral pathogenesis including COVID-19. Finally, we highlight the key outstanding questions in the field that demand critical and timely attention.

Keywords: COVID-19; Calcium; STIM1/Orai1; TPC2; VGCC; Virus.

Fig. 1

Schematic representation of cellular Ca²⁺handling machinery. Ca²⁺ homeostasis is maintained by various Ca²⁺ channels and pumps present on plasma membrane (VGCC, SOC, ROC, PMCA, TRP, NCX etc.) and different intracellular compartments such as ER, mitochondria, Golgi, and lysosomes. The PM localized Ca²⁺ channels and pumps mediate Ca²⁺ entry (as shown by black arrows) from the extracellular milieu to cytosol. The IP₃R and the RyR mediate the release of Ca²⁺ from ER and Golgi. SERCA pumps back Ca²⁺ into ER and Golgi from cytosol. The SPCA mediates Ca²⁺ entry into the Golgi from cytosol. VDACs and MCU mediate Ca²⁺ entry into the mitochondria while NCLX and Letm1 facilitate Ca²⁺ extrusion from mitochondrial matrix. The CHX on lysosomes mediates Ca²⁺ entry into the lysosomes while TPCs, TRPMLs, TRPMs along with others facilitate Ca²⁺ extrusion from the lysosomes. Ca²⁺ ions are shown as red dots. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

PM Ca²⁺handling toolkit and viral infections. A variety of viruses target PM Ca²⁺ handling machinery for increasing cytosolic Ca²⁺ levels and that in turn typically helps in driving viral replication and export. Viruses like JEV, DENV, ZIKV, YFV, WNV target VGCC for driving viral replication. Similarly, RV, HIV, HBV stimulate Orai1 mediated Ca²⁺ influx for enhancing replication. Whereas, ZIKV, HCV and DENV activate TRPV4 dependent signaling cascade for potentiating their replication and exit from host cells. Viruses also target PM Ca²⁺ efflux routes such as PMCA and NCX. For example, HBV and RV target PMCA and NCX respectively, for elevating cytosolic Ca²⁺ levels and this in turn aids in viral replication.

Fig. 3

ER Ca²⁺homeostasis and viral infections. A number of viruses target ER Ca²⁺ handling toolkit, which in turn aids in all three stages of infection i.e. viral entry (eg. HSV), viral replication (eg. HIV and HBV) and viral exit (eg. HIV). Some viruses, such as RV and HCMV can induce ER Ca²⁺ efflux by forming viroporin in the ER membrane. This in turn helps in viral replication and assembly. While oncogenic EBV targets SERCA regulated ER Ca²⁺ homeostasis for driving viral infection and associated oncogenesis.

Fig. 4

Mitochondrial Ca²⁺dynamics and viral infections. Viruses act on mitochondrial Ca²⁺ dynamics for driving their replication and for inducing host cell apoptosis which in turn helps in viral exit. For example, HBV, HCV and HEV target mPTP, MCU and VDAC respectively for enhancing their replication. While HIV and PV stimulate VDAC and MCU activity thereby increasing mitochondrial Ca²⁺ concentration. The rise in mitochondrial Ca²⁺ levels leads to host cell apoptosis.

Fig. 5

Lysosomal Ca²⁺dynamics and viral entry. A variety of viruses target lysosomal Ca²⁺ efflux channels for host cell entry via endocytic route. Viruses such as EBOV, Marburg virus, Polyoma virus and MERS-CoV target TPCs for facilitating receptor mediated entry into host cells. Importantly, TPCs also regulate SARS-CoV-2 entry into host cells. While TRPML1 regulates HIV-1 replication and latent infection.

Fig. 6

Golgi Ca²⁺signaling and viral exit. Viruses frequently target Golgi Ca²⁺ signaling for facilitating their maturation and exit from the host cells. For example, DENV, ZIKV, CHIKV, RSV and Measles virus act on Golgi localized SPCA for enabling maturation of their glycoproteins and for their exit from the host cells. Further, SPCA regulated Golgi and cytosolic Ca²⁺ homeostasis plays a critical role in AAV transduction.