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

Saurav, Suman; Tanwar, Jyoti; Ahuja, Kriti; Motiani, Rajender K.

Viral infections are one of the leading causes of human illness. Viruses take over host cell signaling cascades for their replication and infection. Calcium (Ca(2+)) is a versatile and ubiquitous second messenger that modulates plethora of cellular functions. In last two decades, a critical role of host cell Ca(2+) signaling in modulating viral infections has emerged. Furthermore, recent literature clearly implicates a vital role for the organellar Ca(2+) 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 Ca(2+) homeostasis. The focus of this review is to first discuss the role of host cell Ca(2+) signaling in viral entry, replication and egress. We further deliberate on emerging literature demonstrating hijacking of the host cell Ca(2+) dynamics by viruses. In particular, a variety of viruses including SARS-CoV-2 modulate lysosomal and cytosolic Ca(2+) 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 Ca(2+) handling machinery in inhibiting viral infections. Importantly, we discuss the prospective of targeting intracellular Ca(2+) 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.