CALCIUM ION SIGNALS ARE FUNDAMENTAL IN VIRAL INFECTION

Lobefalo L, Bali N, Lolli A. Calcium ion signals are fundamental in viral infection. International Journal of Infection. 2025;9(3):75-77.

L. Lobefalo^1*, N. Bali² and A. Lolli³

¹ Department of Biomedical Sciences, University of Chieti-Pescara, Chieti, Italy;
² Department of Technology and Innovative Medicine, Dental School, University of Chieti-Pescara, Chieti, Italy;
³ Physical and Rehabilitation Medicine, ASL Civil Hospital, Pescara, Italy.

*Correspondence to:
Lucio Lobefalo, MD,
Department of Biomedical Sciences,
University of Chieti-Pescara,
Chieti, Italy.
e-mail: lobefalo@gmail.com

Received: 03 November, 2025 Accepted: 01 December, 2025

ISSN 3103-6678 [online] Copyright 2025 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Calcium ions (Ca²⁺) are important intracellular signaling messengers that allow cells to communicate and regulate various biological functions. In resting cells, Ca²⁺ is low and then increases after of various types of stimulus. After stimulation, Ca²⁺ returns to the initial resting state. Fura-2 fluorescence is one of the main methods for measuring the concentration of Ca²⁺ levels in the cytosol. Cellular Ca²⁺ is mainly found in the endoplasmic reticulum (ER), nucleus, Golgi apparatus and lysosomes. In viral infections, the virus uses the host cell to replicate, exploiting its metabolism. Infectious states alter cellular Ca²⁺ homeostasis in host cells to facilitate the entry and replication of microorganism. The entry of the virus into the cell is mediated by Ca²⁺ which regulates the replication of new virions. Viruses can influence mitochondrial energy production and induce ER stress with Ca²⁺ release. Rising Ca²⁺ levels activate protein kinase C (PKC), mediate viral replication, and act on pattern recognition receptors (PRRs) and Toll-like receptors (TLRs), resulting in activation of NF-κB and interferon (IFN). Modulation of viral Ca²⁺ can inhibit cell apoptosis and regulate autophagy for viral survival. During an infection, Ca²⁺ in the ER can mediate inflammation and cytokine release. Pharmacological inhibition of Ca²⁺ has antiviral effects, while kinase inhibitors act on viral replication.

KEYWORDS: Virus, infection, calcium ion, intracellular signaling, immune response

INTRODUCTION

Intrinsic and extrinsic stimuli on cells cause a biological response mediated by calcium ion (Ca²⁺) signals which serve as important cellular messengers (1). Normally, cells in the resting state have cytoplasmic Ca²⁺ basal levels of approximately 100 nM that changes upon cell activation (Ca²⁺ signals typically reach peak levels of 0.5–1 µM) (2).

External stimuli on the cell can be of various types: hormones, neurotransmitters, growth factors, antibodies, mechanical or electrical signals, temperature, pH, or osmotic changes, cytotoxic reagents, or microbial invasion (3). Stimuli that influence Ca²⁺ signaling can also be intrinsic to the cell, as occurs within cardiac myocytes (4) and developing neurons (5). Typically, these stimuli lead to an increase in Ca²⁺ concentration and modification of the cellular response. At the end of the stimulation, the Ca²⁺ concentration returns to the resting state (6). The Ca²⁺ levels in the cytosol also depend on the intensity of the stimulus, its concentration and duration (7).

A widely used method to monitor the Ca²⁺ values in the cell is fluorescence using Fura-2 (8). After stimulation, the release of Ca²⁺ from intracellular organelles and/or the influx of Ca²⁺ across the plasma membrane triggers signals that

specifically activate or deactivate cellular processes. Ca²⁺ is mostly concentrated in the endoplasmic reticulum (ER), nucleus, Golgi apparatus, and lysosomes (9).  Viruses need the host cell to replicate, exploiting its metabolic apparatus and using its own genetic information.

DISCUSSION

During viral infections, Ca²⁺ signaling plays an important role in both biochemical and immunological reactions (10). In these infections, Ca²⁺ homeostasis in host cells is altered, facilitating viral entry, replication, and assembly. Thus, a change in intracellular Ca²⁺ fluxes causes a biochemical reaction followed by a biological response.

In viral infections, the entry of the virus into the cell is mediated by Ca²⁺ with fusion of the virus to the host cell membrane (11). In addition, endocytosis is also used by viruses to penetrate the cell (12). Viruses use Ca²⁺-dependent enzymes such as kinases and phosphatases to regulate their replication (13).  Ca²⁺ influences cytoskeletal reorganization, vesicular trafficking, and budding of new virions (14).

Many viruses, for example hepatitis viruses, induce ER stress, an effect that leads to the release of Ca²⁺ from the ER via inositol 1,4,5-triphosphate receptors (IP3R) (15). Many microorganisms, including viruses, manipulate mitochondrial Ca²⁺ levels, influencing energy metabolism and apoptosis (16). These effects mediate immune responses and the production of reactive oxygen species (ROS) (17). Ca²⁺ activated by protein kinase C (PKC), is involved in viral replication and influences pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) (18). In addition, activation of TLRs involves NF-κB and interferon (IFN) regulatory factors, regulating the antiviral response (19).

Many viruses modulate Ca²⁺ to inhibit apoptosis, enhance replication, and spread the infection (20). Another function of Ca²⁺ is to regulate autophagy, an effect that some viruses exploit to survive (21). Many viral proteins modulate Ca²⁺ signaling by interacting with host Ca²⁺ channels to manipulate host homeostasis (22). These proteins increase intracellular Ca²⁺, influencing neuronal function and inflammation (23). During viral infection, Ca²⁺ stores in the ER are manipulated to promote inflammation and cytokine release (24).

Ca²⁺ channel blockers, such as verapamil and nifedipine, produce antiviral effects, and kinase inhibitors inhibit viral replication by modulating Ca²⁺ signaling (25). ER stress modulators can also limit viral replication (26).

CONCLUSIONS

Ca²⁺ fluxes are an important factor in viral infections, as they impact viral replication, the immune response, and host cell survival. These important observations may be useful to improve the understanding of the relationship between Ca²⁺ and viruses, but future studies will be needed to address new therapeutic challenges regarding this topic.

Conflict of interest

The authors declare that they have no conflict of interest.

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