# Monocellular and Multicellular Parasites Infesting Humans: A Review of Calcium Ion Mechanisms

## TL;DR

This paper reviews how calcium ion signaling affects human defenses against parasites and suggests using calcium blockers and calcineurin inhibitors to improve treatments.

## Contribution

The paper highlights novel therapeutic strategies using calcium ion manipulation to enhance antiparasitic therapies.

## Key findings

- Calcium ion manipulation with blockers and calcineurin inhibitors can improve host defenses against parasites.
- Calcineurin inhibitors like cyclosporine reduce inflammation and parasite growth in Trypanosoma and Taenia.
- Inhibitors of calmodulin and calcineurin blunt the growth of Plasmodium and Schistosoma.

## Abstract

Calcium (Ca2+) is a signal messenger for ion flow in and out of microbial, parasitic, and host defense cells. Manipulation of calcium ion signaling with ion blockers and calcineurin inhibitors may improve host defense while decreasing microbial/parasitic resistance to therapy. Ca2+ release from intracellular storage sites controls many host defense functions (cell integrity, movement, and growth). The transformation of phospholipids in the erythrocyte membrane is associated with changes in deformability. This type of lipid bilayer defense mechanism helps to prevent attack by Plasmodium. Patients with sickle cell disease (SS hemoglobin) do not have this protection and are extremely vulnerable to massive hemolysis from parasitic infestation. Patients with thalassemia major also lack parasite protection. Alteration of Ca2+ ion channels responsive to environmental stimuli (transient receptor potential) results in erythrocyte protection from Plasmodium. Similarly, calcineurin inhibitors (cyclosporine) reduce heart and brain inflammation injury with Trypanosoma and Taenia. Ca2+ channel blockers interfere with malarial life cycles. Several species of parasites are known to invade hepatocytes: Plasmodium, Echinococcus, Schistosoma, Taenia, and Toxoplasma. Ligand-specific membrane channel constituents (inositol triphosphate and sphingosine phospholipid) constitute membrane surface signal messengers. Plasmodium requires Ca2+ for energy to grow and to occupy red blood cells. A cascade of signals proceeds from Ca2+ to two proteins: calmodulin and calcineurin. Inhibitors of calmodulin were found to blunt the population growth of Plasmodium. An inhibitor of calcineurin (cyclosporine) was found to retard population growth of both Plasmodium and Schistosoma. Calcineurin also controls sensitivity and resistance to antibiotics. After exposure to cyclosporine, the liver directs Ca2+ ions into storage sites in the endoplasmic reticulum and mitochondria. Storage of large amounts of Ca2+ would be useful if pathogens began to occupy both red blood cells and liver cells. We present scientific evidence supporting the benefits of calcium channel blockers and calcineurin inhibitors to potentiate current antiparasitic therapies.