Potential Sabotage of Host Cell Physiology by Apicomplexan Parasites for Their Survival Benefits

Abstract

Plasmodium, Toxoplasma, Cryptosporidium, Babesia, and Theileria are the major apicomplexan parasites affecting humans or animals worldwide. These pathogens represent an excellent example of host manipulators who can overturn host signaling pathways for their survival. They infect different types of host cells and take charge of the host machinery to gain nutrients and prevent itself from host attack. The mechanisms by which these pathogens modulate the host signaling pathways are well studied for Plasmodium, Toxoplasma, Cryptosporidium, and Theileria, except for limited studies on Babesia. Theileria is a unique pathogen taking into account the way it modulates host cell transformation, resulting in its clonal expansion. These parasites majorly modulate similar host signaling pathways, however, the disease outcome and effect is different among them. In this review, we discuss the approaches of these apicomplexan to manipulate the host-parasite clearance pathways during infection, invasion, survival, and egress.

Keywords: Babesia; Cryptosporidium; Plasmodium; Theileria; Toxoplasma; host signaling pathways.

Figure 1

An outline of the invasion mechanism used by Theileria, Plasmodium, Toxoplasma, Cryptosporidium, and Babesia. The figure is the representation of the invasion process, which happens during internalization of Theileria, Plasmodium, Toxoplasma, Cryptosporidium, and Babesia. The apical region of all the parasites faces toward the cell surface for their entry. In Plasmodium, invasion occurs in two types of cells, erythrocyte (non-nucleated cell) and hepatocyte (nucleated cell) as compared to other parasites where invasion occurs in the nucleated cell.

Figure 2

Overall survival mechanism used by the Apicomplexan parasites in different host cells. Toxoplasma and Cryptosporidium bind to the surface receptor of host cells through the ligands such as EGF, TNF-α, and parasitic surface proteins such as circumsporozoite protein (CSP). After invasion into the host cells such as enterocytes, macrophages, hepatocytes, etc., the parasite modify the host signaling pathway such as TRADD, NF-kB, PKB/AKT resulting in production and upregulation of anti-apoptotic proteins such as Bcl-2, Bcl-xl, and anti-inflammatory cytokines such as IL-10 thereby stopping cytochrome-c (Cyt-c), TNF-alpha-related-apoptosis-inducing ligand (TRAIL) and BAD, BAX production, and ensuring its survival in the host. Plasmodium parasite mainly modifies host PKB/AKT signaling pathway causing upregulation of anti-apoptotic protein and downregulation of pro-apoptotic proteins such as BAD/BAX. Theileria schizont proliferates uncontrollably within the host macrophages and lymphocytes. Right after invasion, it upregulates anti-apoptotic proteins such as c-FLIP, IAPs, Bcl-2, Bcl-XL, and proto-oncogenic proteins such as C-myc, antiapoptotic genes such as C-FLIP, Bcl-2, and matrix metallo-protein (MMP9) by majorly targeting host signaling pathways such as NF-κB, JNK/AKT, JAK/STAT, phosphoinositide 3-kinase (PI3-K)/MAPK, and TGF-β2. The regulation of these host signaling pathways causes continuous survival and proliferations of the parasite infected cells which are also common in some cases.