Entamoeba histolytica and pathogenesis: A calcium connection

Abstract

Calcium signaling plays a key role in many essential processes in almost all eukaryotic systems. It is believed that it may also be an important signaling system of the protist parasite Entamoeba histolytica. Motility, adhesion, cytolysis, and phagocytosis/trogocytosis are important steps in invasion and pathogenesis of E. histolytica, and Ca 2+ signaling is thought to be associated with these processes leading to tissue invasion. There are a large number of Ca 2+-binding proteins (CaBPs) in E. histolytica, and a number of these proteins appear to be associated with different steps in pathogenesis. The genome encodes 27 EF-hand-containing CaBPs in addition to a number of other Ca 2+-binding domain/motif-containing proteins, which suggest intricate calcium signaling network in this parasite. Unlike other eukaryotes, a typical calmodulin-like protein has not been seen in E. histolytica. Though none of the CaBPs display sequence similarity with a typical calmodulin, extensive structural similarity has been seen in spite of lack of significant functional overlap with that of typical calmodulins. One of the unique features observed in E. histolytica is the identification of CaBPs (EhCaBP1, EhCaBP3) that have the ability to directly bind actin and modulate actin dynamics. Direct interaction of CaBPs with actin has not been seen in any other system. Pseudopod formation and phagocytosis are some of the processes that require actin dynamics, and some of the amoebic CaBPs (EhC2Pk, EhCaBP1, EhCaBP3, EhCaBP5) participate in this process. None of these E. histolytica CaBPs have any homolog in organisms other than different species of Entamoeba, suggesting a novel Ca 2+ signaling pathway that has evolved in this genus.

Dynamism of PI4-Phosphate during Interactions with Human Erythrocytes in Entamoeba histolytica

“…PI(4,5)P 2 is further metabolized to DAG and inositol 3-phosphate (IP 3 ) by phospholipase C (PLC). IP 3 works as a trigger of Ca 2+ release and is involved in cytoskeletal remodeling [ 16 ], and is thus likely involved in erythrophagocytosis where Ca 2+ -dependent cytoskeletal reorganization plays a major role [ 17 , 18 ]. It was previously reported that E. histolytica has an IP 3 and IP 4 -dependent Ca 2+ release to the cytosol [ 19 ].…”

Rab7D small GTPase is involved in phago‐, trogocytosis and cytoskeletal reorganization in the enteric protozoan Entamoeba histolytica

“…E. histolytica exploits elaborate biological processes that contribute to its parasitism and pathogenesis, including motility, adherence, phago‐ and trogocytosis, cytotoxicity, defence against nutrient starvation, temperature changes, and host immune systems (Faust & Guillen, 2012; Marie & Petri Jr, 2014; Nakada‐Tsukui & Nozaki, 2016; Orozco, Guarneros, Martinez‐Palomo, & Sánchez, 1983; Ralston et al, 2014; Tavares et al, 2005; Tovy et al, 2011). All of these processes require coordinated regulation of signal transduction, cytoskeletal reorganization, and vesicular trafficking (Aguilar‐Rojas, Olivo‐Marin, & Guillen, 2016; Babuta, Bhattacharya, & Bhattacharya, 2020; Nozaki & Nakada‐Tsukui, 2006). Recent studies indicate in particular that trogo‐ and phagocytosis play a pivotal role in disease manifestations and host immune evasion (Miller, Suleiman, & Ralston, 2019; Nakada‐Tsukui & Nozaki, 2020; Ralston et al, 2014; Somlata, Nakada‐Tsukui, & Nozaki, 2017).…”

“…Recent studies indicate in particular that trogo‐ and phagocytosis play a pivotal role in disease manifestations and host immune evasion (Miller, Suleiman, & Ralston, 2019; Nakada‐Tsukui & Nozaki, 2020; Ralston et al, 2014; Somlata, Nakada‐Tsukui, & Nozaki, 2017). It has been shown that both amebic trogo‐ and phagocytosis are energy dependent and require Gal/GalNAc lectin, protein and lipid kinases such as C2‐domain‐containing protein kinase (EhC2PK), atypical kinase (EhAK1), and phosphoinositide‐3‐kinase (PI3K), phosphatidylinositide‐binding proteins such as FYVE domain containing protein 4 (Nakada‐Tsukui, Okada, Mitra, & Nozaki, 2009) and SNXs (Watanabe, Nakada‐Tsukui, & Nozaki, 2020), and proteins involved in actin rearrangement such as calcium binding proteins, ArpA2/3, Rho/Rac, EhP3, and EhFP10 (Agarwal et al, 2019; Babuta et al, 2020; Babuta, Kumar, Gourinath, Bhattacharya, & Bhattacharya, 2018; Babuta, Mansuri, Bhattacharya, & Bhattacharya, 2015; Bharadwaj et al, 2018; Bharadwaj, Arya, Shahid Mansuri, Bhattacharya, & Bhattacharya, 2017; Gautam, Ali, Bhattacharya, & Gourinath, 2019; Nakada‐Tsukui et al, 2009; Powell et al, 2006; Ralston et al, 2014; Somlata, Bhattacharya, & Bhattacharya, 2011; Watanabe et al, 2020). EhAGC kinase 1 represents only protein that is known to be engaged with only trogocytosis, but not phagocytosis, whereas EhAGCK2 is involved in both processes, but on the different stages of target internalisation.…”

Revisiting Drug Development Against the Neglected Tropical Disease, Amebiasis

“…The downregulation of kinase expression and overexpression of non-functional kinases lead to defects in phagocytosis ( Mansuri et al., 2014 ). Various experimental studies indicate EhAK1 to be downstream of EhC2PK, coupling Ca 2+ signalling and actin dynamics at the site of phagocytosis ( Babuta et al., 2020 ). Apart from these, a conserved AGCK family kinase, EhAGCK1, has been shown to be exclusively involved in trogocytosis.…”

“…For example, CaBPs (calcium binding proteins), C2PK (C2 domain containing protein), EhAK1, APSK (an unconventional alpha kinase), etc. ( Mansuri et al., 2014 ; Babuta et al., 2020 ). Further, probiotics, drugs and small molecules which act on the gut microbiota and alter the parasite biology can prevent invasion and subsequent pathogenesis, thereby offering an interesting alternative for the treatment of amebiasis and other parasitic intestinal infections ( Burgess and Petri, 2016 ).…”