Host-parasite interactions in infections due to Entamoeba histolytica: A tale of known and unknown : Tropical Parasitology

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Review Article

Host-parasite interactions in infections due to Entamoeba histolytica

A tale of known and unknown

Singh, Aradhana; Banerjee, Tuhina

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Tropical Parasitology 12(2):p 69-77, Jul–Dec 2022. | DOI: 10.4103/tp.tp_81_21
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Entamoeba histolytica (E. histolytica) is an enteric microaerophilic protozoan parasite responsible for millions of cases worldwide. Majority of the infections due to E. histolytica remain asymptomatic; however, it can cause an array of symptoms ranging from devastating dysentery, colitis, and abscesses in different vital organs. The interactions between the E. histolytica and its host are a multifaceted chain of events rather than merely destruction and invasion. There are manifold decisive steps for the establishment of infections by E. histolytica which includes degradation of mucosal layer, adherence to the host epithelium, invasion into the host tissues, and dissemination to vital organs. It is widely hypothesized that, for establishment of infections, the interactions at the intestinal mucosa decides the fate of the disease. The delicate communications between the parasite, the host factors, and the associated bacterial microflora play a significant role in the pathogenesis of E. histolytica. In this review, we summarize the interactions between the E. histolytica and it's host at the genetic and immunological interphases emphasizing the crucial role of microbiota in these interactions.


According to the World Health Organisation, amoebiasis is a major health problem in developing nations.[1] Entamoeba histolytica (E. histolytica), an enteric dwelling protozoan parasite, is the causative agent of amoebiasis. Amoebiasis was primarily considered as the disease of the underdeveloped and developing nations. However, there has been increasing reports of infections due to E. histolytica in developed nations in particular groups such as travellers from endemic regions, homosexual males, and institutionalised individuals.[2345] There are 50 million cases of infections caused by E. histolytica per year leading to 100,000 deaths.[6] Individuals usually harbor the parasite in the lumen of the colon as a harmless commensal and become asymptomatic carriers. However, it can cause devastating dysentery, colitis, and abscesses in different vital organs.[7] E. histolytica invades the intestinal mucosa often forming the “flask-shaped” ulcers. The reason behind the sudden switch to the pathogenic phenotype in asymptomatic carriers, leading to the onset of the disease, remains largely unknown. In this context, there is increasing awareness about the complexity of the host-parasite interactions in cases of infections due to E. histolytica.[8] The interactions between the E. histolytica and its host is a complex chain of events rather than solely destruction and invasion. It has been hypothesized that for millions of Entamoeba infections each year, the interactions at the intestinal mucosa decides the fate of the disease susceptibility.[8] There are multiple crucial steps for the establishment of infections by this parasite including degradation and invasion of mucosal layer, adherence of the parasite to the host epithelium, invasion into the host tissues, and finally dissemination to other vital organs.[9] The subtle interactions between the parasite, the host factors, and the resident bacterial flora most likely play an important role in the pathogenesis. As the concepts on the several interactions of E. histolytica and the host are evolving, we tried to provide an update of these interactions at immunological and genetic interphases along with the role of bacterial flora in the disease onset and progression.


Literature search was focused on published data about interactions of the host and E. histolytica at different phases and those of the parasite with the associated microflora. The relevant literature search was done using databases such as PubMed and Google Scholar. Key words “pathogenesis of Entamoeba” were used. Finally, “role of microflora in Entamoeba infections,” such as “host parasite interactions,” the screened articles were included as reference for this review.


Ingestion of cysts through contaminated food or water marks the beginning of the infection due to E. histolytica. The cysts undergo excystation in the terminal ileum, leading to the release of the trophozoites. The different events during the interactions of the host with E. histolytica and the major molecules involved have been included in Figure 1. Several such interactions are encountered during entry of the cyst inside the host.

Figure 1:
Events in host-parasite interactions with major molecules involved during infections due to E. histolytica infections. Gal/GalNAc lectin: Galactose/N-Acetyl D-galactosamine, EhCP: E. histolytica cysteine proteases, MMPs: Matrix Metalloproteinases)

Interactions at the mucus barrier

The first line of host defence in a colonic environment is the mucus layer. It covers the epithelial layer restricting entry of any harmful substances, commensal, and pathogenic bacteria. The main component of the mucus layer is a large protein, MUC2 mucin secreted by the goblet cells of small and large intestine.[10] For the establishment of the pathogenesis, E. histolytica binds to the mucus layer through galactose/N-acetyl-D-galactosamine (Gal/GalNAc) lectin to gain access to the epithelial cells.[11] Calcium ions (Ca+2) play crucial role in the binding of the ligands by Gal/GalNAc lectin. The mutant of the Ca+2 binding site had shown loss of red blood cells agglutination property of E. histolytica, thus confirming that the Ca+2 plays an important role in regulating some of the properties of Gal/GalNAc lectin.[12] In addition, it has been shown that Ca+2 is involved in different processes, leading to the host tissue invasion.[1314] E. histolytica also possesses a number of glycosides that can remove the branched polysaccharides from the mucin or the host cells.[15] These include α-d-glucosidase, β-d-galactosidase, α-N-acetyl-d-galactosaminidase, β-N-acetyl-d-glucosaminidase, and β-l-fucosidase. Among these, β-N-acetyl-d-glucosaminidase has a central role in degradation of the carbohydrates of mucin.[16] This scarcity of the free carbohydrate creates a competition with the commensal microflora which can be the potential reason for turning on the switch for the pathogenic nature of E. histolytica. As mucin is the biggest source of carbohydrate in the colonic environment, the degradation of the mucus layer is increased. In addition, β-amylase and E. histolytica cysteine protease (EhCP), EhCP5 have been known to play a critical role causing a breachin the mucus layer for the invasive trophozoites.[1718] After digestion of carbohydrates, cysteine proteases cause robust destruction of the protein backbone in mucin layer.[9] Lysine-glutamic acid rich protein 1 (KERP1) has also been known to play an important role in the adherence of the E. histolytica to the host through α-helical region.[19]

Intestinal epithelial cell responses

As the epithelial cells come in contact with the parasite, it produces different cytokines. Intestinal epithelial cells (IECs) generate a pro-inflammatory response by interleukin (IL)-1 β and IL-8, resulting in recruitment of the neutrophils.[11] E. histolytica also induces the IECs to release monocytes and other chemokines.[20] E. histolytica responds by producing the secreted products that inhibit chemotaxis and mobility of the monocytes. E. histolytica also possess homology with tumor necrosis factor (TNF) receptor causing chemotaxis toward TNF-α.[21] These events cause reorganization of the actin cytoskeleton and upregulation of the E. histolytica Gal/GalNAc lectin, further resulting in the penetration of E. histolytica in the IECs and entry into the lamina propria. Recently, it has been explored that dysregulation of the micro-RNA occurs in the epithelial colon cells during the E. histolytica infections. The upregulation of miR150, miR-525, miR-526b-5p, miR-615-5p, miR-643, and downregulation of miR-409-3p during the E. histolytica infections impacts the gene expression of many important pathways.[22] In addition, E. histolytica can also induce apoptosis in host cells through altering the miRNA regulating genes involved in the PI3K/AKT signalling pathway, lipid metabolism, and apoptosis.[23]

Changes in tight junction permeability

E. histolytica regulates the tight junction permeability by a number of different mechanisms. The change in the permeability leads to the water and electrolyte imbalance causing diarrheal disease. The degradation of the tight junctions, ZO1, and dephosphorylation of ZO2 has been related to the permeability changes in the tight junction.[24] Along with it, E. histolytica has been known to regulate the tight junction permeability using the prostaglandin E2 (PGE2). The PGE2 is capable of disrupting the transepithelial resistance, thus causing paracellular leakage of chloride ions in the lumen which in turn causes the water electrolyte imbalance in diarrheal diseases.[25]

Extra-intestinal invasion

The mortality due to infections by E. histolytica is mainly because of the extra-intestinal manifestations, among which amebic liver abscess (ALA) is the most common one.[26] The exact reason for invasion of the trophozoites to the extra-intestinal regions remains unknown. The parasite E. histolytica has cytopathic effects on a number of epithelial cells and immune cells. E. histolytica causes killing of host cells through contact dependent mechanism using Gal/GalNAc lectins.[8] After the degradation of the epithelial cells, E. histolytica navigates through the extracellular matrix for dissemination to the extra-intestinal sites. When E. histolytica propagates through extra-intestinal system, it takes a path similar to that of cancer metastasis.[27] The trophozoites require glycosidases and proteases for the basement membrane disintegration and entry into the circulation. The invading E. histolytica also secretes EhCPs, leading to the activation of the host matrix metallo proteinases (MMPs).[28] Human factors such as human MMPs are believed to play a role in the extracellular matrix exploitation.[29] However, it has been hypothesized that, instead of complete degradation, the parasite goes for the remodelling of the collagen to increase the porosity of the extracellular matrix for the invading trophozoites. Over expression of the MMPs has been reported in protozoan parasitic diseases including amebic colitis and recurrent cases of ALA.[30] E. histolytica has 22 genes encoding for the metalloproteinases.[31]

Infection in the liver is the interplay between the E. histolytica trophozoites and hepatic cells. As the E. histolytica trophozoite reaches the liver, it creates lesions of well-circumscribed area with dead hepatocytes, liquified cells, and cellular debris. The abscess is surrounded by connective tissues with inflammatory cells and trophozoites.[32] However, the host and parasitic factors leading to liver abscess formation largely remain undescribed.

Immunological responses during progression to invasive amoebiasis

The host recruits immune cells to the site of invasion which attack the parasite and enhance the pathology. The host cell also releases nitric oxide and reactive oxygen species (ROS) for damaging the invading trophozoites.[933] However, E. histolytica has specific mechanisms to minimize these damages and they phagocytose the host immune cells to overcome the immune barrier. E. histolytica seems to have effective immune evasion strategies to overcome the adaptive immunity in the host. The different immunological factors involved during the interactions have been included in Table 1.

Table 1:
Major immunological components involved in the events during the infections due to Entamoeba histolytica

Trophozoite colonization

Apart from the absorptive role, gastrointestinal tract (GIT) regulates the immune response against the invading pathogens.[34] The existence of the parasite in the host requires interactions in favor of the parasite with the intestinal compartments, thus allowing its survival. IECs are the first to interact with the parasite antigens through a variety of pathogen recognition receptors (PRRs).[35] Upon binding to the ligand, these PRRs activate KFκB, a critical component for inflammatory IEC response. This recognition leads to the production of a sequence of inflammatory cytokines such as IL-6, IL-8, IL-12, IL-1 β, interferon-gamma, and TNF-α.[3637] These cytokines are known to have an array of activity against the invading trophozoites.[383940] In this context, secretory amebic components are known to induce cytoprotective property in human intestinal epithelium.[41] Secreted components from E. histolytica trophozoites induce a protective stress response in human colonic epithelial cells by interaction with the macrophages that suppress activation of KFκB.[41] The host tolerance against the invading trophozoites is maintained using different host factors. IL-10 maintains the mucosal barrier integrity. An amebic colitis model had demonstrated that IL-10 deficient mice were highly susceptible to the intestinal invasion.[42] The host's anti-Gal lectin prevents trophozoites’ adherence to mucous layer and epithelial cells. Studies have reported that intestinal anti-Gal-lectin immunoglobulin A (IgA) reduces the colonization of the trophozoites in the gut.[43] One of the studies had stated that participants with stool IgA recognizing Gal-lectin carbohydrate recognition domain were protected from new infections caused by E. histolytica.[44] In the absence of secretory IgA, the host may elicit a more robust inflammatory response, driving E. histolytica from commensal status to pathogen by increasing its ability to survive in high oxygen levels. EhCPs are known to cleave human IgA, thus protecting the parasite against host defences.

Invasion of colonic mucosa

The exact reason behind the invasion of E. histolytica is unknown. E. histolytica is known to synthesize and secrete PGE2, which disrupts IEC tight junctions.[25] Upon disruption of IEC junction, the parasite components are transferred to the basolateral surface of IEC. Invasion of colonic mucosa by trophozoites leads to acute inflammatory response and adaptive immunity.[43] The inflammation is believed to protect the host from invasive pathogens. However, it can also lead to severe tissue damage. In case of invasive intestinal infections, the initial inflammation is believed to exaggerate and drive further pathogenesis. The epithelial cells produce inflammatory cytokines like IL-1 β/α, IL-8, TNF-α, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1 which results in the moderate epithelium and sub-epithelium inflammation.[4546] The recruitment of the neutrophils, monocytes, and macrophages leads to diarrhea or dysentery in host. The T helper cell type 2 (Th2 cell) response from the host through IL-4, IL-5, IL-13, results in nonhealing intestinal lesions.[47] E. histolytica also expresses pore-forming protein, amoebapores, and hydrolytic enzymes such as cysteine proteases as weapons to penetrate host epithelium.[4849] After invasion of the colonic mucosa, trophozoites can also move to portal circulation leading to extra-intestinal manifestations such as abscesses of different vital organs, empyema, pericarditis, broncho-hepatic fistula, inferior vena cava thrombosis, and hemolytic uremic syndrome.

Extra-intestinal dissemination

The extra-intestinal dissemination of trophozoites through blood circulation requires ability to survive high oxygen concentration and protection against the host's immune system components. Intravascular immunity of the host may detect and kill trophozoites through complement system, anti-parasitic immunoglobulin G (IgG), and oxidative attack.[950] However, if trophozoites survive, the innate response and adaptive Th2 response leads to the formation of ALA. EhCPs are known to inactivate the circulating IgG, resulting in decreased affinity of theantibodies for the antigens.[28] The “capping” of the surface receptors is another mechanism used by the trophozoites to avoid targeted immune responses. E. histolytica from liver abscesses and colitis patients show resistance to complement-mediated killing, which can be attributed to Gal-lectin and a 21 kDa surface protein.[51] The immune response in liver against the trophozoites is due to invariant natural killer T cells. Along with it, the detection of trophozoites in the liver can lead to acute inflammatory response resulting in the recruitment of massive number of neutrophils. As the lesion progresses, influx of macrophages occurs coinciding with the granuloma formation. Trophozoites aggregate at the inner walls of granulomas and lyse any cell they encounter. As the chronic stage of ALA progresses, macrophage and T-cell suppression occurs. In addition, defects in the cell-mediated immunity occur during the advanced chronic stage of ALA.[52]

Genes involved in the host-parasite interactions

The genome-based studies of E. histolytica have improved the knowledge of pathogenesis of E. histolytica regarding host-parasite interactions. Comparison of the virulent and nonvirulent strains along with the related species had shown the different genes involved in the pathogenesis. The different genes having a role in the events of host-parasite interactions during infections by E. histolytica have been shown in Table 2.

Table 2:
Different genes involved during the phases of infections due to Entamoeba. histolytica mentioned in the study

Mucus barrier degradation and binding to the host cells

A large number of genes are differentially expressed in the early phase of infection due to E. histolytica.[53] However, the exact role of many of these gene's product remains unexplored. It might be due to the stress response associated with the adaptation in the new environment. For the degradation of the mucus layer, the trophozoites release cysteine protease to degrade the main component of the mucus barrier, MUC2. Different genes from cysteine protease family such as CP-A4, CP-A6, and CP-B1 are expressed to a greater degree in culture as well as in the mouse intestine in experimental studies.[53] The trophozoites bind to the mucus layer of the host through Gal/GalNAc lectin complex. The genes encoding for the light subunit of the lectin complex (lgl2 and lgl3) shows downregulation during the course of the infection. Another E. histolytica gene family (EHI_012330, EHI_004340, and EHI_025700) codes for E. histolytica serine-, threonine-, and isoleucine-rich proteins involved in the binding of the trophozoites to the host cells.[54]

Survival strategies against the host responses

A number of genes show differential expression in response to the oxidative and nitrosative stress in pathogenic strain, HM1-IMSS, as compared to nonpathogenic E. histolytica strain, Rahman.[55] Peroxiredoxin gene and Fe-hydrogenase gene showed upregulation in the HM1-IMSS strain. Peroxiredoxin is expressed on the surface of the trophozoites as per the protein and mRNA expression study, where along with Gal/GalNAc lectin it degrades the ROS released from the immune cells.[5657] Upstream regulatory element 3 binding protein, a calcium-binding transcription factor, regulates the gene expression of E. histolytica virulence-associated genes.[58] Similarly, other genes such as superoxide dismutase, EhROM1 (a rhomboid protease), granin-1 and granin-2, alcohol dehydrogenase 3 have shown differential expression between the virulent and nonvirulent species as well as strains of Entamoeba pointing towards the role in virulence and survival of the parasite. The involvement of some other genes such as putative peroxiredoxin genes and putative oxidative stress response gene in host-parasite interactions has been seen. However, their exact functions remain unknown.

Amebic liver abscess formation

The transcriptome analysis of E. histolytica trophozoites axenically grown in vitro with the trophozoites isolated from the ALA showed differential expression of a number of genes including grainin-1, a guanosine triphosphate binding protein, a flavoprotein, and the ribosomal proteins.[5960] The virulent and avirulent lines derived from E. histolytica had shown upregulation of 29 genes and downregulation of 21 genes in the virulent strain. The upregulated genes and proteins included ariel-1, lysine and glutamic acid rich proteins, and lysine-rich proteins.

The comparison between cell lines capable of causing ALA and the one which has lost the ability to form ALA showed differential expression of 87 genes. However, only two genes Fe-hydrogenase-2 and a C2-domain-containing protein were differentially expressed at both transcriptomic and protein level.[6162] Antigen ariel-1 gene, lysine-rich proteins (“KRiPs”) and lysine-and glutamic acid-rich proteins (“KERPs”) have been found to be upregulated in the virulent strains.[63] Knock-down of KERP-1 gene has shown a reduction in the liver abscess forming ability of the trophozoites implying its significant role in the ALA formation.[64] Amoebapore-A gene when inserted into the host plasma membrane forms pores upon contact, lysing the host cells. But its crucial role in the ALA formation still needs to be clarified.[65]

Role of host haplotype in the severity of amoebiasis

It has been long known that not all individuals are equally susceptible to infections due to E. histolytica. Literature suggests that 1 out of 10 infected individuals develops invasive infection.[66] As E. histolytica lacks the sexual cycle of reproduction, thus, this partiality in the disease development cannot be attributed to only parasite genome.[6768] It has been advocated that hosts who carry susceptible alleles are more likely to get invasive infections. Different genome-wide association studies among the children and adults have been carried out to study about the role of genetic make-up of hosts in the susceptibility to invasive disease development.[6970]

An association between the human leukocyte antigen (HLA) class II allele and the symptomatic infections due to E. histolytica has been reported from an endemic region. Particularly, HLA class II allele DQB1 × 0601 and the heterozygous haplotype DQB1 × 0601/DRB1 × 1501 had shown drastically decreased frequency of infections due to E. histolytica in comparison to the individuals lacking this haplotype.[71] Similarly, a study from Mexico showed HLA-DQB1 × 02 allele was found with higher frequency in patients suffering from ALA as compared to the healthy controls. The haplotype HLA-DRB1 × 08/-DQB1 × 04 was reported in less frequency in patients with infections due to E. histolytica than in healthy individuals.[7273] The reason for such a partial behavior could be that the presence or absence of a certain HLA class II allele could vary the repertoire of proteins presented to the CD4+ T cells.[71]

Earlier studies have documented an association of the HLA class II to ALA but not with the intestinal infections due to E. histolytica.[74] A study of the Mexican adults and children has reported an increased frequency of the HLA-DR3 in the patients with ALA as compared to the healthy control subjects irrespective of age or sex. Among the children suffering from ALA, increased frequency of HLA-DR5 and the absence of HLA-DR6 has been reported in comparison to adults with ALA.[75]

At the same time, certain studies have also shown the involvement of the non-HLA host gene in the susceptibility to infections by E. histolytica. Direct correlation between the host genetic marker and the susceptibility to E. histolytica infection was described for a polymorphism in the leptin receptor gene.[69] A study from an endemic region had shown that single amino acid replacement (Q223R) in the leptin receptor's extracellular domain encoded by a single nucleotide polymorphism resulted in four-fold increase in the susceptibility of the individual to the infections by E. histolytica.[76] An association between the anti-amebic IgA and IgG responses to the susceptibility and resistance to the infections due to E. histolytica has also been documented.[71] Genetic variation in a transcriptional regulator, cAMP-responsive element modulator/cullin 2 locus of the host has been found to be associated with the diarrheal infections due to E. histolytica.[70]

Role of microbiota at mucosal interfaces

The GIT of humans is home to at least 400 different species of bacteria.[77] The development of the microbial community starts since birth and evolves influencing the local environment significantly. E. histolytica is found on the lumen of large intestine, which is the site of largest bacterial population in humans. The virulence of E. histolytica against the host has been shown to be significantly enhance by intestinal bacterial population in microbiota-controlled animal models.[7879] Studies suggest that the resident microbiota plays a crucial role at the mucosal interfaces in the transmission of the parasitic protozoans and onset of the disease. The microflora has been known to greatly influence the central energy metabolism of the trophozoites.[9]

Certain species of the bacteria such as Escherichia coli, Shigella dysenteriae, and Staphylococcus aureus promote critical changes in the host response and E. histolytica interactions.[80] Studies have also found the presence of Prevotella sp. in abscess fluid to be significantly associated with the recurrence of ALA.[30] The E. coli serotype O55 has been known to bind strongly with the Gal/GalNAc lectin of E. histolytica. It is attributed to the presence of surface carbohydrate components rich in Gal and N-acetyl galactosamine on the bacterial strain. This event enhances the virulence of E. histolytica in the first hour.[8182] In addition, these bacterial population also affects the host responses related to the epithelial barrier functions, chemoattraction of neutrophils, and inflammatory response.[3783] The synergistic effects of intestinal bacteria on the host and parasite responses make the surrounding environment more permissible for the parasite invasion and the progression of the disease. It may be possible that microbiota affects the host immune response also in the case of E. histolytica infection similar to that of rheumatoid arthritis, obesity, diabetes, and cancer.[84858687] The microbiota-mediated immunomodulation can be a potential factor in the E. histolytica disease establishment. Studies have reported that the germ-free animals showed resistance to infection caused by E. histolytica, supporting the potential role of the microflora in the establishment of the infection. However, the critical analysis of the various role of the associated microflora on the virulence and survival of the Entamoeba in the host needs to be finely explored.


The study of parasite interactions and host response is challenging in case of human diseases. However, for the study of the host and parasite interactions in the case of E. histolytica infections different animal models such as hamsters, gerbil, or severe combined immunodeficiency diseased mouse are available. The understanding of the different aspects of E. histolytica pathogenesis such as adherence, invasion, degradation of mucin and extracellular matrix, extra-intestinal dissemination has greatly advanced in the recent times. However, the different interactions responsible for switching of Entamoeba from commensal to pathogen status needs to be thoroughly explored. In addition, the reason behind the partiality in virulence leading to intestinal symptoms in some and extra-intestinal invasion in others needs to be evaluated. The role of the microbiota, along with the variety of genes showing differential expressions and different immunological factors needs to be described. The broad spectrum of relationship, i.e., host-parasite-microbiota should be considered instead of host-parasite interactions for proper understanding of the progression of disease in natural situations.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


The authors thank Banaras Hindu University and Department of Science and Technology, India, for providing facility to conduct this study.


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Adherence; epithelial cells; haplotype; immunological responses; invasion; microbiota

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