Host-microbe interactions and defense mechanisms in the development of amoebic liver abscesses

Abstract

Amoebiasis by Entamoeba histolytica is a major public health problem in developing countries and leads to several thousand deaths per year. The parasite invades the intestine (provoking diarrhea and dysentery) and the liver, where it forms abscesses (amoebic liver abscesses [ALAs]). The liver is the organ responsible for filtering blood coming from the intestinal tract, a task that implies a particular structure and immune features. Amoebae use the portal route and break through the sinusoidal endothelial barrier to reach the hepatic parenchyma. When faced with systemic and cell-mediated defenses, trophozoites adapt to their new environment and modulate host responses, leading to parasite survival and the formation of inflammatory foci. Cytopathogenic effects and the onset of inflammation may be caused by diffusible products originating from parasites and/or immune cells either by their secretion or by their release after cell death. Liver infection thus results from the interplay between E. histolytica and hepatic cells. Despite its importance in terms of public health burden, the lack of integrated data on ALA genesis means that we have only an incomplete description of the initiation and development of hepatic amoebiasis. Here, we review the main steps of ALA development as well as the responses triggered in both the host and the parasite. Transcriptome studies highlighted parasite factors involved in adherence to human cells, cytopathogenic effects, and adaptative and stress responses. An understanding of their role in ALA development will help to unravel the host-pathogen interactions and their evolution throughout the infection.

FIG. 1.

Vascular structure of a hepatic lobule. The liver is composed of elementary functional units called lobules. A single lobule is depicted. Each lobule is made of parenchymal cells, mainly hepatocytes (HCs), which account for up to 80% of the total liver volume, and nonparenchymal cells (6.5% of the total volume) located in the sinusoidal compartment. Inside the lobule, hepatocytes are arranged in irregular radiating columns bathed by blood-carrying spaces called sinusoids. Lobules are prisms with a hexagonal cross section, the vertices of which are marked by the portal triad: the hepatic arteriole (HA), portal veinule (PV), and bile duct (BD). Around 75% of the blood entering the sinusoids comes from the portal veinule. The remainder enters the sinusoids principally through branches of the hepatic arterioles via the arteriosinus twigs. Sometimes, direct connections (arterioportal anastomoses [APA]) are observed within the terminal portal veinules. Blood then leaves the sinusoids through the efferent centrolobular vein (CV). Please note that for reasons of clarity, this schematic view does not respect the exact scale and numbers of cells within a lobule.

FIG. 2.

Entamoeba histolytica trophozoite within a sinusoid. The sinusoidal wall is made of LSECs and, with hepatocytes (HCs), delimitates the DS, in which SCs and components of the ECM are found. Leukocytes (LCs) are present in the sinusoidal lumen (SL), as are KCs, which additionally straddle the endothelium. The diagram presents the major factors involved in the interaction between E. histolytica and the liver endothelium. Within the hepatic sinusoids, trophozoites undergo complement attack and oxidative stress provoked by the high-oxygen partial pressure. Amoebae resist these threats by using Gal/GalNAc lectin (blue ellipses), lytic factors such as cysteine proteases (white ellipses), reducing enzymes (purple ellipse), and potentially other molecules of as-yet-unknown function (black ellipses). Trophozoites adhere to the endothelium and cause the apoptosis of LSECs. Amoebae can then migrate to the parenchyma (yellow arrow) through the newly created breach or between LSECs.

FIG. 3.

Amoebic liver abscess. Seven days after intraportal injection, the typical histological presentation of amoebic liver abscess in hamsters resembles a centripetral trophozoite layer (indicated by an arrow) stained with antiamoebic antibodies (in red) surrounding a central necrotic zone (indicated by “N”) and facing an external area containing large numbers of inflammatory cells (indicated by an arrowhead and stained with hematoxylin [in blue]). Scale bar, 50 μm.

FIG. 4.

Control of host responses by Entamoeba histolytica. Following stimulation by Gal/GalNAc lectin (blue ellipses) and (probably) other amoebic surface factors (black ellipses), macrophages produce TNF, which promotes the production of reactive oxygen intermediates (ROI) or reactive nitrogen intermediates (RNI), with the latter including NO. ROI and RNI are detoxified by the parasite's reducing enzymes (purple ellipses): among them are peroxiredoxin, p34 thioredoxin reductase (p34), and an iron-containing superoxide dismutase (Fe-SOD). Trophozoites can also prevent NO production by converting arginine to ornithine. Amoebae can also synthesize (and make host cells synthesize) PGE₂, which reduces TNF and class II MHC (MHC II) production. The above-described mechanisms that E. histolytica uses to subvert the inflammatory response appear to be essential for ALA development, along with other amoebic features supported by the Gal/GalNAc lectin, lytic proteins like amoebapores and CPs (white ellipses), and molecules of unknown function (black ellipses), such as the virulence factor KERP1.