Abstract
Entamoeba histolytica is an invasive enteric protozoan, whose infections are associated to high morbidity and mortality rates. However, only less than 10% of infected patients develop invasive amebiasis. The ability of E. histolytica to adapt to the intestinal microenvironment could be determinant in triggering pathogenic behavior. Indeed, during chronic inflammation, the vagus nerve limits the immune response through the anti-inflammatory reflex, which includes acetylcholine (ACh) as one of the predominant neurotransmitters at the infection site. Consequently, the response of E. histolytica trophozoites to ACh could be implicated in the establishment of invasive disease. The aim of this study was to evaluate the effect of ACh on E. histolytica virulence. Methods include binding detection of ACh to plasma membrane, quantification of the relative expression of virulence factors by RT-PCR and western blot, evaluation of the effect of ACh in different cellular processes related to E. histolytica pathogenesis, and assessment of the capability of E. histolytica to migrate and form hepatic abscesses in hamsters. Results demonstrated that E. histolytica trophozoites bind ACh on their membrane and show a clear increase of the expression of virulence factors, that were upregulated upon stimulation with the neurotransmitter. ACh treatment increased the expression of L220, Gal/GalNAc lectin heavy subunit (170 kDa), amebapore C, cysteine proteinase 2 (ehcp-a2), and cysteine proteinase 5 (ehcp-a5). Moreover, erythrophagocytosis, cytotoxicity, and actin cytoskeleton remodeling were augmented after ACh treatment. Likewise, by assessing the formation of amebic liver abscess, we found that stimulated trophozoites to develop greater hamster hepatic lesions with multiple granulomas. In conclusion, ACh enhanced parasite pathogenicity by upregulating diverse virulence factors, thereby contributing to disease severity, and could be linked to the establishment of invasive amebiasis.
Highlights
Entamoeba histolytica, an enteric protozoan parasite, is the causative agent of amebiasis, a worldwide-spread disease, for which 50 million new infections and over 100,000 deaths are estimated every year (Stanley, 2003; Bercu et al, 2007)
Invasive amebiasis could be associated to the parasite’s virulence state, together with environmental conditions and host susceptibility, the present study demonstrates that ACh upregulates E. histolytica virulence factors, thereby promoting phagocytosis, cytopathic effect on liver cells, and liver abscess formation in a hamster model
ACh could be implicated in the establishment of invasive amebiasis (Leon-Coria et al, 2020)
Summary
An enteric protozoan parasite, is the causative agent of amebiasis, a worldwide-spread disease, for which 50 million new infections and over 100,000 deaths are estimated every year (Stanley, 2003; Bercu et al, 2007). Amebic infections are asymptomatic; less than 10% of the infected patients develop extraintestinal disease (Walsh, 1986) This data suggests that most of the population might carry commensal trophozoites, which under certain stimuli or environmental conditions could switch from a commensal to a pathogenic stage. The life cycle of E. histolytica begins when infective cysts are ingested and travel through the gastrointestinal tract until reaching the colon; excystation occurs and the trophozoites colonize the gut lumen. This step is thought to be critical, in which the ameba can behave as a commensal or pathogen (Ali et al, 2012). Acute amebiasis could result from the parasite’s ability to respond to extracellular cues and from its rapid adaptation to environmental conditions that trigger the ameba’s invasive behavior (Labruyère et al, 2019)
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