Entamoeba histolytica–Encoded Homolog of Macrophage Migration Inhibitory Factor Contributes to Mucosal Inflammation during Amebic Colitis

Abstract

Understanding the mechanisms by which Entamoeba histolytica drives gut inflammation is critical for the development of improved preventive and therapeutic strategies. E. histolytica encodes a homolog of the human cytokine macrophage migration inhibitory factor (MIF). Here, we investigated the role of E. histolytica MIF (EhMIF) during infection. We found that the concentration of fecal EhMIF correlated with the level of intestinal inflammation in persons with intestinal amebiasis. Mice treated with antibodies that specifically block EhMIF had reduced chemokine expression and neutrophil infiltration in the mucosa. In addition to antibody-mediated neutralization, we used a genetic approach to test the effect of EhMIF on mucosal inflammation. Mice infected with parasites overexpressing EhMIF had increased chemokine expression, neutrophil influx, and mucosal damage. Together, these results uncover a specific parasite protein that increases mucosal inflammation, expands our knowledge of host-parasite interaction during amebic colitis, and highlights a potential immunomodulatory target.

Tissue Destruction Caused by Entamoeba histolytica Parasite: Cell Death, Inflammation, Invasion, and the Gut Microbiome

“…Many parasitic pathogens, including E. histolytica , express a homolog of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) [ 24 – 28 , 29 ••]. E. histolytica MIF ( Eh MIF) was recently shown to be a crucial parasite mediator of gut inflammation [ 29 ••]. A positive correlation was found between Eh MIF levels and intestinal inflammation in persons with amebic colitis.…”

“…A positive correlation was found between Eh MIF levels and intestinal inflammation in persons with amebic colitis. Eh MIF induced chemokine expression, neutrophil influx, and mucosal damage in cellular and mouse models of amebiasis [ 29 ••]. Also, Eh MIF enhanced TNF-α production by macrophages [ 25 ].…”

“…Also, Eh MIF enhanced TNF-α production by macrophages [ 25 ]. Infected children develop antibodies against Eh MIF, which correlates with protection from future infection [ 25 , 29 ••]. These studies suggest that Eh MIF might have a role as an effective immunomodulatory target to prevent or reduce immunopathology in amebiasis.…”

“…Eh MIF has been found to influence the levels of MMP production. The inflammation induced by Eh MIF resulted in an increase in MMP production [ 29 ••]. Therefore, E. histolytica parasites may produce MIF to exploit the host inflammatory response to promote tissue invasion.…”

Learning from the research on amebiasis and gut microbiome: Is stimulation by gut flora essential for effective neutrophil mediated protection from external pathogens?

“…22 Notably, in in vivo experiments, it was shown that the anti-inflammatory cytokine IL-10 is protective in E. histolytica infection by counteracting an exaggerated proinflammatory immune response by inhibiting the production of proinflammatory mediators, such as TNF-α. 23 Interestingly, E. histolytica secretes cytokine-like proteins such as prostagrandin-E2 24,25 and mammalian inflammatory factor during tissue invasion, 26,27 which induces excessive proinflammatory responses by neutrophils at the infection site. Thus, neutrophils play a critical role both in the protection against tissue invasion by E. histolytica and in the promotion of tissue damage by E. histolytica.…”