Sexual Dimorphism in the Control of Amebic Liver Abscess in a Mouse Model of Disease

Abstract

Amebic liver abscess (ALA) is the most common extraintestinal manifestation of human infection by the enteric protozoan parasite Entamoeba histolytica. In contrast to intestinal infection, ALA greatly predominates in males but is rare in females. Since humans are the only relevant host for E. histolytica, experimental studies concerning this sexual dimorphism have been hampered by the lack of a suitable animal model. By serial liver passage of cultured E. histolytica trophozoites in gerbils and mice, we generated amebae which reproducibly induce ALA in C57BL/6 mice. Interestingly, all animals developed ALA, but the time courses of abscess formation differed significantly between the genders. Female mice were able to clear the infection within 3 days, whereas in male mice the parasite could be recovered for at least 14 days. Accordingly, male mice showed a prolonged time of recovery from ALA. Immunohistology of abscesses revealed that polymorphonuclear leukocytes and macrophages were the dominant infiltrates, but in addition, ␥,␦-T cells, NK cells, and natural killer T (NKT) cells were also present at early times during abscess development, whereas conventional ␣,␤-T cells appeared later, when female mice had already cleared the parasite. Interestingly, male and female mice differed in early cytokine production in response to ameba infection. Enzyme-linked immunospot assays performed with spleen cells of infected animals revealed significantly higher numbers of interleukin-4-producing cells in male mice but significantly higher numbers of gamma interferon (IFN-␥)-producing cells in female mice. Early IFN-␥ production and the presence of functional NKT cells were found to be important for the control of hepatic amebiasis as application of an IFN-␥-neutralizing monoclonal antibody or the use of NKT knockout mice (V␣14iNKT, J␣ 18؊/؊ ) dramatically increased the size of ALA in female mice. In addition, E. histolytica trophozoites could be reisolated from liver abscesses of J␣18 ؊/؊ mice on day 7 postinfection, when wild-type mice had already cleared the parasite. These data suggest that the sexual dimorphism in the control of ALA is due to gender-specific differences in early cytokine production mediated at least in part by NKT cells in response to E. histolytica infection of the liver.Entamoeba histolytica, the causative agent of human amebiasis, is endemic in most tropical and subtropical countries and is considered to be responsible for tens of millions of cases of dysentery and liver abscesses each year (32, 33). Following fecal-oral transmission, the parasite colonizes the large bowel, where it multiplies and may persist for months or even years as an asymptomatic luminal gut infection (3). Only in about 10% of infected individuals does the parasite penetrate the intestinal mucosa and induce colitis or disseminate to other organs, and it most commonly disseminates to the liver, where it induces abscess formation (13). At present, the factors that trigger ameba invasion are largely unknown.Another unresolved enig...

Epidemiology of Domestically Acquired Amebiasis in Japan, 2000–2013

“…[1][2][3][8][9][10]14,27,28 The specific reason(s) for the observed gender difference in the Japanese surveillance data requires further investigation.…”

“…However, the absolute risk of amebiasis for females appears to be lower, as predominance of male amebiasis cases has been reported consistently from various locations that differ culturally, racially, and socioeconomically, 8,10 and females appear to be less affected by amebiasis (e.g., liver abscess), 26,27 which has also been found in animal studies. 28 Moreover, while a higher proportion of males in their 50s are screened for colon cancer during annual *Cases with specific colonic mucosa lesions, such as erythema, edematous mucosa, erosion, white exudates, and ulcers, but otherwise asymptomatic and reported through National Epidemiological Surveillance of Infectious Diseases, were classified as asymptomatic cases.…”

Amebiasis: aspectos clínicos, terapéuticos y de diagnóstico de la infección

“…También el absceso hepático amebiano (AHA) es más frecuente en hombres 24 . Estudios realizados en ratones sugieren que el aumento del interferón-g y las células T citotóxicas en las mujeres pudieran determinar la resistencia al AHA 31 , habiéndose observado además que, los sueros de hombres y mujeres difieren en la habilidad de lisar a E. histolytica in vitro 32 .…”

Gender Difference in the Composition of Fecal Flora in Laboratory Mice, as Detected by Denaturing Gradient Gel Electrophoresis (DGGE)

“…Even in identical inbred strains, male and female mice are genetically different in ways other than just gender. In fact, gender differences in the severity of infectious diseases and in the immune system have been reported [1,2,10,16,17,27]. Therefore, it is important to elucidate the interrelationships between the composition of intestinal flora and gender-specific phenomena in mice, including infection, immunity, and other physiological phenomena.…”