Gender Is a Major Determinant of the Clinical Evolution and Immune Response in Hamsters Infected withLeishmaniaspp

Abstract

In regions where leishmaniasis is endemic, clinical disease is usually reported more frequently among males than females. This difference could be due to disparate risks of exposure of males and females, but genderrelated differences in the host response to infection may also play a role. Experimental studies of the influence of gender on Leishmania infection have not included parasites of the subgenus Viannia, which is the most common cause of cutaneous leishmaniasis in the Americas. Mice are not readily susceptible to infection by Leishmania (Viannia) spp., but cutaneous infection of hamsters with L. (V.) panamensis or L. (V.) guyanensis resulted in chronic lesions typical of the human disease caused by these parasites. Strikingly, infection of male hamsters resulted in significantly greater lesion size and severity, an increased rate of dissemination to distant cutaneous sites, and a greater parasite burden in the draining lymph node than infection in female animals. Two lines of evidence indicated this gender-related difference in disease evolution was determined at least in part by the sex hormone status of the animal. First, prepubertal male animals had smaller and/or less severe cutaneous lesions than adult male animals. Second, infection of testosterone-treated female animals resulted in significantly larger lesions than in untreated female animals. The increased severity of disease in male compared to female animals was associated with significantly greater intralesional expression of interleukin-4 (IL-4) (P ‫؍‬ 0.04), IL-10 (P ‫؍‬ 0.04), and transforming growth factor ␤ (TGF-␤) (P < 0.001), cytokines known to promote disease in experimental leishmaniasis. There was a direct correlation between the expression of TGF-␤ mRNA and lesion size (Spearman's correlation coefficient ‫؍‬ 0.873; P < 0.001). These findings demonstrate an inherent risk of increased disease severity in male animals, which is associated with a more permissive immune response.The outcome of Leishmania infection depends on several biological traits of both the host and the infecting parasite strain. A number of epidemiological studies indicate that leishmaniasis occurs more frequently among adult males than females (3,13,38). It is unclear whether this difference is due merely to dissimilar risks of exposure because of the distinct activities of males and females or whether gender-related differences in the host immune response play a role in resistance and susceptibility to infection.Epidemiological data for children Ͻ15 years of age, where both genders would seem to have similar risks of infection, indicate that boys are threefold more likely to develop visceral leishmaniasis than girls (35). Similarly, the disease rate for cutaneous leishmaniasis in an area of Brazil where the disease is endemic was shown to be 50% higher in males than females in all age groups, including children, who are expected to have comparable risks of exposure for both sexes (13). In studies of several different endemic foci in both the New and Old Worlds, re...

Immunity to a salivary protein of a sand fly vector protects against the fatal outcome of visceral leishmaniasis in a hamster model

“…An additional factor in the success of the current model is the use of male hamsters (29). It was previously demonstrated that host gender has a significant influence on the clinical evolution and immunological response to Leishmania (Viannia) infection (29). Taken together, we were able to reliably and reproducibly bring about a rapid onset of progressive disease in 3-to 4-month-old hamsters.…”

“…In the current model, the rapid onset of clinical symptoms in older hamsters could be the result of the inoculation of parasites in a highly vascularized tissue (the ear) facilitating visceralization and establishment of disease. An additional factor in the success of the current model is the use of male hamsters (29). It was previously demonstrated that host gender has a significant influence on the clinical evolution and immunological response to Leishmania (Viannia) infection (29).…”

Urban Transmission of American Cutaneous Leishmaniasis in Argentina: Spatial Analysis Study

“…This difference could be caused by sex-related higher susceptibility to the disease, which has been suggested in animal studies in a hamster model. 36 Additionally, a continuous increase in the strength of association between age and prevalence for cases in persons > 15 years of age was also observed. This increase may be related to the inception or intensification of labor and recreational activities (e.g., fishing and hunting) in younger persons.…”

Variables associated with the post-treatment healing of lesions in patients with American cutaneous leishmaniasis in Paraná State, Brazil

“…Neither IFA positivity at initial diagnosis, nor the time of the first return for evaluation of treatment, were found to be factors associated with the healing of lesions. No differences in lesion healing between men and women were found, despite the findings of Travi et al (2002), who studied hamsters infected with Leishmania (Viannia) and observed that the immune response was more permissive to infection among males than females. The factors that contribute to the cutaneous disease evolving into one of the later forms are not fully understood, but delay in healing the first lesion and inadequate treatment are both known predictors (Carvalho et al, 1995).…”