Sex-Related Differences in Immune Response and Symptomatic Manifestations to Infection with Leishmania Species

Abstract

Worldwide, an estimated 12 million people are infected with Leishmania spp. and an additional 350 million are at risk of infection. Leishmania are intracellular parasites that cause disease by suppressing macrophage microbicidal responses. Infection can remain asymptomatic or lead to a spectrum of diseases including cutaneous, mucocutaneous, and visceral leishmaniasis. Ultimately, the combination of both pathogen and host factors determines the outcome of infection. Leishmaniasis, as well as numerous other infectious diseases, exhibits sex-related differences that cannot be explained solely in terms of environmental exposure or healthcare access. Furthermore, transcriptomic evidence is revealing that biological sex is a variable impacting physiology, immune response, drug metabolism, and consequently, the progression of disease. Herein, we review the distribution, morbidity, and mortality among male and female leishmaniasis patients. Additionally, we discuss experimental findings and new avenues of research concerning sex-specific responses in cutaneous and visceral leishmaniasis. The limitations of current therapies and the emergence of drug-resistant parasites underscore the need for new treatments that could harness the host immune response. As such, understanding the mechanisms driving the differential immune response and disease outcome of males versus females is a necessary step in the development of safer and more effective treatments against leishmaniasis.

Genetic variation in Interleukin-32 influence the immune response against New World Leishmania species and susceptibility to American Tegumentary Leishmaniasis

“…Using ancestry-informative DNA polymorphisms in individuals from the four most populous regions of the country, a previous study has unraveled great ancestral diversity between and within different regions of the country [57]. Thus, although the sex-related differences in ATL susceptibility was not addressed in the present study, data from across Brazil show that males are more susceptible to develop cutaneous manifestations of leishmaniasis than females [58]. Since this is first study investigating the role of genetic variations in IL32 associated with susceptibility to ATL, the use of a collective dataset including for genetic associated studies with large number of samples as well as matched asymptomatic and healthy controls, epidemiological variables and host biological factors respresent a promising new endeavor within the scientific community in the field of Leishmania research in Brazilian subjects.…”

Cutaneous leishmaniasis in north-central Ethiopia: trend, clinical forms, geographic distribution, and determinants

“…Cultural activities that mostly males are faced with outdoor activities including farming, keeping cattle, staying around gorges, and/or farmland for a long period and the presence of endemic sites that mostly males could travel there for work. Furthermore, the gender difference in CL incidence is attributable to sex hormonal effects or immune responses [42], as it has been noted in some other parasitic diseases [43]. Differences in exposure or access to healthcare per se do not necessarily explain genderbased differences for infection or clinical disease.…”

Male predominance in reported Visceral Leishmaniasis cases: Nature or nurture? A comparison of population-based with health facility-reported data

“…Unfortunately, no information on outcome of the disease was available for our study. Important to note is that these sex-related differences seem to be dependent on the leishmania species, the host species, and the affected tissue [34,35]. While all data on L. donovani show the incidence of VL in humans to be higher in males than in females, for L. tropica the opposite has been observed in more than one study [36,37].…”

“…Overall, the median age of VL patients identified through the cohort studies was 18 years (IQR 9-39). The median age of VL patients identified was significantly different among the specific study-sites; 10 years in Kalanet India (IQR 7-27), 35 in Kalanet Nepal (IQR 14-42) and 19 years in TMRC (IQR 9-39) (p-value <0.001). Median age in male VL patients was significantly higher than in females; 19 years (IQR 9-42) for males versus 16 years (IQR 8-33) for females (p-value = 0.001).…”