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.
Highlights
There is abundant transforming growth factor-β (TGF-β) in the organs of BALB/c mice as well as bone marrow of VL patients infected with L. infantum, recent studies have shown that progressive visceral leishmaniasis in humans and mouse models is associated with IL-10-producing CD4 + T cells [128,129,130,131,132]
The ultimate outcome of Leishmania infection will depend on a multitude of host-pathogen interactions and the development, or lack thereof, of immune responses that restrict parasite growth [2, 65]
Collective data from experimental models and studies of human infection suggest that there are biological predispositions leading to sex-specific parasite burden and symptomatic disease during infection with Leishmania spp
Summary
Sex-related differences in immunophysiology may underlie distinct male or female susceptibility to certain cancers and autoimmune conditions as well as infectious diseases, including several that are caused by parasites [8, 12,13,14,15,16]. Both pathogen and host factors likely drive these dichotomous rates in disease [16,17,18]. We outline ongoing efforts to elucidate the immune mechanisms contributing to sex-specific responses in disease
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