Influence of biological sex on the infection of human macrophages with Leishmania parasites and response to immunostimulatory therapy
Dr. Helena Fehling, Annika Bea
Many parasitic diseases occur with a sex-bias in terms of incidence, morbidity and mortality towards male individuals. Leishmaniasis is such an example as significantly higher number of cases are present in male patients in various endemic areas. However, this phenomenon cannot only be explained by cultural or behavioral determinants, indicating that biological factors can alter the susceptibility towards an infection and influence the outcome of the disease. Besides sex steroid hormones, such as testosterone or estradiol, chromosomal factors (XX, XY) can affect the host immune response and potentially the pathogenic agent respectively. Leishmania parasites can survive and multiply in innate immune cells, such as macrophages or dendritic cells, while suppressing an effective clearance of the parasite by creating an anti-inflammatory environment. Macrophages are the primary host cells and the key players to determine the outcome of the infection. To understand biological sex differences in leishmaniasis, we investigate the influence of the host sex in the infection of macrophages by Leishmania ssp. on a cellular, molecular biological and immunological level.
Since intracellular microorganisms such as Leishmania parasites or bacteria of the genus Mycobacterium that target immune cells can circumvent their clearance by manipulating the innate and the acquired immune response of the host, immune stimulatory molecules that activate or re-activate target cells such as macrophages represent promising therapeutic tools for the treatment of these diseases.
We recently isolated such an immunostimulatory molecule from the membrane of Entamoeba (E.) histolytica, a lipopeptidephosphoglycan (EhLPPG). The native molecule exhibited considerable immune cell stimulation leading to the reduction of the intracellular load of leishmania parasites in vitro and in a mouse model for the disease. In cooperation with Prof. Yukari Fujimoto from the Keio University in Japan and Prof. Chris Meier from the University of Hamburg we developed a series of synthetic analogs deduced from the two Phosphatidylinositol anchors of EhLPPG. So far, several analogs reproduced the anti-leishmanial activity of the parent compound in vitro and in vivo, presumably by inducing production of pro-inflammatory cytokines, and exhibited bactericidal activity against Mtb in vitro (Patent BNI002).
Funding Annika Bea: https://www.joachim-herz-stiftung.de/