C4: Improved diagnosis and therapy of visceral Leishmaniasis

Project description:

A reliable diagnosis and treatment of humans and dogs (reservoir host) suffering from visceral leishmaniasis (VL) is crucial for the control of this infection. Currently available diagnostic tests based on the antibody reaction with the Leishmania kinesin protein show poor sensitivity in some endemic areas. We have developed and patented a kinesin antigen (rKLi8.3) with an improved diagnostic performance in humans and animals. This was possible by developing a kinesin antigen with an optimized kinesin structure (repeats) and sequence. Currently various test formats with the rKLi 8.3 antigen are produced and tested with sera from infected humans and dogs.

The treatment of VL is problematic in terms of effectiveness and side effects. An inhibitor (GNF-6702) that selectively inhibits the proteasome of the Kinetoplastida (T. brucei, T. cruzei and L. donovani) has been developed. GNF-6702 binds to a proteasome subunit of Kinetoplastida (beta 4 subunit) that is structurally distinct from humans. The specific bind-ing to the kinetoplast proteasome seems to be the reason for the very low toxicity in mam-malian cells. We could demonstrate that the proteasomal beta 4 subunit is conserved in all Leishmania isolates, tested to date. Thus, the proteasome is a promising therapeutic target.

Scientific goal:

In the diagnostic part of the project, various formats of a sero-diagnostic VL rapid test will be manufactured and tested in cooperation with our industrial partner. In the treatment part of the project, we validate the specificity, effectiveness and toxicity of the new, kinetoplastid-specific proteasome inhibitors in cell culture experiments of Leishmania infected macrophages.

DRUID Collaboration partners:

B1 Diederich/Kolb lab, C2 Kempf lab, D3 van Zandbergen lab

References C4: [1] Abass et al. (2013) PLoS Negl Trop Dis. 18;7; [2] Abass et al. (2015) PLoS One. 3;10; [3] Martínez Abad et al. (2017) Acta Trop. 166:133-138; [4] Pereira et al. (2020) Eur J Microbiol Immunol 27;10:165-171. [5] Khare et al. (2016) Nature 537: 229-233