Ben Kelly, Ph.D.

Molecular mechanisms required for parasite viability and virulence in leishmaniasis.

Leishmaniasis is an infectious disease that impacts approximately 12 million people worldwide. This sandfly-borne parasitic disease is caused by infection of vertebrate host macrophages with trypanosomatid protozoa from the genus Leishmania.

The pathogenesis of leishmaniasis is biologically fascinating yet clinically frustrating since it encompasses a large diversity of pathologies that are difficult to treat. These pathologies range from self-healing skin lesions to lethally disseminating visceral disease.

Current treatments for leishmaniasis remain inadequate due largely to their toxic side effects in humans, high cost and the increasing incidence of drug-resistant parasite strains. We are interested in identifying pathogenically important parasite molecules and their molecular mechanism of action as potential targets for new, effective anti-parasitic therapies.

The pathogenic success of Leishmania relies on its ability to transform between the promastigote (insect form) and amastigote (macrophage form) stages of its life cycle by responding to environmental changes it encounters during transition between its vertebrate and insect hosts. Despite its importance, however, our understanding of how this parasite environmental response works at the molecular level remains very limited. We are especially interested in elucidating parasite signaling/response pathways that are important for parasite transformation and stage-specific replication during the infectious life cycle of Leishmania. 

Current research projects: 

I. Determining the role of LACK, a putative spatial regulator of parasite signaling pathways, in Leishmania 

We have determined that LACK, the Leishmania ortholog of RACK1, a multi functional spatial regulator of signaling pathways and other processes in mammalian and yeast cells, as being especially critical for disease development in leishmaniasis. Our studies indicate it is particularly important in amastigote replication. We are currently investigating molecular mechanisms that underlie the importance of LACK in Leishmania, including determining its role in protein translation and identifying LACK-binding partners.

II. Characterizing the function of an “AT-hook” binding protein in Leishmania

In collaboration with Dr. Ashok Aiyar (LSUHSC Department of Microbiology, Immunology and Parasitology) we are investigating the function of a Leishmania protein that contains an “AT-hook” chromosome binding domain. We have demonstrated that this protein has chromosome binding functions similar to other AT-hook proteins. Furthermore, we have also shown that drugs which specifically inhibit the binding of AT-hook proteins to DNA also disrupt the nuclear localization of this domain and inhibit parasite replication. We have also used a novel AT-hook inhibitor to preferentially hinder Leishmania replication, with minimal effect on macrophage host cells.