Leishmaniasis is a debilitating infectious disease, with clinical manifestations ranging from skin lesions to fatal visceral infections. This sandfly-borne parasitic disease results from infection of human macrophages with trypanosomatid protozoan parasites belonging to the genus Leishmania. Current treatments for leishmaniasis are inadequate due to their high cost, low efficacy, toxicity, and the increasing incidence of drug-resistant strains. Consequently, it is vitally important to identify new targets for therapies against Leishmania. Using bioinformatic strategies, we have identified a class of Leishmania genes previously not studied in trypanosomatid protozoans. These genes code for AT-hook proteins, a class of proteins that participate in multiple cellular processes, including DNA replication, and transcription. The importance of these processes is indicated by their conservation across all species. DNA replication and transcription have served as targets for the development of anti-microbials, including anti-retroviral therapies against HIV to reduce disease burden in AIDS patients. The essential nature of DNA replication and transcription for the survival/replication of all pathogens renders them attractive targets against diseases associated with Leishmania infections. Therefore, elucidating the role of AT-hook proteins in Leishmania promises new avenues through which effective novel therapeutics against this protozoan parasite may be developed. As their name suggests, AT-hook proteins bind AT-rich DNA. Although Leishmania genomes are highly GC-rich, they contain AT-rich sequences, some of which lie in """"""""strand-switch regions"""""""" that are associated with initiation of RNA transcription. Toward understanding the role of AT-hook proteins in the biology of Leishmania, we have chosen to study the Leishmania major gene, LmjF06.0270, that is predicted to encode a 180 kD AT-hook protein. LmjF06.0270 was selected because it is highly conserved in all Leishmania species, but is absent in other eukaryote species, including closely-related trypanosomatids such as Trypanosoma and Crithidia. Therefore, LmjF06.0270 represents a novel target against diseases caused by all species of Leishmania. In this application, we have proposed studies to characterize the molecular functions of LmjF06.0270. In addition, based on known properties of AT-hook proteins conserved from Archaebacteria to metazoan eukaryotes, we propose to exploit LmjF06.0270 to develop a novel tool that will significantly augment genetic and molecular studies in all Leishmania species.
Leishmaniasis threatens 350 million people worldwide, with 500,000 new cases of fatal visceral leishmaniasis each year. The WHO estimates that this often debilitating and fatal disease is widespread in 88 countries worldwide, affecting Americans working in endemic areas, including military personnel. The goal of this research is to develop therapies to reduce these numbers, thus alleviating suffering and promote human health and productivity.
| Cardenas, Daviel; Carter, Pamela M; Nation, Catherine S et al. (2015) LACK, a RACK1 ortholog, facilitates cytochrome c oxidase subunit expression to promote Leishmania major fitness. Mol Microbiol 96:95-109 |
