Kinetoplastids: related protozoan pathogens, different diseases

Abstract

Kinetoplastids are a group of flagellated protozoans that include the species Trypanosoma and Leishmania, which are human pathogens with devastating health and economic effects. The sequencing of the genomes of some of these species has highlighted their genetic relatedness and underlined differences in the diseases that they cause. As we discuss in this Review, steady progress using a combination of molecular, genetic, immunologic, and clinical approaches has substantially increased understanding of these pathogens and important aspects of the diseases that they cause. Consequently, the paths for developing additional measures to control these "neglected diseases" are becoming increasingly clear, and we believe that the opportunities for developing the drugs, diagnostics, vaccines, and other tools necessary to expand the armamentarium to combat these diseases have never been better.

Deoxyhypusine Modification of Eukaryotic Translation Initiation Factor 5A (eIF5A) Is Essential for Trypanosoma brucei Growth and for Expression of Polyprolyl-containing Proteins

“…1B). To confirm that TbeIF5A is modified by deoxyhypusine/hypusine in vivo, PF T. brucei were incubated with the spermidine precursor [1,[4][5][6][7][8][9][10][11][12][13][14] C]putrescine for 48 h to determine whether radioactivity would be incorporated into TbeIF5A. [1,4-14 C]Putrescine is converted to [ 14 C]spermidine by spermidine synthase, providing the radiolabeled form of spermidine to serve as a substrate for deoxyhypusination of eIF5A.…”

“…Human African trypanosomiasis, also known as sleeping sickness, is a fatal vector-borne disease caused by the single celled parasitic protozoan Trypanosoma brucei (1)(2)(3)(4). Although the disease reached epidemic levels in the 1990s, the World Health Organization now reports fewer than 10,000 cases, although millions in sub-Saharan Africa remain at risk (5).…”

An Essential Type I Nitroreductase from Leishmania major Can Be Used to Activate Leishmanicidal Prodrugs

“…These infections are endemic in 88 countries around the world with ϳ350 million people living in "at risk" areas (1). Recently, as a result of military activity, population migration, modern medical practices, intravenous drug usage, and global warming, leishmaniasis has emerged as a problem in nonendemic areas (2)(3)(4).…”

“…Use of the frontline antimonial-based therapies is problematic as they are toxic, clinical resistance is on the rise, and they often require medical supervision to administer (5). Recent progress has been made in developing new leishmanicidal agents with several compounds such as amphotericin B, paromomycin, and miltefosine coming to market (1). However, there are issues associated with the use of these as they are expensive and require medical administration with some having teratogenic and other unwanted toxicity problems (6).…”

Inhibition of Isoleucyl-tRNA Synthetase as a Potential Treatment for Human African Trypanosomiasis

“…The amino acid sequence of IleRS is conserved among T. brucei, Trypanosoma cruzi, and Leishmania sp. Because the genomes of these parasites are highly conserved (18), the validation of drug targets and the discovery of inhibitors for T. brucei may also aid in the development of new drugs for leishmaniasis and Chagas disease (19,20).…”