Sleeping Sickness in the ‘Omics Era

Abstract

Sleeping sickness is a neglected tropical disease caused by Trypanosoma brucei parasites, affecting the poorest communities in sub-Saharan Africa. The great efforts done by the scientific community, local governments, and non-governmental organizations (NGOs) via active patients' screening, vector control, and introduction of improved treatment regimens have significantly contributed to the reduction of human African trypanosomiasis (HAT) incidence during the last 15 years. Consequently, the WHO has announced the objective of HAT elimination as a public health problem by 2020. Studies at both parasite and host levels have improved our understanding of the parasite biology and the mechanisms of parasite interaction with its mammalian host. In this review, the impact that 'omics studies have had on sleeping sickness by revealing novel properties of parasite's subcellular organelles are summarized, by highlighting changes induced in the host during the infection and by proposing potential disease markers and therapeutic targets.

In cellulo crystallization of Trypanosoma brucei IMP dehydrogenase enables the identification of genuine co-factors

“…In 1994, an IMPDH encoding gene was identified in the genome of T. brucei 20 . Transmitted by tsetse flies, this protozoan parasite, which still represents a severe human pathogen 21 , infects the blood and the lymphatic system before invading the brain, causing clinical manifestations within weeks or months that are denoted as human African trypanosomiasis (HAT), or sleeping sickness. As the metabolic pathway for the production of purine nucleotides is conspicuously different between parasites and the human hosts, TbIMPDH was proposed to represent a suitable target for anti-trypanosomal drugs to treat T. brucei infections, strongly supported by enzymatic differences of TbIMPDH compared to the human counterparts 22 .…”

Experimental Strategies to Explore Drug Action and Resistance in Kinetoplastid Parasites

“…Untargeted transcriptomics to compare treated versus untreated parasites was only performed once in T. cruzi [ 78 ]. However, the evaluation of mRNA transcript abundance in kinetoplastids has mostly been used in fundamental biology studies evaluating changes in expression between the various life cycle stages or to evaluate host-pathogen interactions [ 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. The measurement of RNA levels can provide a broad range of information, but it should be kept in mind that gene expression in kinetoplastids relies on post-transcriptional regulation.…”

“…In kinetoplastids, proteomics have been used to understand the differentiation processes in the various life cycle stages, to identify biomarkers, to support vaccine development, as well as to elucidate the MoA/MoR of drugs ( Table 4 ) [ 85 , 138 , 139 , 140 , 141 ]. Several techniques can be used to compare the relative protein expression, but most employ labelling techniques such as 2D differential gel electrophoresis (2D-DIGE), stable isotope labeling of amino acids in cell culture (SILAC), or isobaric tags for relative and absolute quantitation (iTRAQ) [ 18 , 142 ].…”

“…Most studies employing proteomics, especially in Leishmania , compared sensitive to resistant strains to elucidate the MoR of drugs. In contrast, most studies in T. cruzi and T. brucei compared treated and untreated samples to evaluate the MoA, resulting in a large number of possibly involved proteins that need further mining and follow-up studies to confirm their actual involvement [ 79 , 85 ]. The extracellular parasite stages are mostly used in these proteomics studies, which is not ideal as the proteome may differ depending on the life cycle stage [ 157 , 158 , 159 , 160 ].…”

Proteomics‐Based Investigations of Neglected and Tropical Diseases

“…Owing to the significant contribution of scientific community and NGOs, trypanosomiasis has significantly reduced in Africa. A review article by Tibeti and Sanchez has highlighted the impact of “omics” studies to identify the disease markers and therapeutic targets in human African trypanosomiasis. A viewpoint article by Srivastava and colleagues have also described applications of proteomics‐based approaches to study infectious diseases and how advances in “omics” technologies and integration of multi‐omics analysis could contribute to better understanding of disease pathogenesis.…”