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Sleeping sickness or not? Insight into differential trypanosome infectivity
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A new study has shed light on factors that cause some species of the trypanosome parasites to be infective of humans while other aren’t. The study, published in the journal PLoS Pathogens, was carried out by researchers in the London School of Hygiene and Tropical Medicine and the University of Dundee.

African trypanosomes, which are tsetse fly-transmitted protozoan parasites of the genus Trypanosoma, cause devastating diseases in both humans and livestock. The different members of the group are distinguished by their sensitivity to innate immune factors in human serum, which results in different host infectivity. The species Trypanosoma brucei brucei infects cattle, causing the disease nagana, but humans are resistant. On the other hand, the species T. b. gambiense and T. b. rhodesiense infect humans, causing sleeping sickness in Western and Eastern Africa respectively. Distinguishing the factors that cause T. b. brucei to be sensitive to the innate immune response in humans, which is the rapid, first-line immune response, could facilitate development of badly needed new drugs. The existing drugs for sleeping sickness have serious and unpleasant side-effects.

In the new study, the researchers carried out a comprehensive RNA interference (RNAi) screen of the T. b .brucei genome in order to identify factors that reduced their sensitivity to human serum factors. This entailed use of a library of small T. b. brucei RNA molecules designed to interfere with expression of mRNA from T. b. brucei genes. This strategy enabled the research team to identify four genes that sensitised the trypanosome to human serum factors. These included three previously identified genes, namely the haptoglobin-haemoglobin receptor, a lysosomal membrane protein called p67 and inhibitor of cysteine peptidase (ICP). The fourth gene was a previously unidentified gene predicted to encode a so-called transmembrane channel which might be predicted to take up human defence factors.

The research team studied ICP in more detail and discovered that it induced sensitivity to human serum innate immunity factors by modulating the activity of an enzyme called cathepsin-L (CATL). CATL is a member of a family of proteins called lysosomal cysteine peptidases, which can degrade proteins and thereby help overcome the immune factors in human serum. CATL modulation by ICP appears to be an important factor in T. b. brucei sensitivity to human immune responses. If ICP was down-regulated, CATL remained fully active and able to degrade human serum immune factors.

CATL is currently the target of proposed new drugs for sleeping sickness; the results of the current study suggest that it would be an effective strategy. However, the authors of this study urge caution and increased understanding of how CATL interacts with other trypanosomal factors involved in infectivity. Lead author Dr Sam Alsford explains: “CATL is under consideration as a potential drug target, and our results suggest that its inactivation could indeed support the human defense system in fighting off disease-causing trypanosome strains. However, as CATL might also be involved in the generation or break-down of other factors involved in parasite-host interactions, it will be important to develop an improved understanding of the complex interplay of all of these factors in human-infective trypanosomes”.

Future plans for the researchers include elucidation of the role of the new gene identified as a result of their research. In all, the study increased understanding of the interaction between trypanosomes and the human innate immune system, which can only be of benefit in consideration of new, safe therapeutic strategies.

Sources:

Alsford, S., Currier, R.B., Guerra-Assunção, J.A., Clark, G. and Horn, D. (2014) Cathepsin-L Can Resist Lysis by Human Serum in Trypanosoma brucei brucei. PLoS Pathog 10(5): e1004130. doi:10.1371/journal.ppat.1004130

Press release: PLoS Pathogens
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Sleeping sickness or not? Insight into differential trypanosome infectivity00