Chagas- Kissing Bug Disease
Selected Abstracts
Nature. 2016 Aug 8. doi: 10.1038/nature19339. [Epub ahead of print]
Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness.
Khare S1, Nagle AS1, Biggart A1, Lai YH1, Liang F1, Davis LC1, Barnes SW1, Mathison CJ1, Myburgh E2,3, Gao MY1, Gillespie JR4, Liu X1, Tan JL1, Stinson M1, Rivera IC1, Ballard J1, Yeh V1, Groessl T1, Federe G1, Koh HX5, Venable JD1, Bursulaya B1, Shapiro M1, Mishra PK1, Spraggon G1, Brock A1, Mottram JC2,3, Buckner FS4, Rao SP5, Wen BG1, Walker JR1, Tuntland T1, Molteni V1, Glynne RJ1, Supek F1.
Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually1. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively.
These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drug(s) modulating the activity of a conserved parasite target2. However, no such molecular targets or broad spectrum drugs have been identified to date.
Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection.
GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice.
Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.
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Int J Antimicrob Agents. 2016 Aug 3. pii: S0924-8579(16)30194-7. doi: 10.1016/j.ijantimicag.2016.06.024. [Epub ahead of print]
HIV aspartic peptidase inhibitors are effective drugs against the trypomastigote form of the human pathogen Trypanosoma cruzi.
Sangenito LS1, Gonçalves DS2, Seabra SH3, d'Avila-Levy CM4, Santos AL5, Branquinha MH6.
There is a general lack of effective and non-toxic chemotherapeutic agents against Chagas' disease despite more than a century of research. In this regard, we have verified the impact of human immunodeficiency virus aspartic peptidase inhibitors (HIV-PIs) on the viability and morphology of infective trypomastigote forms of Trypanosoma cruzi as well as on the aspartic peptidase and proteasome activities produced by this parasite.
The effects of HIV-PIs on viability were assessed by counting motile parasites in a Neubauer chamber. Morphological alterations were detected by light microscopy of Giemsa-stained smears and scanning electron microscopy.
Modulation of aspartic peptidase and proteasome activities by the HIV-PIs was measured by cleavage of fluorogenic peptide substrates. The majority of the HIV-PIs (6/9) were able to drastically decrease the viability of trypomastigotes after 4 h of treatment, with nelfinavir and lopinavir being the most effective compounds presenting LD50 values of 8.6 µM and 10.6 µM, respectively.
Additionally, both HIV-PIs were demonstrated to be effective in a time- and cell density-dependent manner. Treatment with nelfinavir and lopinavir caused many morphological/ultrastructural alterations in trypomastigotes; parasites became round in shape, with reduced cell size and flagellar shortening.
Nelfinavir and lopinavir were also capable of significantly inhibiting the aspartic peptidase and proteasome activities measured in trypomastigote extracts.
These results strengthen the data on the positive effects of HIV-PIs on parasitic infections, possibly by targeting the parasite aspartic peptidase(s) and proteasome(s), opening a new possibility for the use of these clinically approved drugs as an alternative chemotherapy to treat Chagas' disease.
Copyright © 2016. Published by Elsevier B.V.
10.1016/j.ijantimicag.2016.06.024
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Mem Inst Oswaldo Cruz. 2005 Dec;100(8):829-32. Epub 2006 Jan 20.
Ticks, ivermectin, and experimental Chagas disease.
Dias JC1, Schofield CJ, Machado EM, Fernandes AJ.
Following an infestation of dogticks in kennels housing dogs used for long-term studies of the pathogenesis of Chagas disease, we examined the effect of ivermectin treatment on the dogs, ticks, trypanosome parasites, and also on triatomine vectors of Chagas disease.
Ivermectin treatment was highly effective in eliminating the ticks, but showed no apparent effect on the dogs nor on their trypanosome infection. Triatominae fed on the dogs soon after ivermectin treatment showed high mortality, but this effect quickly declined for bugs fed at successive intervals after treatment.
In conclusion, although ivermectin treatment may have a transient effect on peridomestic populations of Triatominae, it is not the treatment of choice for this situation.
The study also showed that although the dogticks could become infected with Trypanosoma cruzi, this only occurred when feeding on dogs in the acute phase of infection, and there was no evidence of subsequent parasite development in the ticks.
Link Here- http://www.ncbi.nlm.nih.gov/pubmed/16444412
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Cleve Clin J Med. 2008 Jul;75(7):521-30.
Blood smear analysis in babesiosis, ehrlichiosis, relapsing fever, malaria, and Chagas disease.
Blevins SM1, Greenfield RA, Bronze MS.
Abstract
Blood smear analysis is especially useful for diagnosing five infectious diseases: babesiosis, ehrlichiosis, relapsing fever due to Borrelia infection, malaria, and American trypanosomiasis (Chagas disease). I
t should be performed in patients with persistent or recurring fever or in those who have traveled to the developing world or who have a history of tick exposure, especially if accompanied by hemolytic anemia, thrombocytopenia, or hepatosplenomegaly.
Link here- http://www.ncbi.nlm.nih.gov/pubmed/18646588
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