Drastic reduction in the notification of acute cases of Chagas disease in the Northeast region of Brazil. Epidemiological evaluation in the period 2001-2021.

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi (T. cruzi), is a neglected disease endemic to some Latin American countries, including Brazil. Soon after infection, individuals develop an acute phase, which in most cases is asymptomatic and may go undetected. However, when CD is detected early, notification in the Notifiable Diseases Information System (SINAN), is mandatory. This study aimed to evaluate the information registered in the SINAN database and to determine the epidemiological profile of acute CD in Northeast Brazil, an endemic region, from 2001 to 2021. According to this survey, 1,444 cases of acute CD were reported in the Northeastern region of Brazil during this period. During the first six years, referred to as period 1, 90.24% of the notifications were registered, while the number of notifications significantly decreased in the subsequent years, referred to as period 2. Most individuals diagnosed with acute CD were Afro-Brazilian adults. All known routes of infection by the parasite were reported. Vector-borne transmission was predominant during period 1 (73.29%) and oral transmission during period 2 (58.87%). All nine states in Northeast Brazil reported cases in both periods. A higher incidence of disease was reported in Rio Grande do Norte (RN) during period 1, and in Maranhão (MA) during period 2. Our results show that CD remains a significant public health challenge.

Correction: How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosoma brucei cell.

[This corrects the article DOI: 10.1371/journal.ppat.1011522.].

How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosoma brucei cell.

ATP hydrolysis is required for the synthesis, transport and polymerization of monomers for macromolecules as well as for the assembly of the latter into cellular structures. Other cellular processes not directly related to synthesis of biomass, such as maintenance of membrane potential and cellular shape, also require ATP. The unicellular flagellated parasite Trypanosoma brucei has a complex digenetic life cycle. The primary energy source for this parasite in its bloodstream form (BSF) is glucose, which is abundant in the host's bloodstream. Here, we made a detailed estimation of the energy budget during the BSF cell cycle. As glycolysis is the source of most produced ATP, we calculated that a single parasite produces 6.0 x 1011 molecules of ATP/cell cycle. Total biomass production (which involves biomass maintenance and duplication) accounts for ~63% of the total energy budget, while the total biomass duplication accounts for the remaining ~37% of the ATP consumption, with in both cases translation being the most expensive process. These values allowed us to estimate a theoretical YATP of 10.1 (g biomass)/mole ATP and a theoretical [Formula: see text] of 28.6 (g biomass)/mole ATP. Flagellar motility, variant surface glycoprotein recycling, transport and maintenance of transmembrane potential account for less than 30% of the consumed ATP. Finally, there is still ~5.5% available in the budget that is being used for other cellular processes of as yet unknown cost. These data put a new perspective on the assumptions about the relative energetic weight of the processes a BSF trypanosome undergoes during its cell cycle.

L-Glutamine uptake is developmentally regulated and is involved in metacyclogenesis in Trypanosoma cruzi.

Trypanosoma cruzi, the aetiological agent of Chagas disease, can obtain L-glutamine (Gln) through the enzyme glutamine synthetase (GS) using glutamate (Glu) and ammonia as substrates. In this work, we show additional non-canonical roles for this amino acid: its involvement in ATP maintenance and parasite survival under severe metabolic stress conditions and its participation in the differentiation process occurring in the insect vector (metacyclogenesis). These roles are dependent on the supply of Gln from an extracellular source. We show that T. cruzi incorporates Gln through a saturable and specific transport system, which results in unusual stability at elevated temperatures. The activity was moderately higher at pH values between 6 and 7 and was sensitive to the dissipation of the H+ gradient at the plasma membrane. When analysed in the different life cycle stages, we found that Gln transport is developmentally regulated. In fact, Gln uptake and GS activity seem to be finely regulated at most stages: when GS activity is increased, transport is decreased and vice versa, with the exception of trypomastigotes, where both sources of Gln are diminished. This metabolic adaptation reflects the relevance of Gln in T. cruzi biology and the plasticity of these parasites to adjust their metabolism to changing environments.

Application of bioisosterism in design of the semicarbazone derivatives as cruzain inhibitors: a theoretical and experimental study.

A series of semicarbazone, thiosemicarbazone, and aminoguanidine derivatives were synthesized and tested as antitrypanosomal agents. The theoretical NMR of the compounds was calculated using molecular modeling techniques (density functional theory (DFT) calculations) and confirmed the formation of the compounds. The ability to inhibit cruzain and Trypanosoma cruzi epimastigote replication was evaluated. Cruzain inhibition ranged between 70 and 75% (100 µM), and IC50 values observed in epimastigote forms of T. cruzi ranged from 20 to 140 µM. Furthermore, the compounds did not present cytotoxicity at concentrations up to 50 and 250 µM in MTT tests. Molecular modeling studies were conducted using DFT method (B3LYP functional and the basis set 6-311G(d,p)) to understand the activity of the compounds, corroborating the observed cruzain inhibitory activity. In docking studies, the obtained analogs showed good complementarity with cruzain active site. In addition, docking results are in accordance with the susceptibility of these analogs to nucleophilic attack of the catalytic Cys25. Taken together, this study shows that this class of compounds can be used as a prototype in the identification of new antichagasic drugs.

Resveratrol inhibits Trypanosoma cruzi arginine kinase and exerts a trypanocidal activity.

Arginine kinase catalyzes the reversible transphosphorylation between ADP and phosphoarginine which plays a critical role in the maintenance of cellular energy homeostasis. Arginine kinase from the protozoan parasite Trypanosoma cruzi, the etiologic agent of Chagas disease, meets the requirements to be considered as a potential therapeutic target for rational drug design including being absent in its mammalian hosts. In this study a group of polyphenolic compounds was evaluated as potential inhibitors of arginine kinase using molecular docking techniques. Among the analyzed compounds with the lowest free binding energy to the arginine kinase active site (<-6.96kcal/mol), resveratrol was chosen for subsequent assays. Resveratrol inhibits 50% of recombinant arginine kinase activity at 325µM. The trypanocidal effect of resveratrol was evaluated on the T. cruzi trypomastigotes bursting from infected CHO K1 cells, with IC50=77µM. Additionally epimastigotes overexpressing arginine kinase were 5 times more resistant to resveratrol compared to controls. Taking into account that: (1) resveratrol is considered as completely nontoxic; (2) is easily accessible due to its low market price; and (3) has as a well-defined target enzyme which is absent in the mammalian host, it is a promising compound as a trypanocidal drug for Chagas disease.