Peroxiredoxins from Trypanosoma cruzi: virulence factors and drug targets for treatment of Chagas disease?

Cytosolic and mitochondrial Trypanosoma cruzi tryparedoxin peroxidases belong to the family of 2-Cys peroxiredoxins. These enzymes play an essential role as antioxidants by their peroxidase and peroxynitrite reductase activities. TXNPx are key components of the trypanosomatid peroxide detoxification pathways. The aim of this work was to determine the role of TXNPx as virulence factors in the parasite, and whether these enzymes are good candidates for drug design. We observed that peroxiredoxins are not highly abundant proteins expressed at similar levels throughout the T. cruzi life cycle. In order to study the role of c-TXNPx and m-TXNPx in invasion and infectivity, parasites overexpressing TXNPx were produced, and infection experiments were carried out using phagocytic and non-phagocytic cells. Parasites overexpressing peroxiredoxins showed a significant increase in infectivity with respect to the control ones. The results presented in this work point out that the T. cruzi peroxiredoxins are important in survival, replication and differentiation of T. cruzi and could constitute virulence factors. Moreover, their expression in the infective forms of the life cycle and their low intracellular concentration make them good candidates to become targets for drug design.     

Does Trypanosoma cruzi stress its vectors?

Trypanosoma cruzi seems to compete with its vector, Triatoma infestans, for nutrients. When starved the resistance of infected Triatoma is reduced but it is rarely affected i f it is given an adequate food supply. Infected individuals also might be more sensitive than uninfected bugs to other environmental stress factors. Günter Schaub believes that the theory, that T. cruzi does not affect its vectors, should be re-examined.     

Are dead Triatoma infestans a competent vector of Trypanosoma cruzi?

After Triatoma infestans death, Trypanosoma cruzi survived several days, maintaining the ability to infect a vertebrate host. Dead bugs from an endemic area collected during an official spraying campaign showed mobile rectal trypanosomes up to 14 days after vector death. Two days after vector death 2,760 trypomastigotes were found alive in its rectal material. However, the number of mobile trypomastigotes decreased significantly from the 5th day after death. Laboratory proofs with third and fifth nymphal stage showed similar results. Living trypanosomes were found in their rectal material at 10 days in third stage and even at 30 days in fifth nymphal stage. The mean number of trypomastigotes had no changes up to 10 days in third nymphal stage and increased significantly from 1 to 10 days in the fifth stage. Conjunctival instillation as well as intraperitoneal inoculation to mice, of metacyclic forms from dead T. infestans produced infection in the vertebrate host. Present results show that human contact with dead vector is highly probable in summer and living and infective T. cruzi are available for transmission in the vector.     

Isoenzymatic strains of Trypanosoma cruzi: recent or ancient, homogeneous or heterogeneous origin?

Genetic variability studied among 13 Trypanosoma cruzi laboratory reference stocks confirms the existence of three principal isozymic categories. As the main part of enzymic variability is now recognized, it seems possible to attribute any stock to the taxon T. cruzi with safety. Genetic parameters allow to infer two main hypotheses relative to the evolutionary origin of these categories: ancient origin (either by mitotic evolution or by speciation), or recent origin (by clone sampling among a sexual ancestral population). The possibility of a heterogeneous origin of the strains is discussed.     

Virulence and resistance in malaria: who drives the outcome of the infection?

Theoretical and experimental studies have established the dynamic nature of virulence and that, like all traits, it has evolved. Understanding parasite evolution offers a conceptual framework for diverse fields and can contribute greatly to decision-making in disease control. Recently, Grech et al. investigated the effects of host genotype-by-parasite genotype interactions on the expression of virulence in an artificial rodent-malaria system. They found that both parasite and host effects explained most of the variance in the virulence, resistance and transmission potential. These findings are a major contribution to the emerging debate on the pros and cons of a coevolutionary approach of virulence evolution; they also hold great potential for more effective control strategies.     

Does myoglobin protect Trypanosoma cruzi from the antiparasitic effects of nitric oxide?

The hemoflagellate protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, a progressive fatal cardiomyopathy widespread in South and Central America. Here, we postulate that the preferential colonization of cardiomyocytes by T. cruzi may reflect the role of myoglobin (Mb) as a nitric oxide (NO) scavenger, protecting the parasite from the trypanocidal effects of NO. The proposal of this novel function of Mb is based on knowledge that ferrous oxygenated Mb reacts rapidly and irreversibly with NO yielding nitrate and ferric oxidized Mb, which is reduced back to the physiologically active form by an intracellular reductase. The postulated protective role of Mb on the viability of T. cruzi is reminiscent of that postulated for hemoglobin in protecting intraerythrocytic Plasmodia from the parasiticidal effect of NO.     

Postcopulatory vocalizations of fallow bucks: who is listening?

Fallow bucks (Dama dama) produce a postcopulatory vocalization(PCV), consisting of an increase in the short-term groaningrate during the first min after mating. In this article, weconsider two main hypotheses to assess the possible functionof the postcopulatory vocalization. First, the PCV could bedirected at females, and used to advertise the current fertilitystatus of the male. Second, the PCV could be directed at males,and used to transmit an intrasexual threat signal. We foundthat during days when a male gained many matings, his PCVsdid not decline, and males with larger intervals between matingsdid not produce higher PCVs. Lower PCVs were not associatedwith infertile matings, and for females that mated twice withinthe same estrus, the PCVs of their first matings were not lowerthan other PCVs. In addition, higher PCVs were not associatedwith shorter intervals to a male's next mating. Thus, therewas no evidence to suggest that the PCV was involved in transmittinga signal of fertility assurance, either to females that hadmated, or to those that were about to mate. We found that PCVsdeclined as males reached the end of their mating success,therefore suggesting that PCVs are more likely to be involvedin transmitting an intrasexual threat signal related to currentcondition and/or motivation. We suggest that this signal isprobably involved in mate guarding.     

Trypanosoma cruzi dihydrolipoamide dehydrogenase is inactivated by myeloperoxidase-generated “reactive species”

Dihydrolipoamide dehydrogenase (LADH) from Trypanosoma cruzi was inactivated by treatment with myeloperoxidase (MPO)-dependent systems. With MPO/H₂O₂/NaCl, LADH lipoamide reductase and diaphorase activities significantly decreased as a function of incubation time. Iodide, bromide, thiocyanide and chloride effectively supplemented the MPO/H₂O₂ system, KI and NaCl being the most and the least effective supplements, respectively. LADH inactivation by MPO/H₂O₂/NaCl and by NaOCl was similarly prevented by thiol compounds such as GSH, L-cysteine, N-acetylcysteine, penicillamine and N-(2-mercaptopropionyl-glycine) in agreement with the role of HOCl in LADH inactivation by MPO/H₂O₂/NaCl. LADH was also inactivated by MPO/NADH/halide, MPO/H₂O₂/NaNO₂ and MPO/NADH/NaNO₂ systems. Catalase prevented the action of the NADH-dependent systems, thus supporting H₂O₂ production by NADH-supplemented LADH. MPO inhibitors (4-aminobenzoic acid hydrazide, and isoniazid), GSH, L-cysteine, L-methionine and L-tryptophan prevented LADH inactivation by MPO/H₂O₂/NaNO₂. Other MPO systems inactivating LADH were (a) MPO/H₂O₂/chlorpromazine; (b) MPO/H₂O₂/monophenolic systems, including L-tyrosine, serotonin and acetaminophen and (c) MPO/H₂O₂/di- and polyphenolic systems, including norepinephrine, catechol, nordihydroguaiaretic acid, caffeic acid, quercetin and catechin. Comparison of the above effects and those previously reported with pig myocardial LADH indicates that both enzymes were similarly affected by the MPO-dependent systems, allowance being made for T. cruzi LADH diaphorase inactivation and the greater sensitivity of its LADH lipoamide reductase activity towards the MPO/H₂O₂/NaCl system and NaOCl.     

Does Trypanosoma cruzi calreticulin modulate the complement system and angiogenesis?

Calreticulin, a calcium-binding protein that is highly conserved in its multiple functions, is present in a wide spectrum of subcellular compartments in virtually every cell of higher organisms. In this article, we propose a dual role for parasite calreticulin, with emphasis on the Trypanosoma cruzi model. By modulating the vertebrate complement system, calreticulin might provide the parasite with an effective immune-escape mechanism. Alternatively, by inhibiting angiogenesis, the parasite molecule might protect the host from ongoing neoplasic aggressions. Many questions are still unanswered, particularly those regarding the consequences that these interactions could have in vivo for both the parasite and the host.     

Does inhibition of Trypanosoma cruzi key enzymes affect parasite life cycle and geographic distribution?

The hemoflagellate protozoan parasite Trypanosoma cruzi is the causative agent of the Chagas disease, a progressive fatal cardiomyopathy that afflicts more than 20 million people in Central and South America. The T. cruzi life cycle is affected by changes in temperature and pH, the parasite replication being facilitated in mammalian hosts rather than in insect vectors. Here, we postulate that the modulation of key enzymes by pH- and temperature-dependent substrate inhibition may affect the T. cruzi life cycle and limit the geographic range covered by the parasite.     

Effects of some β-carboline alkaloids on intact Trypanosoma cruzi epimastigotes

Several β-carboline (9H-pyrido-[3,4-b]-indole) alkaloids were evaluated for in vitro trypanosomicidal activity against Trypanosoma cruzi epimastigotes belonging to two different strains (Tulahuén and LQ) showing different sensitivity to nifurtimox. Important differences were observed in the susceptibility of the parasites to these natural substances, with the relatively nifurtimox-resistant LQ strain showing greater sensitivity to the β-carbolines. Respiratory chain inhibition appears to be a possible determinant of the trypanosomicidal activity of these compounds.