Drug Discovery, Genetic Diversity and Vector Resistance: the predictable uncertainty of Trypanosoma cruzi research
In ancient Greece, the Pythia, a priestess and Oracle at Delphi, was expected to speak about the future (the prophecies) on the seventh day of each month during the warmest nine months of the year. The oracle was highly regarded and respected at that time and she was frequently consulted by the kings. The king of Lydia, Croesus, asked her about the outcome of a military action against the Persians; her answer was: "If you cross the river, a great empire will be destroyed". The King then attacked the Persians and lost the war (en.wikipedia.org/wiki/Oracle). Was the prophecy wrong? Well, it depends on who is asking. For the Persians, the prophecy was absolutely correct! During a period of much uncertainty about the future and scarce knowledge of nature, the advice of the oracle was a bright prospect for anyone starting a new venture. In 1909, Carlos Chagas described the complete cycle of a new disease and uncovered a wealth of details about a haemoflagellate parasite of the Trypanosomatidae family. He could hardly imagine how prophetic his words on describing the morphological variety of this microorganism would be: "Considering that the trypanosomide shows “distinct morphologies” according to the infected mammal, we decided to study the adult parasite morphology in the “three most important” vertebrate hosts: man, monkey and guinea pigs..." (Chagas 1909). More than 100 years later, the diversity of Trypanosoma cruzi still causes uncertainty in certain experimental ventures. Despite the massive amount of information regarding T. cruzi strains and isolates, researchers are revisiting the impact that this genetic and biological diversity has on areas such as drug discovery, which is perhaps the most challenging, high-demand and costly research enterprise in infectious diseases, especially the neglected tropical diseases. In the case of Chagas disease, new drugs that will enter the final phase of clinical development are highly anticipated, but the actual results are very deceptive. To date, no effective drug is available to cure infected patients and, to our dismay, the results from researchers working on T. cruzi diversity do not recommend linear and predictable experiments and T. cruzi strain diversity should not be ignored in the search for new drugs. These suggestions appear in issue 109(6) of Memórias do Instituto Oswaldo Cruz by Zingales et al. (2014), who propose that the screening or development of new drugs against T. cruzi must account for strain diversity as well as the parasite stage and the number of strains/clone. T. cruzi cells exhibit an enormous capacity to adapt to highly diverse environments and also to live under varied stress levels. Millions of years under selective pressures resulted in a spectrum of populations that are now clustered into six discrete typing units [(DTU) I-VI] (Zingales et al. 2009). This population heterogeneity notwithstanding, most molecular methods that have been developed so far to probe the taxonomical status of unicellular organisms describe all T. cruzi populations as part of a single unique species. Does this mean that the generalisation offered by an experimental model is not an option to researchers working in drug discovery for Chagas disease? Even though analysing six typical strains (DTU I-VI) for every drug to be tested increases both the financial cost and time required, the results from Zingales et al. suggest that ignoring or bypassing the uncertainty caused by T. cruzi biological diversity may raise hurdles for the translation of the bench research results to successful clinical ventures aimed at getting effective medicines to patients.
On another front to control the Chagas disease, one co-lateral effect that should have been avoided by the current strategies in vector control is the threat in the countries where the transmission is known to be either controlled or decreasing: the resistance and re-infestation of triatomines involved in direct transmission of T. cruzi. However, a report in this issue of Memórias do Instituto Oswaldo Cruz by Carvajal et al. (2014) demonstrates that pyrethroid-resistant bug populations can be controlled by a non-pyrethroid insecticide. These authors propose that imidacloprid, a chemical of the neonicotinoid class and a neurotoxin that acts on the central nervous system of insects, efficiently controls populations that are already resistant to pyrethroid. This is good news in face of another opinion that poses a question about which certification definition should be used in regions that are affected by direct T. cruzi transmission by native vectors (e. g., certain locations in South and Central America). According to Hashimoto and Yoshioka (2014), the term "control" would be a more accurate than "interruption". If expansion of resistance is no longer “a probable scenario”, but a harsh reality, vector control programs that are based on direct insecticide spraying strategies are at risk of being superseded by a most likely scenario involving hybrid resistant individuals. The unpredictable nature of biological hybridisation may give rise to resistant individuals with a high potential to expand the parasite transmission cycle, as has been suggested by a recent chromosomal marker analysis of Triatoma infestans lineages and pyrethroid-resistant populations from the Argentinean-Bolivian border (Panzera et al. 2014).
Among the many statements attributed to the oracle at Delphi, one symbolically represents all the ambiguity of the prophecies: "Go, return not die in war.". A change in the position of the comma in this simple phase perfectly describes any outcome for the asker in case he or she “goes to war”. This is the best way to gain successful insight into the future; the days of unparalleled technological capabilities and terabytes of databases call for a "brute force strategy" to predict success or failure like the Pythia: amass all of these data through powerful data mining algorithms and see the future in two clicks. To obtain predictable outcomes and bypass the uncertainty of T. cruzi direct transmission, it would be necessary that all the interplay between population diversity and response to environmental changes be completely known and controlled by the research community. This is certainly not true for the conventional wisdom on the host-parasite relationship that exists between T. cruzi and triatomine vectors. Taken together, these opinions and experimental results suggest that regardless of the certainties and amount of information on the T. cruzi and its vectors, it may be good to remember the words supposedly spoken by Sócrates in a probable response to a Delphic oracle's statement that he was the wiser man on earth: "I know that I know nothing." (en.wikipedia.org/wiki/I_know_that_I_know_nothing).
Adeilton Alves Brandão | Publisher Editor
Carvajal G, Picollo MI, Toloza AC 2014. Is imidacloprid an effective alternative for controlling pyrethroid-resistant populations of Triatoma infestans (Hemiptera: Reduviidae) in the Gran Chaco ecoregion? Mem Inst Oswaldo Cruz 109: 761-766.
Chagas C 1909. Nova tripanozomiaze humana. Estudos sobre a morfolojia e o ciclo evolutivo do Schizotrypanum cruzi n. gen., n. sp., ajente etiolojico de nova entidade morbida do homem. Mem Inst Oswaldo Cruz 1: 159-218.
Hashimoto K, Yoshioka K 2014. Certifying achievement in the control of Chagas disease native vectors: what is a viable scenario? Mem Inst Oswaldo Cruz 109: 834-837.
Panzera F, Ferreiro MJ, Pita S, Calleros L, Pérez R, Basmadjián Y, Guevara Y, Brenière SF, Panzera Y 2014. Evolutionary and dispersal history of Triatoma infestans, main vector of Chagas disease, by chromosomal markers. Infect Genet Evol 27: 105-113.
Zingales B, Andrade SG, Briones MRS, Campbell DA, Chiari E, Fernandes O, Guhl F, Lages-Silva E, Macedo AM, Machado CR, Miles MA, Romanha AJ, Sturm NR, Tibayrenc M, Schijman AG 2009. A new consensus for Trypanosoma cruzi intraspecific nomenclature: second revision meeting recommends TcI to TcVI. Mem Inst Oswaldo Cruz 104: 1051-1054.
Zingales B, Miles MA, Moraes CB, Luquetti A, Guhl F, Schijman AG, Ribeiro I 2014. Drug discovery for Chagas disease should consider Trypanosoma cruzi strain diversity. Mem Inst Oswaldo Cruz 109: 828-833.