1. Introduction
Chagas disease (CD) or American Trypanosomiasis is a life-long and life-threatening disease caused by infection with the protozoan parasiteTrypanosoma cruzi . According to the World Health Organization, CD is classified as a neglected tropical disease, the most important parasitic disease in America and, after AIDS and tuberculosis, the third most spread infectious disease in this region. In addition, CD is the most prevalent of poverty-caused and poverty-promoting disease in Latin America countries (Rassi Jr et al. , 2010; Urbina, 2010; Bern, 2015; DNDi. Drugs for Neglected Diseases Initiative, 2018; Lidaniet al. , 2019).
Although CD was limited for many decades to Latin America as a silent and silenced disease, CD has become more widespread due to the increase mobility and migration, with large number of infected individuals, particularly in Europe, and recorded outbreaks in Australia, New Zealand and Japan (Pérez-Molina et al. , 2012; Jackson et al. , 2014; Strasen et al. , 2014; Lidani et al. , 2019). CD is currently a global health problema, with 6-8 million infected people, 14-50 thounsand deaths annually, and 70-100 million people ar risk of infection worldwide (Belaunzarán, 2015; PAHO. Pan American Health Organization, 2018; CDC. Centers for Disease Control and Prevention, 2019; Lidani et al. , 2019; Martín-Escolano et al. , 2020a; WHO. World Health Organization, 2021).
Despite many efforts, the long-term nature and the complex pathology of CD have resulted in a lack of effective treatments and vaccines. Approved treatments are limited to two nitroheterocyclic drugs, benznidazole (BNZ) and nifurtimox, developed more than 50 years ago, and lead to serious drawbacks. The aim is to find a specific treatment that allows the eradication of the parasite and, hence, the elimination of the signs and symptoms of CD. The development of new drugs, safer, more effective, that provide a shorter treatment course, and to devise paediatric formulations, preferably oral, is an important need (Hotezet al. , 2008; Bern, 2015; Morillo et al. , 2017; Aldasoroet al. , 2018). In this way, the urgency of further research to discover new therapeutic alternatives and tools for CD drug discovery is justified.
CD is far from innocuous and, in mammal hosts, it is an obligate intracellular parasite for replication (Tyler and Engman, 2001; Kessleret al. , 2017; Martín-Escolano et al. , 2020a). During the initial acute-phase, parasites can be detected in the bloodstream and they become widely disseminated in tissues and organs. Later, CD progresses to a long-lasting asymptomatic chronic-phase, which is characterized by an extremely low parasite burden. Around 30% of infected people will advance to a symptomatic chronic-phase, which is characterized by cardiomyopathy and organomegaly, outcomes for which there are few therapeutic options (Ribeiro et al. , 2012; Cunha-Neto and Chevillard, 2014; Morillo et al. , 2017). It is interesting to note that the outcome of the infection in a particular individual is the result of a set of complex interactions among the host genetic background and the genetic composition of the parasite, and modulated by environmental and social factors; all of which can be complicated by mixed infections and re-infections (Campbell et al. , 2004).
The genetic diversity of T. cruzi is extensively known. Currently, T. cruzi is divided into seven DTUs, showing different genotypes and phenotypes, evolutionary relationships, ecological and epidemiological associations, pathogenesis, tropism and drug resistance (Zingales, 2017; Martín-Escolano et al. , 2020a). Besides the well-known limitations of current treatments, other drawbacks are the natural resistance of the T. cruzi genotype to the drugs used (Mejia et al. , 2012) and the cross-resistance (Wilkinson et al. , 2008; Mejia et al. , 2012). Here, we present T. cruziArequipa strain (MHOM/Pe/2011/Arequipa, isolated from a human from Arequipa, Peru) as an interesting tool for CD drug discovery. We have determined the in vitro BNZ resistance profile of the different morphological forms of T. cruzi Arequipa, we have characterized acute-phase parasitaemia and chronic-phase tropism in BALB/c mice, and we have determined the in vitro BNZ resistance profile ofT. cruzi Arequipa in both acute and chronic phases of CD. The tropism of this strain makes it an interesting tool for CD drug discovery.