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.