Chapter Four - Role of myeloid-derived suppressor cells during Trypanosoma cruzi infection

Trypanosoma cruzi (T. cruzi) is a hemoflagellate protozoan parasite that causes Chagas Disease (CD). Despite the efforts made to control the transmission of the parasite, more than 50 million people live in areas at risk of T. cruzi infection (Lidani et al., 2019). After the initial characterization of the T. cruzi parasite by Carlos Chagas in 1909 (Chagas, 1909), numerous aspects of the immunological interactions that take place between the host and the parasite have been elucidated. However, many questions remain unanswered and, importantly, a prophylactic or therapeutic vaccine is not yet available.

The immune system could be arbitrarily subdivided into an effector arm, whose main function consists of eradicating pathogens or anomalous cells, and a regulatory arm, which serves numerous regulatory/suppressive functions involved in tolerance and control of inflammation and the effector immune response. To be successful in its life cycle, T. cruzi has evolved numerous strategies to cope with and evade the effector immune system and to take advantage and subvert the regulatory arm of the immune system (Cardillo et al., 2015; Cardoso et al., 2016; da Costa et al., 2014; DosReis, 2011; Flávia Nardy et al., 2015; Fresno and Gironès, 2021; Morrot et al., 2016; Nardy et al., 2016).

A substantial number of reports have already reviewed the role of the components of the effector immune response during T. cruzi infection (Acevedo et al., 2018; Acosta Rodríguez et al., 2019; Junqueira et al., 2010; Kumar and Tarleton, 1998; Machado et al., 2012; Padilla et al., 2009). Regarding the regulatory arm, different cells have been postulated to participate in the infection process, including myeloid-derived suppressor cells (MDSCs) (Arocena et al., 2014; Cuervo et al., 2011; Fresno and Gironès, 2018, Fresno and Gironès, 2021; Goñi et al., 2002; Prochetto et al., 2017), CD4+ Foxp3+ regulatory T cells (Tregs) (Acosta Rodríguez et al., 2019; Bonney et al., 2015; Cabrera and Marcipar, 2019; Ersching et al., 2016; Flores-García et al., 2013; González et al., 2015, González et al., 2016; Mariano et al., 2008; Nihei et al., 2014; Poncini et al., 2015; Sales et al., 2008), regulatory dendritic cells (Alba Soto et al., 2010; Gutierrez et al., 2020, Gutierrez et al., 2021; Poncini et al., 2008; Van Overtvelt et al., 1999), and others (Cardillo et al., 1993, Cardillo et al., 1996, Cardillo et al., 2015; Somoza et al., 2021; Tosello Boari et al., 2012). The alterations in the percentage and numbers as well as the physiological importance of each type of cell are aspects under study. Consistent data indicate that MDSCs are notably affected during experimental T. cruzi infection. It has been shown that this population increases to almost 20–30% of the spleen of infected mice (Arocena et al., 2014; Goñi et al., 2002; Prochetto et al., 2017); increases were also reported in the liver and the heart (Arocena et al., 2014; Cuervo et al., 2011). Moreover, depletion experiments could be considered a reliable tool to assess the physiological importance of each population. From this point of view, there is strong evidence that MDSCs play an important role during T. cruzi infection because depletion of those cells may cause 100% mortality of infected mice in experimental models, likely as a consequence of exacerbated inflammation, as has been suggested (Arocena et al., 2014; Gamba et al., 2021; Poncini and González-Cappa, 2017). In this sense, the aim of this review is to analyze the available data regarding the major role that MDSCs may play during T. cruzi infection, with emphasis on potential crosstalk with other cell populations, which may shape the immune response against the parasite.

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