Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease

Abstract

In this study, we document the development of stable, antigen-independent CD8+ T cell memory after drug-induced cure of a chronic infection. By establishing a system for drug cure of chronic Trypanosoma cruzi infection, we present the first extensively documented case of total parasite clearance after drug treatment of this infection. Cure resulted in the emergence of a stable, parasite-specific CD8+ T cell population with the characteristics of central memory cells, based upon expression of CD62L, CCR7, CD127, CD122, Bcl-2 and a reduced immediate in vivo CTL function. CD8+ T cells from treated and cured mice also expanded more rapidly and provided greater protection following challenge than those from chronically infected mice. These results show that complete pathogen clearance results in stable, antigen-independent and protective T cell memory, despite the potentially exhausting effects of prior long-term exposure to antigen in this chronic infection.

Chagas disease: Present status of pathogenic mechanisms and chemotherapy

“…In the same way, Caldas et al (Caldas et al, 2008) observed a significant decrease in parasite load in mice treated with Bz during the acute phase of infection, without effect on chronic cardiac lesions. Whereas, Bustamante et al (Bustamante et al, 2008) showed that when Bz is administered for 40 days, parasitological cure and stable and protective CD8+ T central memory response are obtained. Furthermore, Bz itself can modulate the immune response during indeterminate and chronic Chagas disease (Sathler-Avelar et al, 2008;SathlerAvelar et al, 2009).…”

“…This can be done through sensitive methods such as immunohistochemistry, polymerase chain reaction (PCR), and in situ hybridization (Britto, 2009;Deborggraeve et al, 2009;Duffy et al, 2009;Rassi et al, 2009a;Rassi and Rassi, 2009;Rassi et al, 2009c). Experimentally, this is demonstrated by attenuation of cardiomyopathy with parasite load reduction by trypanocidal treatment (Britto, 2009;Bustamante et al, 2008;Coura, 2009;Marin-Neto et al, 2009;Perez-Molina et al, 2009;Urbina, 2009b;Viotti et al, 2009). However, myocardial inflammatory infiltrates and lesions are not uniformly reduced in mice infected with different T. cruzi strains and treated with benznidazole (Bz) (Caldas et al, 2008;MarinNeto et al, 2009;Rassi and Rassi, 2009).…”

In vitro and in vivo experimental models for drug screening and development for Chagas disease

“…PCR was identified as one of the necessary criteria because it is more sensitive and time efficient than haemoculture (Camandaroba et al 2003, Caldas et al 2008a, Miyamoto et al 2008) and it reduces the technicians' levels of exposure to the parasite. The use of cyclophosphamide to enhance the sensitivity of the parasitological cure analysis was also discussed because immunosuppressed animals that experience therapeutic failure quickly recover their high levels of parasitaemia (Bustamante et al 2008, Santos et al 2008.…”

Ergosterol biosynthesis and drug development for Chagas disease

“…The reasons for the marked difference in the antiparasitic efficacy of nitro-heterocyclic compounds in the acute and chronic stages of the disease are unclear (Cançado 2002), but they may be related to unfavourable pharmacokinetic properties, such as relatively short half-lives and limited tissue penetration (Raaflaub & Ziegler 1979, Raaflaub 1980, Workman et al 1984, which will limit their action in the chronic stage when the parasites are mostly confined in deep tissues and undergo slow replication (Urbina 1999a, Urbina & Docampo 2003. In any case, verifying a true parasitological cure in chronic infection, where the levels of circulating parasites can be extremely low or undetectable even with the most sensitive PCR methods available (Martins et al 2008), remains an extremely challenging problem that requires developing other criteria, such as immunological assays that measure T-cell responses to drug treatment (Bustamante et al 2008).…”