T. cruzi is a kinetoplastid protozoan and the causative agent of Chagas disease. Despite the restriction of the insect-vectored T. cruzi transmission cycle solely to the Americas, Chagas disease is among the top causes of infection-induced cardiomyopathy globally. T. cruzi naturally infects a very wide range of mostly mammalian species, and importantly, infections in these various natural hosts involve the same parasite populations and mimic the infection control and disease process in humans [1]. Thus, infections in these natural host species are not simply models of human infection; they faithfully represent the human infection and disease.

T. cruzi infection results in primarily muscle-focused pathology because 1) T. cruzi maintains a continuous cycle of infection and multiplication primarily in muscle tissue, and 2) the infection is generally life-long. The biological basis of these attributes — that is, why the infection is controlled but not eliminated and why it is relatively restricted to muscle — is not fully understood. However, they are likely connected; T. cruzi is able to persist despite the generation of highly effective immune responses in part because of its ability to invade and replicate in muscle tissues. Here, we refer to this ability to maintain a protracted, albeit frequently very low-level, but constantly active infection cycle in most hosts as persistence.

Below, we discuss the biology of the T. cruzi: host interface that allows for persistence. But first, it is important to discuss the factors that do not contribute to T. cruzi persistence. Multiple pathogens actively suppress immune responses, and multiple mechanisms for immune regulation in T. cruzi infection have been proposed. However, there is little direct in vivo evidence for attenuated immune responses actively preventing the control of T. cruzi infection and abundant evidence of robust and highly effective anti-T. cruzi adaptive immune responses as discussed below. Furthermore, blocking potential immune regulatory pathways fails to further enhance parasite control 2, 3. Although immune exhaustion is evident in chronic T. cruzi infection, this appears to be the result of the long-standing infection, rather than its cause 4, 5. Thus, the persistence of T. cruzi is not caused by an active inhibition of host immunity.

Persistence of T. cruzi is also not the result of a parasite life-cycle option, such as the development of an arrested or encysted stage as in some other parasites (reviewed in Ref. [6]). Indeed, the bulk of parasites in a persistently infected host continuously cycle in and out of host cells and are thus always targets for immune clearance. However, occasionally an amastigote in host cells assumes a metabolically inactive state, a process we have termed dormancy [7]. This dormancy state was only recently identified and, in part due to its infrequency, relatively little is understood about the causes or mechanisms. Unlike dormant states described in other pathogens, dormancy in T. cruzi is neither a programmed stage in the lifecycle nor a response to stressors, such as drugs. Most importantly for the discussion here, dormancy is not involved in T. cruzi persistence, and so we prefer the designation of ‘dormants’ to describe these temporarily inactive amastigotes, to the term ‘persisters’, to avoid any confusion. Dormant amastigotes appear to become relevant to parasite persistence only when drug treatment is involved.

Here, we review the data supporting the role of parasite biology in persistence of T. cruzi in highly immune-competent hosts and the challenges that this biology may present with respect to attempts to tilt this host:parasite interaction toward complete parasite clearance — with the ultimate goal of preventing disease development. We then discuss the limited data on dormancy and possible future directions on this topic.