Host‐parasite dynamics in Chagas disease from systemic to hyper‐local scales

Abstract

Trypanosoma cruzi is a remarkably versatile parasite. It can parasitize almost any nucleated cell type and naturally infects hundreds of mammal species across much of the Americas. In humans, it is the cause of Chagas disease, a set of mainly chronic conditions predominantly affecting the heart and gastrointestinal tract, which can progress to become life threatening. Yet around two thirds of infected people are long‐term asymptomatic carriers. Clinical outcomes depend on many factors, but the central determinant is the nature of the host‐parasite interactions that play out over the years of chronic infection in diverse tissue environments. In this review, we aim to integrate recent developments in the understanding of the spatial and temporal dynamics of T. cruzi infections with established and emerging concepts in host immune responses in the corresponding phases and tissues.

Incomplete recruitment of protective T cells facilitatesTrypanosoma cruzipersistence in the mouse colon

“…Despite the generation of a vigorous and specific CD8 + T cell response (4,14,29,30), T. cruzi infections in mice are rarely cleared to sterility, even in vaccinated animals. Instead, the parasite persists in a small number of reservoir tissue sites, typically for the life-time of the host (10). Intermittent dissemination from these locations to less permissive organs, such as the heart, may promote repeated episodes of infection, resulting in localised inflammatory responses that contribute to disease pathology in a cumulative manner (31).…”

“…The reasons why protective T cells are not recruited to a small sub-set of infection foci are unclear. Hypothesised mechanisms to account for T. cruzi immune evasion include a general absence of pathogen associated molecular patterns (PAMPs) (39), cytokine-mediated inhibition of effector responses (10), insufficiently strong chemoattractant signalling in low parasite load settings (36), the extensive antigenic diversity expressed by the large families of trans -sialidase and mucin genes (14,40,41), and stress-induced cell-cycle arrest and dormancy (42). However, none of these obviously correspond with our observation that there is an apparent lack of association between the extent or longevity of an individual cellular infection and the magnitude of hyper-local leukocyte recruitment (Figure 5).…”

“…T. cruzi infection induces a high titre polyclonal B cell/antibody response during the acute stage of infection, which although delayed and initially unfocussed (43), does contribute to parasite control and can protect against virulent infections. In the chronic stage, a role for the humoral response in suppressing the dissemination of persistent parasites is unresolved (10), and a key role for B cells has not been identified. Here, we show that in the absence of PBMCs, circulating antibodies, which in the short-term are not profoundly affected by cyclophosphamide treatment (44) (Figure 1d), are unable to maintain tissue-specific repression of the parasite burden (Figure 2d).…”

“…Although the innate immune system is able to detect the parasite (9,10), there is a delay in the subsequent induction of an adaptive response relative to other pathogens (5,11). This, together with a rapid rate of parasite division (12), allows T. cruzi to disseminate widely during the acute stage, with most organs and tissues becoming highly infected (13).…”

Parasites and tissue microenvironment

“…Other recent technological advances include the development of real‐time bioluminescence and fluorescence imaging methods, allowing for real‐time tracking of parasites in live tissues. Perez‐Masliah et al 4 discuss the additional benefits of using such technology in research on Trypanosoma cruzi (Chagas disease) host‐pathogen interactions. The authors underscore the findings from in vivo imaging studies that the gastrointestinal tract appears to be a universal site of continual parasite persistence in the chronically infected host, where blood parasitemia is typically subpatent; analysis at single cell resolution level also reveals that smooth muscle cells are the most frequent targets of the parasite in the colon.…”