Putting Infection Dynamics at the Heart of Chagas Disease

Abstract

In chronic Trypanosoma cruzi infections, parasite burden is controlled by effective, but nonsterilising immune responses. Infected cells are difficult to detect because they are scarce and focally distributed in multiple sites. However, advances in detection technologies have established a link between parasite persistence and the pathogenesis of Chagas heart disease. Long-term persistence likely involves episodic reinvasion as well as continuous infection, to an extent that varies between tissues. The primary reservoir sites in humans are not definitively known, but analysis of murine models has identified the gastrointestinal tract. Here, we highlight that quantitative, spatial, and temporal aspects of T. cruzi infection are central to a fuller understanding of the association between persistence, pathogenesis, and immunity, and for optimising treatment.

Figure 1. Key Figure. Modes of parasite persistence in long-term Trypanosoma cruzi infections

In chronic infections T. cruzi predominantly parasitizes myocytes. These infected cells are typically scarce and focally distributed; they can be within cardiac, skeletal or smooth muscle tissues, such as those from the vasculature or the gastrointestinal (GI) tract. The heart is the most common site of pathology. Parasite persistence within an individual host may occur through different modes: a) Continuous persistence describes an ever-present, low abundance parasite load that is sustained as a locally contained equilibrium between intracellular parasite replication and host immune responses; b) Although they have not been proven to exist, dormant forms of T. cruzi may reside within tissues and evade host immunity. As seen for other pathogens, reactivation into typical replication cycles could occur on an intermittent basis; c) Due to the ability of T. cruzi to invade multiple tissues and migrate between them, an organ may be subject to discrete episodes of infection by reinvasion. These three modes are not mutually exclusive and may overlap to different degrees at different times. Over time, the cumulative parasite load is likely to dictate the frequency and intensity of local inflammatory responses, which, depending on their quality, result in differing degrees of pathology. The figure is intentionally simplified and does not convey the molecular and cellular complexity of Chagas disease immunopathogenesis.

Figure 2. Model for a link between host-parasite genetics, infection dynamics and chagasic cardiac pathology

In experimental murine models of chronic Trypanosoma cruzi infection, varying host and parasite genotype combinations can generate different severities of cardiac pathology. Real-time in vivo imaging studies of tissue-specific infection dynamics [16, 34] have suggested that an important factor is the extent of parasite dissemination. Regions of the gastrointestinal (GI) tract serve as permanent reservoirs of infection, especially the proximal large intestine and stomach, regardless of the host-parasite genotype combination. The photos show ex vivo imaged GI tracts overlaid with pseudocolour heat-maps of bioluminescence intensity, which is used as a proxy for parasite numbers. Other tissue sites, including the heart, are actively infected more sporadically. Some models, such as C57BL/6 mice infected with a T. cruzi type VI strain (CLBR) have low parasite burdens outside the gut, heart infection is relatively infrequent and cardiac fibrosis is relatively mild. Other models, particularly C3H/HeN mice with chronic T. cruzi type I infections, have more broadly disseminated infections, frequent infection foci localized to the heart and more severe cardiac fibrosis.