Host and parasite genetics shape a link between Trypanosoma cruzi infection dynamics and chronic cardiomyopathy

Abstract

SummaryHost and parasite diversity are suspected to be key factors in Chagas disease pathogenesis. Experimental investigation of underlying mechanisms is hampered by a lack of tools to detect scarce, pleiotropic infection foci. We developed sensitive imaging models to track Trypanosoma cruzi infection dynamics and quantify tissue‐specific parasite loads, with minimal sampling bias. We used this technology to investigate cardiomyopathy caused by highly divergent parasite strains in BALB/c, C3H/HeN and C57BL/6 mice. The gastrointestinal tract was unexpectedly found to be the primary site of chronic infection in all models. Immunosuppression induced expansion of parasite loads in the gut and was followed by widespread dissemination. These data indicate that differential immune control of T. cruzi occurs between tissues and shows that the large intestine and stomach provide permissive niches for active infection. The end‐point frequency of heart‐specific infections ranged from 0% in TcVI‐CLBR‐infected C57BL/6 to 88% in TcI‐JR‐infected C3H/HeN mice. Nevertheless, infection led to fibrotic cardiac pathology in all models. Heart disease severity was associated with the model‐dependent frequency of dissemination outside the gut and inferred cumulative heart‐specific parasite loads. We propose a model of cardiac pathogenesis driven by periodic trafficking of parasites into the heart, occurring at a frequency determined by host and parasite genetics.

Putting Infection Dynamics at the Heart of Chagas Disease

“…A key development was the introduction of a firefly luciferase gene engineered to emit longer wavelength light, which has enhanced tissue penetrating capacity [30, 31]. The use of T. cruzi expressing this red-shifted luciferase enabled highly sensitive imaging of chronically infected mice [16, 32-34]. Drawbacks include the high associated costs and, potentially, a reduced ability to detect parasites that are metabolically quiescent.…”

“…For the CL Brener strain (TcVI), cardiac-localised parasite bioluminescence was not detected in C57BL/6, and only ~10% of BALB/c or C3H mice, but frequencies of 40%, 50% and 88% respectively, were detected for a TcI strain (JRcl4) [16, 34]. Cardiac fibrosis was consistently observed, but there was no correlation with parasite loads in individual animals.…”

“…Furthermore, models exhibiting the most broadly disseminated infections had significantly higher levels of cardiac fibrosis. This correlation, together with additional lines of evidence, implied that infection of the heart is likely to be sporadic and repetitive, rather than continuous, and to occur at a frequency determined by the overall systemic distribution of parasites [34] (Figure 2). Further work is required to validate this hypothesis and to determine whether it can help to explain the relationship between cardiac parasitism and pathogenesis.…”

“…Indeed, adipose tissue was a major site of T. cruzi persistence associated with posaconazole treatment failure in acutely infected mice [33], and panniculitis (inflammation of the fatty subcutaneous tissue) is a common symptom of reactivated Chagas disease [78]. The majority of C3H mice with long-term TcI infections have parasites in adipose tissue [34, 77], but this is less frequent for other genotype combinations [34]. A small study that analysed subcutaneous fat samples from ten seropositive patients found that three of them contained T. cruzi kDNA [86].…”

“…The development of sensitive real-time imaging has largely overcome this issue, at least for mouse models. Recent work in our laboratory revealed that the GI tract, specifically the large intestine and stomach, is the predominant site of parasite persistence for multiple mouse-parasite genotype combinations [16, 34]. One reason for this may be a local trade-off between incentives for the host to limit parasite numbers and to avoid bacterial translocation, which can occur in an inflamed gut [89].…”