“Autoimmune rejection” of neonatal heart transplants in experimental Chagas disease is a parasite-specific response to infected host tissue

Abstract

Infection with the protozoan parasite Trypanosoma cruzi often results in chronic heart-and gutassociated disease known as Chagas disease. In this study we show that contrary to previous reports, neonatal hearts transplanted into mice chronically infected with T. cruzi do not exhibit signs of autoimmune-type rejection or any significant inf lammatory response. In addition to an absence of inf lammation, these syngeneic heart transplants survive for more than 1 year and are absolutely free of parasites as determined by in situ PCR analysis. However, if well-established transplanted hearts in chronically infected mice are directly injected with live parasites, a rapid and dramatic inf lammatory response ensues that results in cessation of heart function. Likewise, transplanted hearts established in mice prior to systemic infection with T. cruzi or hearts transplanted into mice during the acute stage of T. cruzi infection become parasitized and develop inf lammatory foci. In these cases where the transplanted hearts become parasitized, the ensuing inf lammatory response is nearly identical to that observed in the native hearts of T. cruzi-infected mice in terms of cell types present and adhesion molecules and cytokines expressed. Importantly, this response is strikingly different from that observed in the allogeneic heart rejection. These results clearly document that parasitization of heart tissue is both necessary and sufficient for the induction of tissue damage in Chagas disease and strongly argue against a principal autoimmune etiology for this disease.

Trypanosoma cruzi persistence at oral inflammatory foci in chronic chagasic patients

“…This statement is supported by previous reports from experimental hosts or natural infected individuals (Tarleton et al, 1997;Olivares-Villagomez et al, 1998). The finding of persistent myocardial T. cruzi forms in CCP has been correlated with the presence and degree of inflammatory lesions which tend to be diffuse and progressive (Almeida et al, 1984;Tavares-Neto, 1990;Jones et al, 1993;Añez et al, 1999).…”

“…The present findings also suggest a wide distribution of T. cruzi during its circulating phase colonizing tissues like the gum in which the parasite persist establishing secondary or satellite small foci for the maintenance of hidden or inapparent chagasic infection. On the other hand, the here found T. cruzi persistence in CCP may be explained considering the gum as a tissue where parasites have been restrained as a consequence of the systemic immune response, which although highly efficient, was not able to totally clear T. cruzi from all the tissues, a fact widely considered by previous authors (Tarleton, 2001;Zhang and Tarleton, 1999;Tarleton et al, 1997). Whatever the mechanism allowing the parasite persistence in the inflamed gums in CCP, it may be considered as one of the reasons to explain the low parasitemia detected when serial hemoculture or xenodiagnosis are applied to confirm diagnosis in chronic individuals.…”

Ergosterol biosynthesis and drug development for Chagas disease

“…This fact, coupled with the finding that T. cruzi-specific CD8+ and CD4+ T cells, are consistently associated with inflammatory infiltrates rich in Th1 cytokines, has led to the notion that parasite persistence is a necessary and sufficient condition to generate and sustain a Th1-biased inflammatory response in infected tissues, which may include autoimmune phenomena (Tarleton et al 1997, Tarleton & Zhang 1999, Tarleton 2001, Marin-Neto et al 2007.…”

“…However, more recent studies using more sensitive methodologies have shown clear correlations between the presence of the parasite and the inflammatory processes that underlie the pathological processes associated with chronic Chagas disease (Tarleton et al 1997, Tarleton & Zhang 1999, Tarleton 2001, Marin-Neto et al 2007). This fact, coupled with the finding that T. cruzi-specific CD8+ and CD4+ T cells, are consistently associated with inflammatory infiltrates rich in Th1 cytokines, has led to the notion that parasite persistence is a necessary and sufficient condition to generate and sustain a Th1-biased inflammatory response in infected tissues, which may include autoimmune phenomena (Tarleton et al 1997, Tarleton & Zhang 1999, Tarleton 2001, Marin-Neto et al 2007.…”

Murine susceptibility to Chagas' disease maps to chromosomes 5 and 17

“…The pathogenesis of this inflammation is not fully understood, but it has been associated with autoimmune reactivity. However, an increasing body of evidence has accumulated indicating that chronic symptoms are mediated by persistence of parasites, 3,4 even when present in low or undetectable numbers. Little is known about the host genetics of T. cruzi infection.…”