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TABLE 30.2 Evidence for autoimmune and Parasite-Induced Inflammatory Mechanisms in
Chronic Chagas Disease
Evidence for autoimmune-Mediated Disease Evidence for Parasite-Induced Inflammatory Disease
Inflammatory disease presents in tissues with few or no parasites on routine Sensitive parasite detection techniques (polymerase chain reaction
histopathology studies [PCR], immunohistochemistry) correlate with the presence of
parasites (or parasite material) and severity of inflammatory disease
Peculiar pattern of organ involvement (heart and gastrointestinal tract) in Organs free of parasites (by sensitive parasite detection techniques)
patients with chronic disease are also free of disease
Long delay in the onset of chronic disease following infection; only a minority Absence of effective cellular immune response (in mice or humans)
of infected persons develops disease almost invariably exacerbates rather than reduces the parasite
burden and disease
Wide variability in the expression of disease among infected people In chronically infected mice, the destruction of a transplanted heart is
dependent on parasite infiltrating the transplanted tissue
Self-reactive antibodies and T cells demonstrable in infected people and in Degree of disease in hearts transplanted into chronically infected
experimental animals. Level of antibodies to the ribosomal P protein (R13 mice correlates with level of parasite burden in transplanted tissue
peptide) and cardiac myosin (B13 antigen) correlate with cardiac disease
Transient or limited disease reported in experimental models following Reduction of parasite burden by chemotherapy usually leads to
lymphocyte transfer decreased tissue inflammation and disease

antimicrobial effector activity provides a safe haven for the tissue, but an intense chronic inflammatory infiltrate with fibrosis
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intracellular parasite. Infected macrophages have decreased and loss of muscle fibers is evident. In the digestive tract, there
synthesis of IL-1 and IL-12, and blunted IFN-γ-mediated activa- is lymphohistiocytic infiltration of the myenteric plexuses, with
tion through the disruption of signal transduction pathways reduction in the number of ganglion cells.
involving JAK/STAT, protein kinase C, p38 MAPK, ERK, AP-1, The tissue damage of acute T. cruzi infection is the result of
and NF-κB. Signaling mediated by tyrosine phosphorylation is a direct effect of the parasite and an indirect effect of the acute
decreased by the rapid induction of the host phosphotyrosine inflammatory response. In chronic infection, the balance between
phosphatase SHP-1. Conversely, there is increased synthesis of immune-mediated parasite containment and host-damaging
the immunosuppressive molecules IL-10, TGF-β, and PGE 2 . inflammation determines the course of disease. The pathological
Parasite factors and IL-4/IL-13 enhance expression of arginase mechanisms related to chronic Chagas disease are controversial
by infected macrophages. Arginase promotes infection through and certain to be multifactorial. Trypanosomal clonal variation
depletion of l-arginine, enhanced production of polyamines, and host genetic polymorphisms both contribute to tissue tropism,
+
+
and reduced NO production. IL-10 produced by CD4 CD25 T parasite persistence, and disease severity. Whether tissue damage
regulatory cells (Tregs) has an essential role in parasite persistence. is caused directly by parasites or indirectly through parasite-driven
Recently, it was shown that metastasizing parasites that cause inflammatory or autoimmune mechanisms, parasite persistence
mucosal disease harbor a high burden of Leishmania RNA virus, is a significant driver of disease (Table 30.2). 18,19 Autoimmunity
which subverts the host immune response and promotes parasite could arise from molecular mimicry of self by parasite antigens
persistence through activation of Toll-like receptor 3 (TLR3). 17 or by the release of self molecules from damaged or dying host
cells within the environment of an activated immune response.
Trypanosoma cruzi There is evidence for both of these autoimmune mechanisms.
The production of IL-10 by T. cruzi–infected cells may down-
Pathogenesis regulate the pathological cellular immune response.
T. cruzi is transmitted to the mammalian host when the infectious
metacyclic trypomastigote, which is deposited on skin in the Innate Immunity
feces of the reduviid insect vector while it takes a blood meal, The early innate immune response to T. cruzi infection is mediated
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is scratched into the wound or transferred to a mucous membrane by NK cells, DCs, and macrophages. Macrophages and DCs
(e.g., the eyes). The trypomastigotes can infect almost any cell exposed to T. cruzi trypomastigote antigens produce IL-12 and
type and replicate as amastigotes in the cytoplasm. Eventually, TNF, through a MyD88-dependent mechanism. MyD88-deficient
the amastigotes transform back into trypomastigotes and rupture mice had impaired inflammatory responses and host defense
the cell to enter the bloodstream, from where they invade other against T. cruzi. Immune activation through another protein
cells or are picked up by another insect vector. involved in TLR2 signaling, the Toll/IL1R domain-containing
Following primary infection, the parasites replicate locally adapter protein– inducing IFN-β (TRIF), promotes resistance
and then disseminate through the bloodstream to a variety of through production of IFN-β and downstream expression of
tissues. Muscle and glial cells are the most frequently infected IFN-β inducible genes, such as the p47 guanosine triphosphatases
cells, and acute myocarditis or meningoencephalitis can develop. (GTPase) IRG47. IL-12 activates NK cells to secrete IFN-γ, which
In most cases, however, primary infection occurs without clinical synergizes with TNF to activate macrophages to control parasite
symptoms, and the infected individual may enter an indeterminate replication. The generation of NO is the primary trypanocidal
phase of asymptomatic seropositivity. Only 10–30% of chronically mechanism in murine macrophages. A number of trypomastigote
infected individuals will ultimately develop symptomatic Chagas antigens, including free glycosyl-phosphatidylinositol (GPI)
disease, usually involving the heart or the gastrointestinal (GI) anchors, glycoinositol phospholipids (GIPLs), GPI-linked gly-
tract. Pathologically, there are few parasites observed in cardiac coproteins, and GPI-mucins activate the innate immune response,