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Biology Articles » Parasitology » A Role for Extracellular Amastigotes in the Immunopathology of Chagas Disease » Dynamics of Immune Response Early in T.Cruzi Infection

Dynamics of Immune Response Early in T.Cruzi Infection
- A Role for Extracellular Amastigotes in the Immunopathology of Chagas Disease

Host resistance to microbial infection integrates two major and overlapping defense systems, innate and adaptive immunity. Intracellular pathogens can quickly relay activation signals that stimulate non-specific humoral and cellular effector responses in the infected host. Assisted by these innate defense responses, the rate of microbial growth is delayed for several days, while the adaptive branch of immunity gets prepared to confront the pathogen on the long term. The infection can only persist when the organisms succeed to counteract the selective pressure imparted by immune effector cells and/or antibodies. In the case of chronic viral infections, immune subversion is often targeted against intracellular pathways involved in antigen processing and/or presentation by class I MHC molecules.

In the case of T. cruzi, the mechanisms which enable their persistent growth in mammalian tissues were not characterized. As discussed later in this text, there are reasons to think that the molecular diversity of T. cruzi organisms may affect the dynamics of tissue and organ involvement. This is supported by recent evidences showing that acute infection with parasite stocks pertaining to different genotypic groups induce distinct histopathology patterns in acutely infected mice (de Diego et al. 1998) Recently confirmed by research in genetic epidemiology (Souto et al. 1996, Brisse et al. 1998), the concept that T. cruzi has a multi-clonal descent was earlier proposed on the basis of isoenzyme (Miles et al. 1978, Romanha et al. 1979, Ready & Miles 1980, Tibayrenc et al. 1986) and fingerprint analysis of k-DNA (Morel et al. 1980). While not excluding the importance of host genetics as a determinant of host susceptibility in vivo (Trischman et al. 1978), studies performed with laboratory strains of T. cruzi (Brener 1965, Andrade & Andrade 1966, Mello & Brener 1978) and also with parasite clones (Postan et al. 1986, de Diego et al. 1998, Macedo & Pena, 1998) suggested that the variable expression of Chagas disease may caused, at least to some extent, by the genetic and biological diversity of the T. cruzi clones which circulate in sylvatic and domestic reservoirs.

In spite of the poor knowledge about the innate responses which metacyclic trypomastigotes stimulate in wound tissues, this system is fully operative by the time the first cycles of intracellular infection are completed. Once released from disrupted cells, the trypomastigotes spread the infection via the bloodstream and/or lymphatics. At this early stage of infection, a wide range of non-phagocytic host cells can be invaded by the trypomastigotes, but host cell target preference can differ markedly from one parasite clone to another due to the variable composition and expression levels of their cell surface adhesion molecules, some of which are highly polymorphic (Affranchino et al. 1989, Colli 1993, Tackle & Cross 1991, Schenckman et al. 1994, Giordanno et al. 1994, Pereira et al. 1996, Salazar et al. 1996) or due to differential signalling ability of the invading parasite clones (Ming et al 1995, Burleigh and Andrews 1998). The survival strategies of the T. cruzi clones which preferentially invade macrophages are not well characterized. In hosts that are innately resistant, these parasite subpopulations must inhibit macrophage activation or somehow defend themselves from their microbicidal machinary. As true for other intracellular pathogens, innate immunity against T. cruzi depends on the release of g-IFN by NK cells (Aliberti et al. 1996, Cardillo et al. 1996). In genetically resistant strains, the onset of this T cell independent pathway depends on IL-12 production by activated macrophages and appears to be stimulated by tGPI-mucins, a potent class of pro-inflammatory molecules expressed by trypomastigotes and by amastigotes (Camargo et al. 1997). Synergized by TNF-a (Munoz-Fernandez et al. 1992), g-IFN induces a heightened state of microbicidal activation of macrophages in genetically resistant animals, at least so during the first days of infection. The mechanisms by which activated macrophages ultimately exert their anti-parasite activity is somewhat controversial, but there are indications the production of nitric oxide (NO) metabolites is critically involved (Gazzinelli et al. 1992). As for the innately susceptible inbred mice strains, their response to infection is dominated by the macrophage down-regulatory cytokines IL-10 or TGF-b (Silva et al. 1992, Gazzinelli et al. 1992). Interestingly, recent evidences suggest that factors leading to the accumulation of cyclic AMP by macrophages may down-regulate the pro-inflammatory response which tGPI-mucins otherwise stimulate in such cells (Procopio et al. 1999); under these conditions, tGPI-mucins can upregulate IL-10 expression by macrophages, thereby inhibiting the synthesis of both IL-12(p40) and TNF-a. It is thus conceivable that T. cruzi clones that have a relatively stringent preference for mononuclear-phagocytic cells (macrophagic) may actively convert macrophages from innately resistant animals into a susceptible target. Interestingly, macrophage activation in genetically susceptible mice infected by myotropic strains is higher than in resistant strains (Russo et al. 1989).

In contrast to parasite clones that preferentially invade macrophages, those that invade non-phagocytic cells in the first few days of infection inevitably kill the target cells within 5-6 days. The necrosis caused by some myotropic strains can be extensive, sometimes involving multiple tissues and organs (Lenzi et al. 1996, Cotta de Almeida et al. 1977). Inflamed tissues are exposed to high amounts of parasite antigens, either released by extracellular parasites or leaked from killed organisms. Once captured by immature dendritic cells, these antigens are transported to the proximal draining lymph nodes. After upregulating their MHC molecules, the matured dendritic cells present the MHC-bound peptide antigens to naive CD4+ and CD8+ T cells. Depending on the genetic background of the individual, antigen load and cytokine balance, the functional characteristics of CD4+ T cells primed by dendritic cells can be rapidly polarized under the influence of type 1 or type 2 stimulating cytokines (IL-12 and IL-4, respectively). Driven by inflammatory chemokines, these circulating CD4+ Th1 and CD8+ T (Tc1) memory cells attach to the vascular adhesins expressed by activated endothelial cells (Kumar & Tarleton 1998) and are recruited into the inflamed tissues. Upon antigen-stimulation, they secrete g-IFN and TNF-a (Russo et al. 1988). and/or directly kill the infected targets by apoptosis parasite tissue clearance is gradually accompanied by a down-regulatory T cell response mediated by lymphocytes from the Th2 subset. Although the involvement of polarized CD8+ cells from the Tc2 subset has not been shown in T. cruzi infection, in other settings they were shown to produce IL-4, IL-5 and IL-10; while sustaining the capacity to act as cytotoxic T cells upon re-stimulation (Cerwenska et al. 1998). As discussed later on, the Tc2 effectors, if indeed present (Bahia-Oliveira et al. 1998), may play an important role in the regulation of the anti-parasite immune response in Chagas' disease.


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