The selective pressure which the killer T cells exert on the intracellular amastigotes must be very strong in genetically outbred individuals, because class I MHC-restricted CTLs would be more effective by attacking the target before the intracellular amastigotes are transformed into the more aggressive trypomastigotes. Conversely, one might expect that amastigotes must possess special resources to counteract the highly protective amastigote-specific CTL responses. Future attempts to elucidate the mechanims of evasion of T. cruzi must take into account the finding that rates of intracellular division and transforming efficiency of amastigotes vary significantly among different clones (Dvorak & Hyde 1973). Indeed, the measurements of some of these in vitro parameters in a wide collection of T. cruzi stocks permitted their classification into the three main genetic groups, thus showing a strong correlation with genetic distances evaluated by multilocus enzyme electrophoresis (MLEE) or random amplification by polymorphic DNA (RAPD) methods (Revollo et al. 1998). Here we advance the proposition that the phenotypic changes associated with these major genetypes will differentially affect the function of the class I antigen-processing machinary of infected target cells. For example, it is possible that the levels of processed epitopes generated from parasite antigens (from a given parasite clone) might be controlled by parasite-factors that are likewise encoded by other polymorphic genes. The developmentally regulated cysteine-proteinases (cruzipain-issoforms), discussed later in this text, merits investigation in this context, because some of these proteases are targeted to the cell surface of amastigotes. Given the indications that they are stable and active at neutral pH (Murta et al. 1990) and that their substrate specificity may differ (Lima et al. 1994), it will be worth examining if their differential expression by different parasite clones may control the quality and/or quantity of processed epitopes derived from amastigote surface antigens (e.g. ASP-1/2). In principle, these parasite proteinases may act by cleaving the dominant parasite antigens prior to their unfolding, thus either accelerating or blocking the subsequent processing of a given antigen by the proteosomes. Although entirely speculative, this mechanism illustrates how the interplay of products encoded by two different polymorphic gene system (the structurally and functionally diverse cruzipain isoforms and the TS-related antigens) may improve the parasite's ability to resist immune attack. Of course, the amastigote may also engage non-specific mechanisms of evasion (by acting on constitutive or inducible proteosomal sub-units, degradation of TAP, down-regulation of adhesion molecules etc.) to down-regulate class I MHC cell surface molecules. Ultimately, some of these hypothetical pathways may converge, thus further elevating the threshold required for amastigote-epitope presentation by class I MHC molecules. Perhaps subversion by antigen variation (Kahn & Wlekinski 1997) may be further optimized if the amastigotes succed reducing their metabolism (for example, by slowering rates of intracellular division, as would be the case of latent forms), because these maneuvers may also decrease the availability of substrate-antigen in the host cytosol. Alternatively, higher rates of amastigote division and of metabolic activity may be accompanied by upregulation of cruzipain expression (or other proteases), hence allowing for enhanced proteolysis of TS-antigens and/or inactivation of host cell factors implicated in essential APC functions.
Answers to all your Biology Questions
