**2.1.2 Genetic variability of** *Trypanosoma cruzi* **and its relation to its pathogenesis**

The genetics of *T. cruzi* caught the attention of researchers in late 80' and early 90'. First studies on variability were performed analyzing electrophoretic variants on cellular enzymes. The groups resulting were called zymodemes and were named Z1, Z2, Z3. Only Z2 was associated with domestic transmission cycle.

The development of PCR based techniques, allowed the study of new variant regions and the characterization of multiple variants of a great number of genes. All these variants showed significant correlation with each other, suggesting the existence of two subtypes of *T. cruzi* based on these data (Macedo, et al., 2004). Moreover, *T. cruzi II* which is clearly linked to human pathology, being *T. cruzi I* mainly related to infection of wild sylvatic mammals. Even, applying LSSP-PCR to the study of the variable region of kinetoplast minicircle from *T. cruzi* provided evidence of a differential tissue distribution of genetically diverse *T. cruzi* populations in chronic Chagas' disease, suggesting that the genetic variability of the parasite is one of the determining factors of the clinical form of the disease (Vago, et al., 2000).

Pathogenesis and Pathology of Chagas' Chronic Myocarditis 123

**Parasite antigen Human Antigen Immune reaction**  B13 Cardiac myosin heavy chain Autoantibodies

> Ribosomal protein 1-adrenergic receptor M2-muscarinic receptor 38-kDa heart antigen

FL-160 47-kDA neuron protein Autoantibodies

(SAPA) Cha antigen Autoreactive T cells

M2-muscarinic receptor Autoantibodies

SRA Autoantibodies

protein Autoantibodies

Ribosomal protein PO 1-adrenergic receptor Autoantibodies

TENU2845/36 kDa Cha antigen Autoantibodies Calcireticulin Calcireticulin Autoantibodies

Galactosyl-cerebrosides Galactosyl-cerebrosides Autoantibodies Unknown Neurons, liver, kidney, testis Autoantibodies Sulphated glycolipids Neurons Autoantibodies 150-kDa protein Smooth and striated muscle Autoantibodies

Microsomal fraction Heart and skeletal muscle Autoantibodies Cytoskeleton 95-kDa myosin tail Autoantibodies

Table 1. Examples of cross-reacting epitopes (Girones, et al., 2005, Marin-Neto, et al., 2007). compared to non infected people, increased values of pre-natural killer (NK)-cells (CD3-

were found. The higher values of activated B lymphocytes (CD19+ CD23+) contrasted with impaired T cell activation, indicated by lower values of CD4+ CD38+ and CD4+ HLA-DR+ lymphocytes, a lower frequency of CD8+ CD38+ and CD8+ HLA-DR+ cells; a decreased frequency of CD4+ CD25HIGH regulatory T cells was also observed. All these data suggest a rather proinflammatory profile (Vitelli-Avelar, et al., 2006). This profile may be useful to limit parasitemia and confine infection to tissues. In fact, it has been demonstrated that NK cells are important in defense against the spread of parasitic infection (Brener & Gazzinelli, 1997), and are an important source of INF-a key cytokine to activate macrophages and

increased but are in normal range in CCC patients, suggesting a protective role for them (Vitelli-Avelar, et al., 2005). NK cells showing CD56DIM may play a role in the down

MAP MAP (brain) Autoantibodies Soluble extract Myelin basic protein Autoantibodies

), and higher values of proinflammatory monocytes (CD14+ CD16+ HLA-DR++)

Cruzipain Cardiac myosin heavy chain

SRA Skeletal muscle Ca2+ dependent

55-kDa membrane protein 28-kDa Lymphocyte membrane

help with parasite clearance (Camargo, et al., 1997).

In late indeterminate form, CD3-CD16+CD56+ and CD3-

R13 (ribosomal protein)

Shed acute-phase antigen

CD16+ CD56-

Autoreactive T cells

Autoantibodies

Autoreactive T cells

Autoreactive T cells

CD16+CD56DIM NK cells are
