RESUMEN

Being one of the world's neglected diseases, Chagas has neither a vaccine nor a satisfactory therapy. Inoculation of murine models with the ganglioside GM1 has shown a strikingly nonlinear effect, leading to a strong decrease in parasite load at low doses but reverting to a load increase at high doses. Cardiocyte destruction concomitant with the disease is also significantly reduced by a moderate application of GM1. A mathematical model for the interaction between the parasite and the immune system is shown to explain these effects and is used to predict an optimal dosage that maximizes parasite removal with minimal cardiocyte destruction.

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Biochemical and structural modifications were investigated in axenic cultured Trypanosoma cruzi after treatment with gangliosides. Fluorescence anisotropy showed dose dependent increments in parasite membranes of ganglioside treated epimastigotes. NADP-GDH activity increased in parasites treated at day 4 (13%), 7 (137.2%), and 14 (28.50%) while NAD-MDH but decreased from day 7 to 21 (-5.74%, -32.22%, -27.92%). Treated parasites presented electron-lucent vacuoles opposite to the cytostoma, multilamellar bodies and dilated mitochondrion cristae, disorganized kinetoplast and altered heterochromatin structure. Gangliosides inhibited fusogenic ability (80%) and PLA2 activity (>75%) from the parasite. The same occurred with anti-PLA2 antibodies. Trypomastigotes suffered loss of cytoplasmic material and organelles when GM1 was present in culture medium. We propose that exogenous gangliosides produced: altered lipid order, inhibited membrane enzymes, the parasite energy source shifted from glucose to amino acids, ending on a structural transformation which signals parasite cell death.

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RESUMEN

A recently proposed model for the competitive parasite-antibody interactions in Chagas disease is extended by separately describing the parasitic intracellular and extracellular phases. The model solutions faithfully reproduce available population data and yield predictions for parasite-induced cardiac cell damage.

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In a previous work, our group reported that Albino Swiss male mice inoculated with T. cruzi to develop acute lethal infection by day 15 decreased parasitemia and survived when treated with total brain gangliosides (GT; 1 mg, daily). In this paper, GT were replaced by GM1 in 0.1 mg dose that caused diminished parasitemia from day 15 to 30 and survival of 80% by day 120 p.i. Treatment with GT 0.15 mg was ineffective. This indicates that GT effect was due to GM1 and that more sialyl residues on the same lipid moiety produces adverse results. GM1 was compared to other sialylated molecules: fetuine and colominic acid. Both of them increased parasitemias and death by day 16 p.i., suggesting that sialic residues favor parasite replication. Asialo-GM1 (0.1 mg daily) was also adverse. This pointed to GM1 not to other ganglioside or sphingolipid or sialoprotein as the active agent. Gangliosides are [Ca+2]i modulators, so GM1 was compared to nifedipine which blocks calcium channels only in the host. Nifedipine treated mice behaved as controls. It is proposed that if GM1 calcium modulation is involved it must be on the parasite rather than on the host. Electrocardiographic (ECG) records show that while infected mice die with bradycardia, treated mice survive and recover normal frequency. Uninfected treated mice showed no electrocardiographic alterations.

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The immunostains of GD3, c-pathway polysialogangliosides and gangliotetraosylgangliosides belonging to the a- and b-pathways were analyzed in embryo optic lobe cells. Cells were cultured in serum free media with, and without, bovine brain ganglioside mixture (largely gangliotetraosylgangliosides). Control cells differentiated in vitro, whereas ganglioside treated cells emitted almost no neurites. In immature cells, GD3 and c-gangliosides were extensively expressed and their immunostains were observed all over the cell (general localization), whereas gangliotetraosylgangliosides were scanty and their stain was preferentially restricted to discrete areas (in clusters). In control differentiated cells, the GD3 expression was strikingly reduced and its immunostain appeared in clusters; c-gangliosides were abundant and their stain was found with general localization; the expression of gangliotetraosylgangliosides became important and their stain was observed with general localization in most of the positive cells. In ganglioside treated cells, in spite of their undifferentiated morphology, the gangliotetraosylganglioside stain appeared with general localization. These results suggest that gangliosides involved in neural ontogenesis are preferentially located in clusters when they are scarce and have general localization when they are abundant in membranes.

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