Why does GM1 induce a potent beneficial response to experimental Chagas disease?

Abstract

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.

Figure 1. Parasite populations as a function of time for the indicated GM1 doses.

For each value of the dose we present the experimental data (Cossy Isasi et al., 1999) and model fits. The lines joining the experimental points are for eye guidance only. Note that the [GM1]=0.6 mg dose kills all the mice. The model describes what would occur to a putative immortal mouse, for which the parasite number becomes extremely high before being brought under control.

Figure 2. Number of cells destroyed by parasite action as a function of time after inoculation, for the indicated GM1 doses.

Intermediate doses strongly reduce cell damage at all times, while the largest dose strongly reduces the initial damage but has almost no effect at long times.

Figure 3. Asymptotic value of the predicted total cell loss as a function of GM1 dose (dots).

The dashed line corresponds to the maximum cell loss consistent with host survival. The range between the vertical solid lines is then the putative therapeutic dose range.