Abstract
Infection by Leishmania protozoan parasites can cause a variety of disease outcomes in humans and other mammals, from single self-healing cutaneous lesions to a visceral dissemination of the parasite. The correlation between chronic lesions and ecto-nucleotidase enzymes activity on the surface of the parasite is addressed here using damage caused in epithelial cells by nitric oxide. In order to explore the role of purinergic metabolism in lesion formation and the outcome of the infection, we implemented a cellular automata/lattice gas model involving major immune characters (Th1 and Th2 cells, IFN-γ, IL-4, IL-12, adenosine−Ado−, NO) and parasite players for the dynamic analysis of the disease progress. The model were analyzed using partial ranking correlation coefficient (PRCC) to indicate the components that most influence the disease progression. Results show that low Ado inhibition rate over Th-cells is shared by L. major and L. braziliensis, while in L. amazonensis infection the Ado inhibition rate over Th-cells reaches 30%. IL-4 inhibition rate over Th-cell priming to Th1 independent of IL-12 are exclusive of L. major. The lesion size and progression showed agreement with published biological data and the model was able to simulate cutaneous leishmaniasis outcomes. The sensitivity analysis suggested that Ado inhibition rate over Th-cells followed by Leishmania survival probability were the most important characteristics of the process, with PRCC of 0.89 and 0.77 respectively. The simulations also showed a non-linear relationship between Ado inhibition rate over Th-cells and lesion size measured as number of dead epithelial cells. In conclusion, this model can be a useful tool for the quantitative understanding of the immune response in leishmaniasis.
Highlights
Leishmaniasis is an infectious disease caused by parasites from Leishmania species
We propose a model of cutaneous leishmaniasis caused by different Leishmania species, L. major, L. braziliensis, and L. amazonensis, which aims to establish a minimum set of rules that can describe the development of infection for each species and to test the importance of Ado release as a virulence factor
Predictions are Coherent with Experimental Results in Animal Models
Summary
Leishmaniasis is an infectious disease caused by parasites from Leishmania species. It is considered a neglected tropical disease, affecting 96 countries worldwide (Alvar et al, 2012). The clinical form and severity of leishmaniasis depend on the parasite species/strain involved and on the host immune response mounted (Sacks and Noben-Trauth, 2002; Hurdayal and Brombacher, 2014). The susceptibility in the BALB/c strain is related to development of (Th2)-polarized immune response, genetically characterized by a high production of interleukin (IL)-4 by CD4+ T cells (Sacks and Noben-Trauth, 2002; Mougneau et al, 2011). The C57BL/6 strain represents a model for resistance to L. major, due to (Th1) polarized immune response, characterized by the production of high amounts of interferongamma (IFN-γ) by CD4+ T cells (Sacks and Noben-Trauth, 2002; Mougneau et al, 2011). DCs expressing the nuclear factors STAT4 (Buxbaum et al, 2002), STAT1, and IL-12, induce the differentiation of naïve Th cells into the Th1 subtype, in turn producing IFN-γ (Stamm et al, 1999; Sacks and Noben-Trauth, 2002; Jayakumar et al, 2008)
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