Abstract
Chagas’ disease is a protozoosis caused by Trypanosoma cruzi that frequently shows severe chronic clinical complications of the heart or digestive system. Neurological disorders due to T. cruzi infection are also described in children and immunosuppressed hosts. We have previously reported that IL-12p40 knockout (KO) mice infected with the T. cruzi strain Sylvio X10/4 develop spinal cord neurodegenerative disease. Here, we further characterized neuropathology, parasite burden and inflammatory component associated to the fatal neurological disorder occurring in this mouse model. Forelimb paralysis in infected IL-12p40KO mice was associated with 60% (p<0.05) decrease in spinal cord neuronal density, glutamate accumulation (153%, p<0.05) and strong demyelization in lesion areas, mostly in those showing heavy protein nitrosylation, all denoting a neurotoxic degenerative profile. Quantification of T. cruzi 18S rRNA showed that parasite burden was controlled in the spinal cord of WT mice, decreasing from the fifth week after infection, but progressive parasite dissemination was observed in IL-12p40KO cords concurrent with significant accumulation of the astrocytic marker GFAP (317.0%, p<0.01) and 8-fold increase in macrophages/microglia (p<0.01), 36.3% (p<0.01) of which were infected. Similarly, mRNA levels for CD3, TNF-α, IFN-γ, iNOS, IL-10 and arginase I declined in WT spinal cords about the fourth or fifth week after infection, but kept increasing in IL-12p40KO mice. Interestingly, compared to WT tissue, lower mRNA levels for IFN-γ were observed in the IL-12p40KO spinal cords up to the fourth week of infection. Together the data suggest that impairments of parasite clearance mechanisms in IL-12p40KO mice elicit prolonged spinal cord inflammation that in turn leads to irreversible neurodegenerative lesions.
Highlights
Chagas’ disease is an endemic Latin America illness caused by the protozoan Trypanosoma cruzi
Body weight decreased in the IL-12p40KO group later in the infection, whereas it increased in WT mice despite small oscillations
Complementing these data, the inclined plane test showed that WT mice managed to stay on the plane with a slope that varied from 50 to 60 degrees, whereas IL-12p40KO mice were not able to reach such values after 4 weeks of infection (Figure 1B)
Summary
Chagas’ disease is an endemic Latin America illness caused by the protozoan Trypanosoma cruzi. During the acute phase of the infection, symptomatic patients present fever, enlargement of the liver, lymph nodes and spleen and intense inflammatory processes associated with tissue parasitism, while during the chronic phase of the disease, they can develop cardiomyopathy and/or digestive megasyndromes [1,2,3] or, not less frequent, remain asymptomatic for life [2]. Activation of acquired immunity occurs, with IL-12-stimulated-differentiation and expansion of TH1 CD4+ cells, specific antibodies response and generation of CD8+ cytotoxic cells that destroy parasitized cells [3]. The production of IFN-c by CD4+ and CD8+ T cells enhances the effector activity of phagocytes (production of reactive nitrogen and oxygen intermediates – RNIs and ROIs – and GTPAses), a machinery that becomes highly effective when working in conjunction with opsonization induced by specific IgG. T. cruzi parasites frequently manage to evade the immune system response [4,5], establishing a chronic infection
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