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Abstract
Trypanosoma cruzi enters host cells by subverting the mechanism of cell membrane repair. In this process, the parasite induces small injuries in the host cell membrane leading to calcium entry and lysosomal exocytosis, which are followed by compensatory endocytosis events that drive parasites into host cells. We have previously shown that absence of both LAMP-1 and 2, major components of lysosomal membranes, decreases invasion of T. cruzi into host cells, but the mechanism by which they interfere with parasite invasion has not been described. Here we investigated the role of these proteins in parasitophorous vacuole morphology, host cell lysosomal exocytosis, and membrane repair ability. First, we showed that cells lacking only LAMP-2 present the same invasion phenotype as LAMP1/2-/- cells, indicating that LAMP-2 is an important player during T. cruzi invasion process. Second, neither vacuole morphology nor lysosomal exocytosis was altered in LAMP-2 lacking cells (LAMP2-/- and LAMP1/2-/- cells). We then investigated the ability of LAMP-2 deficient cells to perform compensatory endocytosis upon lysosomal secretion, the mechanism by which cells repair their membrane and T. cruzi ultimately enters cells. We observed that these cells perform less endocytosis upon injury when compared to WT cells. This was a consequence of impaired cholesterol traffic in cells lacking LAMP-2 and its influence in the distribution of caveolin-1 at the cell plasma membrane, which is crucial for plasma membrane repair. The results presented here show the major role of LAMP-2 in caveolin traffic and membrane repair and consequently in T. cruzi invasion.
Highlights
Trypanosoma cruzi is the causative agent of Chagas disease
We first decided to test the influence of lysosomal integral membrane protein 2, LAMP-2, in T. cruzi cell infection, when compared to LAMP1/2-/- deficient or wild type (WT) control fibroblasts
It had been shown before that LAMP-1 deficiency had little effect on cell morphology, LAMP-2, membrane repair and T. cruzi infection metabolism or viability and led to overexpression of LAMP-2 in cells, suggesting that LAMP-2 might compensate for LAMP-1 deficiency [25]
Summary
Trypanosoma cruzi is the causative agent of Chagas disease. This parasite is naturally transmitted through the feces of an infected vector, a triatomine bug, but transmission may occur through contaminated food, blood transfusion, placenta or organ transplantation [1]. Originally endemic to Latin America, where the vector is widespread, Chagas disease is found in non-endemic countries, especially in the southern part of the United States and Europe due to human migration [2,3,4,5]. Available treatment is not efficient, especially considering the chronic phase of the infection [7]. The comprehension of the mechanisms involved in these processes is extremely important for the development of more efficient treatment and disease control
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