Abstract
Trypanosoma cruzi infects and replicates within a wide variety of immune and non-immune cells. Here, we investigated early cellular responses induced in NIH-3T3 fibroblasts upon infection with trypomastigote forms of T. cruzi. We show that fibroblasts were susceptible to T. cruzi infection and started to release trypomastigotes to the culture medium after 4 days of infection. Also, we found that T. cruzi infection reduced the number of fibroblasts in 3-day cell cultures, by altering fibroblast proliferation. Infected fibroblasts displayed distinctive phenotypic alterations, including enlarged and flattened morphology with a nuclei accumulation of senescence-associated heterochromatin foci. In addition, infection induced an overexpression of the enzyme senescence-associated β-galactosidase (SA-β-gal), an activation marker of the cellular senescence program, as well as the production of cytokines and chemokines involved with the senescence-associated secretory phenotype (SASP) such as IL-6, TNF-α, IL-1β, and MCP-1. Infected fibroblasts released increased amounts of stress-associated factors nitric oxide (NO) and reactive oxygen species (ROS), and the treatment with antioxidants deferoxamine (DFO) and N-acetylcysteine reduced ROS generation, secretion of SASP-related cytokine IL-6, SA-β-gal activity, and parasite load by infected fibroblasts. Taken together, our data suggest that T. cruzi infection triggers a rapid cellular stress response followed by induction of a senescent-like phenotype in NIH-3T3 fibroblasts, enabling them to act as reservoirs of parasites during the early stages of the Chagas disease.
Highlights
The intracellular protozoan parasite Trypanosoma cruzi is the etiological agent of Chagas disease, the main endemic parasitic disease of Latin America, and a public health issue in non-endemic regions, including USA [1,2,3]
To investigate whether the reduced cell numbers in the infected condition were due to cell death, we further evaluated a reservoir of T. cruzi at the early stages of infection; and that T. cruzi infection may interfere with the cellular proliferative capacity of fibroblasts
The interaction between T. cruzi and phagocytic cells such as macrophages is well established in the literature, little is known about T. cruzi infection in non-immune cells
Summary
The intracellular protozoan parasite Trypanosoma cruzi is the etiological agent of Chagas disease, the main endemic parasitic disease of Latin America, and a public health issue in non-endemic regions, including USA [1,2,3]. Trypomastigotes invade immune and non-immune host cells, where they are converted into the replicative amastigote form. Before the parasites gain access to these cell types, they need to interact/invade epithelial cells and fibroblasts that compose epithelial/mucous barriers to insure dissemination and the establishment of chronic infection [10,11,12]. T. cruzi has the ability to non-selectively infect a wide range of cell types, which is probably due to its ability to simultaneously express several surface glycoproteins, and interact with several mammalian receptors, including toll-like receptors, TGF- and EGF-receptors, and tyrosine kinases receptors; both factors are required for optimal parasite adhesion, penetration, and transit through host cell parasitophorous vacuoles in order to establish an intracellular infection [8, 11, 13, 14]. Several in vitro studies have shown that trypomastigotes infect epithelial cells and fibroblasts [6, 11, 15,16,17]; and an interesting histopathological investigation, that analyzed placentas from mothers who gave birth to babies congenitally infected with T. cruzi, has shown parasites in fibroblasts and macrophages of chorion, membranes, and chorionic plate, mainly in the area of membrane insertion [18]
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