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.
Members of the Regulator of G-protein signaling (Rgs) family regulate the extent and timing of G protein signaling by increasing the GTPase activity of Gα protein subunits. The Rgs family member Rgs1 is one of the most up-regulated genes in tissue-resident memory (TRM) T cells when compared to their circulating T cell counterparts. Functionally, Rgs1 preferentially deactivates Gαq, and Gαi protein subunits and can therefore also attenuate chemokine receptor-mediated immune cell trafficking. The impact of Rgs1 expression on tissue-resident T cell generation, their maintenance, and the immunosurveillance of barrier tissues, however, is only incompletely understood. Here we report that Rgs1 expression is readily induced in naïve OT-I T cells in vivo following intestinal infection with Listeria monocytogenes-OVA. In bone marrow chimeras, Rgs1-/- and Rgs1+/+ T cells were generally present in comparable frequencies in distinct T cell subsets of the intestinal mucosa, mesenteric lymph nodes, and spleen. After intestinal infection with Listeria monocytogenes-OVA, however, OT-I Rgs1+/+ T cells outnumbered the co-transferred OT-I Rgs1-/- T cells in the small intestinal mucosa already early after infection. The underrepresentation of the OT-I Rgs1-/- T cells persisted to become even more pronounced during the memory phase (d30 post-infection). Remarkably, upon intestinal reinfection, mice with intestinal OT-I Rgs1+/+ TRM cells were able to prevent the systemic dissemination of the pathogen more efficiently than those with OT-I Rgs1-/- TRM cells. While the underlying mechanisms are not fully elucidated yet, these data thus identify Rgs1 as a critical regulator for the generation and maintenance of tissue-resident CD8+ T cells as a prerequisite for efficient local immunosurveillance in barrier tissues in case of reinfections with potential pathogens.
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