Trypanosoma cruzi Infection Induces Cellular Stress Response and Senescence-Like Phenotype in Murine Fibroblasts

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.

Circulating Senescent T Cells Are Linked to Systemic Inflammation and Lesion Size During Human Cutaneous Leishmaniasis

“…He we show that the inflammatory T cells that accumulate in the circulation of infected individuals have characteristics of senescent cells and since they are highly secretory, they may have the equivalent of a senescence-associated secretory phenotype (SASP) (13). In addition, we consider that the extent of senescence may depend on the clinical type of leishmaniasis as well as during other parasitic infections (27, 37, 38). A key observation was that the stimulation with Leishmania antigens induced an imbalance in the pro vs. anti-inflammatory cytokine ratio compared with anti-CD3 activation of T cells from infected patients.…”

Eimeria bovis infections induce G1 cell cycle arrest and a senescence-like phenotype in endothelial host cells

“…To analyse the influence of E. bovis infections on host cellular senescence, we here estimated cell proliferation, SA- β -Gal activity, heterochromatin transition and expression of cell cycle-related molecules. In the case of T. cruzi -induced host cellular senescence, a remarkable reduction of cell proliferation was reported (Guimarães-Pinto et al ., 2018 ). Concerning cell proliferation effects, it has to be mentioned that E. bovis culture in BUVECs leading to merozoite I formation is long lasting and takes more than 3 weeks of in vitro culture.…”

“…During senescence, chromatin transition to heterochromatin-rich foci (SAHF) is a well-described characteristic that was also confirmed for T. cruzi -infected host cells (Guimarães-Pinto et al ., 2018 ). In general, two forms of chromatins are known: condensed heterochromatin and diffuse euchromatin.…”

“…In the case of Plasmodium spp., Plasmodium falciparum infections affected mitosis and led to a lack of cell division in HepG2 cells (Hanson et al, 2015) but cell cycle-dependent reactions neither played a role in Plasmodium berghei-or Plasmodium yoelii-infected mouse models nor in P. falciparum-infected primary hepatocytes. Overall, amongst these known examples, an induction of senescence by intracellular parasites has been exclusively described for T. cruzi, so far (Guimarães-Pinto et al, 2018). Cellular senescence occurs in response to excessive intra-or extracellular stress (Campisi, 2013).…”

Infection byTrypanosoma cruziin the central nervous system in non-human mammals: a systematic review

“…The natural route of infection of the obligate intracellular parasite T. cruzi occurs when a triatomine insect vector deposits infective metacyclic trypomastigotes with their feces and urine on the host's skin during blood meal (Guimarães-Pinto et al ., 2018). In addition to humans, T. cruzi infects a wide variety of domestic and wild mammals such as Carnivora, Chiroptera, Didelphidomorphia, Lagomorpha, Perissodactyla, Pilosa, Prieta and Rodentia (Añez et al ., 2009; Herrera, 2010), with dogs being the main domestic reservoir (Montenegro et al ., 2002).…”