Risk Assessment of Etanercept in Mice Chronically Infected With Toxoplasma gondii

Abstract

Toxoplasma gondii (T. gondii) is a zoonotic parasite that severely harms the health of the host. The cysts of T. gondii can reactivate from bradyzoites to tachyzoites, if the individual develops low or defective immunity, causing lethal toxoplasmosis. The host resists T. gondii infection by mediating Th1-type cellular immunity to generate pro-inflammatory cytokines. Tumor necrosis factor (TNF) is an important pro-inflammatory cytokine, which can induce lysosomal fusion of parasitophorous vacuole (PV) to kill parasites. Etanercept is a soluble TNF receptor fusion protein, which is widely used clinically to cure autoimmune diseases. The effects and specific molecular mechanisms of etanercept treatment on patients co-infected with autoimmune diseases and chronic toxoplasmosis are rarely reported. In our study, a mouse model of chronic infection with T. gondii and murine macrophages RAW264.7 cells infected with T. gondii were employed to investigate the impact of etanercept on the status of chronic infection. The cytokines levels and a series of phenotypic experiments in vivo and in vitro were measured. In the present study, the expression levels of TNF, IL-1β, and IL-6 were decreased and the brain cysts number was increased in mice chronically infected with T. gondii after being treated with etanercept. In vivo experiments confirmed that etanercept caused a decrease in the immune levels of the mice and activated the brain cysts, which would lead to conversion from chronic infection to acute infection, causing severe clinical and pathological symptoms. Murine macrophages RAW264.7 cells were pretreated with etanercept, and then infected with T. gondii. In vitro experiments, the expression levels of cytokines were decreased, indicating that etanercept could also reduce the cells’ immunity and promote the transformation of bradyzoites to tachyzoites, but did not affect the intracellular replication of tachyzoites. In summary, etanercept treatment could activate the conversion of bradyzoites to tachyzoites through reducing host immunity in vivo and in vitro. The results obtained from this study suggest that the use of etanercept in patients co-infected with autoimmune diseases and chronic toxoplasmosis may lead to the risk of activation of chronic infection, resulting in severe acute toxoplasmosis.

Immune response against toxoplasmosis—some recent updates RH:Toxoplasma gondiiimmune response

“…Etanercept (a soluble TNF-receptor fusion protein), widely used to treat autoimmune disease, activates the conversion of bradyzoites (chronic toxoplasmosis) to tachyzoites (acute toxoplasmosis) through down-regulation of pro-inflammatory cytokines (TNF, IL-1beta, and IL6). 202 It would be interesting to try to achieve a sterile immunity in an experimental model of chronic toxoplasmosis, at first transforming bradyzoites to tachyzoites through use of Etanercept but not too long after this, treating the tachyzoites to eliminate the parasite from the host body.…”

Toxoplasma gondii α‐amylase deletion mutant is a promising vaccine against acute and chronic toxoplasmosis

“…T. gondii usually can be controlled by immunocompetent hosts. Nevertheless, individuals with inhibited immunity may develop severe clinical symptoms such as encephalitis, ophthalmia, abortion and even death (Williams, 1979; Miedema et al ., 2013; Yang et al ., 2018). The main epidemic strains of T. gondii are classified as types I, II and III: type I, a robust virulence in mice, type II, predominant strain of human infections in Europe and North America, and type III, known for its low virulence in hosts (Howe and Sibley, 1995; Howe et al ., 1997).…”

Global MicroRNAs Expression Profile Analysis Reveals Possible Regulatory Mechanisms of Brain Injury Induced by Toxoplasma gondii Infection

“…Previous research demonstrated a significant increase in the expression of CCL19 , CCL21 , and CCR7 in CNS over the course of T. gondii infection, and that CCR7 –/– mice failed to generate sufficient IFN-γ ( Noor et al, 2010 ). CCR7 might also be an important cytokine activating the Th1-type cellular immunity that is the crucial mechanism for controlling parasite replication and causing inflammatory damage during T. gondii infection ( Noor et al, 2010 ; Yang et al, 2018 ).…”