Priming astrocytes with TNF enhances their susceptibility to Trypanosoma cruzi infection and creates a self-sustaining inflammatory milieu

Abstract

Background: In conditions of immunosuppression, the central nervous sty 5ystem (CNS) is the main target tissue for the reactivation of infection by Trypanosoma cruzi, the causative agent of Chagas disease. In experimental T. cruzi infection, interferon gamma (IFNγ) + microglial cells surround astrocytes harboring amastigote parasites. In vitro, IFNγ fuels astrocyte infection by T. cruzi, and IFNγ-stimulated infected astrocytes are implicated as potential sources of tumor necrosis factor (TNF). Pro-inflammatory cytokines trigger behavioral alterations. In T. cruzi-infected mice, administration of anti-TNF antibody hampers depressive-like behavior. Herein, we investigated the effects of TNF on astrocyte susceptibility to T. cruzi infection and the regulation of cytokine production. Methods: Primary astrocyte cultures of neonatal C57BL/6 and C3H/He mice and the human U-87 MG astrocyte lineage were infected with the Colombian T. cruzi strain. Cytokine production, particularly TNF, and TNF receptor 1 (TNFR1/p55) expression were analyzed. Recombinant cytokines (rIFNγ and rTNF), the anti-TNF antibody infliximab, and the TNFR1 modulator pentoxifylline were used to assess the in vitro effects of TNF on astrocyte susceptibility to T. cruzi infection. To investigate the role of TNF on CNS colonization by T. cruzi, infected mice were submitted to anti-TNF therapy. Results: rTNF priming of mouse and human astrocytes enhanced parasite/astrocyte interaction (i.e., the percentage of astrocytes invaded by trypomastigote parasites and the number of intracellular parasite forms/astrocyte). Furthermore, T. cruzi infection drove astrocytes to a pro-inflammatory profile with TNF and interleukin-6 production, which was amplified by rTNF treatment. Adding rTNF prior to infection fueled parasite growth and trypomastigote egression, in parallel with increased TNFR1 expression. Importantly, pentoxifylline inhibited the TNF-induced increase in astrocyte susceptibility to T. cruzi invasion. In T. cruzi-infected mice, anti-TNF therapy reduced the number of amastigote nests in the brain.

Memory impairment in chronic experimental Chagas disease: Benznidazole therapy reversed cognitive deficit in association with reduction of parasite load and oxidative stress in the nervous tissue

“…Astrocyte-born TNF may contribute to T . cruzi persistence mainly in astrocytes, as parasite-positive spots in the CNS [ 47 , 54 ]. However, in the CNS TNF expression may be restricted to these parasite-positive areas, where TNF may be rapidly consumed.…”

Priming Astrocytes With HIV-Induced Reactive Oxygen Species Enhances Their Trypanosoma cruzi Infection

“…In this context, neurological involvement is observed is the vast majority of HIV-coinfected patients (Ferreira et al, 1997;Cordova et al, 2008). Astrocytes have been proposed as parasite (Weinkauf et al, 2011;Silva et al, 2015Silva et al, , 2017, and also HIV target cells, as we and others have reported (Urquiza et al, 2017;Chen et al, 2020;Li et al, 2020;Proust et al, 2020).…”

Infectious Diseases and the Lymphoid Extracellular Matrix Remodeling: A Focus on Conduit System

“…Since chronic infection causes intense disorganization and fibrosis, it seems that preventing or limiting such events may be the best way to restore homeostasis. The application of coadjuvant drugs, such as pentoxyfylline [70] and infliximab [71], may protect the tissue from a high production of TNF-α, which is also responsible for the activation of several enzymes, limiting the matrix disorganization. Unfortunately, several other molecules contribute to tissue damage, and further research is needed.…”