Astrocyte Apoptosis and HIV Replication Are Modulated in Host Cells Coinfected with Trypanosoma cruzi

Abstract

The protozoan Trypanosoma cruzi is the etiological agent of Chagas disease. In immunosuppressed individuals, as it occurs in the coinfection with human immunodeficiency virus (HIV), the central nervous system may be affected. In this regard, reactivation of Chagas disease is severe and often lethal, and it accounts for meningoencephalitis. Astrocytes play a crucial role in the environment maintenance of healthy neurons; however, they can host HIV and T. cruzi. In this report, human astrocytes were infected in vitro with both genetically modified-pathogens to express alternative fluorophore. As evidenced by fluorescence microscopy and flow cytometry, HIV and T. cruzi coexist in the same astrocyte, likely favoring reciprocal interactions. In this context, lower rates of cell death were observed in both T. cruzi monoinfected-astrocytes and HIV-T. cruzi coinfection in comparison with those infected only with HIV. The level of HIV replication is significantly diminished under T. cruzi coinfection, but without affecting the infectivity of the HIV progeny. This interference with viral replication appears to be related to the T. cruzi multiplication rate or its increased intracellular presence but does not require their intracellular cohabitation or infected cell-to-cell contact. Among several Th1/Th2/Th17 profile-related cytokines, only IL-6 was overexpressed in HIV-T. cruzi coinfection exhibiting its cytoprotective role. This study demonstrates that T. cruzi and HIV are able to coinfect astrocytes thus altering viral replication and apoptosis.

Cell Death Is Counteracted by Mitophagy in HIV-Productively Infected Astrocytes but Is Promoted by Inflammasome Activation Among Non-productively Infected Cells

“…Human astrocytes were challenged with pseudotyped HIV co-expressing G glycoprotein from stomatitis vesicular virus (VSV-G) ( 21 , 22 ). We used pNL4.3, a full-length infectious molecular clone of HIV, obtained through the NIH AIDS Reagent Program (Division of AIDS, NIAID, NIH, USA) from Dr. Malcolm Martin ( 23 ).…”

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).…”

“…Astrocytes are host-cells for both pathogens (Blanchet et al, 2010;Vargas-Zambrano et al, 2013;Urquiza et al, 2017). Then, in a coinfection -with cellular cohabitation or by bystander effect between monoinfected cells -the progress of the infections can be modified.…”

“…Extensive clinical, cerebrospinal fluid (CSF), neuroimaging, and neuropathological data support persistent HIV infection in the CNS (Valcour et al, 2011). We and others have demonstrated that, like other CNS cells, astrocytes can host several infectious agents, including HIV and T. cruzi (Blanchet et al, 2010;Vargas-Zambrano et al, 2013;Urquiza et al, 2017) and are regarded as important performers in Chagasic meningoencephalitis development. HIV can infect the brain and impair CNS function.…”

“…We and others have demonstrated that astrocytes can be productively infected by HIV (Barat et al, 2018;Ojeda et al, 2018;Li et al, 2020) and when T. cruzi is concomitantly present, both pathogens may interact (Urquiza et al, 2017). To assess the influence of HIV infection of astrocytes on its posterior T. cruzi superinfection and multiplication, primary cultured human astrocytes were exposed subsequently to both pathogens ( Figure 3A).…”