Interferon-Gamma Promotes Infection of Astrocytes by <i>Trypanosoma cruzi</i>

<div><p>The inflammatory cytokine interferon-gamma (IFNγ) is crucial for immunity against intracellular pathogens such as the protozoan parasite <i>Trypanosoma cruzi</i>, the causative agent of Chagas disease (CD). IFNγ is a pleiotropic cytokine which regulates activation of immune and non-immune cells; however, the effect of IFNγ in the central nervous system (CNS) and astrocytes during CD is unknown. Here we show that parasite persists in the CNS of C3H/He mice chronically infected with the Colombian <i>T. cruzi</i> strain despite the increased expression of IFNγ mRNA. Furthermore, most of the <i>T. cruzi</i>-bearing cells were astrocytes located near IFNγ⁺ cells. Surprisingly, <i>in vitro</i> experiments revealed that pretreatment with IFNγ promoted the infection of astrocytes by <i>T. cruzi</i> increasing uptake and proliferation of intracellular forms, despite inducing increased production of nitric oxide (NO). Importantly, the effect of IFNγ on <i>T. cruzi</i> uptake and growth is completely blocked by the anti-tumor necrosis factor (TNF) antibody Infliximab and partially blocked by the inhibitor of nitric oxide synthesis L-NAME. These data support that IFNγ fuels astrocyte infection by <i>T. cruzi</i> and critically implicate IFNγ-stimulated <i>T. cruzi</i>-infected astrocytes as sources of TNF and NO, which may contribute to parasite persistence and CNS pathology in CD.</p>