Migratory Activation of Primary Cortical Microglia upon Infection with Toxoplasma gondii

Abstract

Disseminated toxoplasmosis in the central nervous system (CNS) is often accompanied by a lethal outcome.Studies with murine models of infection have focused on the role of systemic immunity in control of toxoplasmic encephalitis, while knowledge remains limited on the contributions of resident cells with immune functions in the CNS. In this study, the role of glial cells was addressed in the setting of recrudescent Toxoplasma infection in mice. Activated astrocytes and microglia were observed in the close vicinity of foci with replicating parasites in situ in the brain parenchyma. Toxoplasma gondii tachyzoites were allowed to infect primary microglia and astrocytes in vitro. Microglia were permissive to parasite replication, and infected microglia readily transmigrated across transwell membranes and cell monolayers. Thus, infected microglia, but not astrocytes, exhibited a hypermotility phenotype reminiscent of that recently described for infected dendritic cells. In contrast to gamma interferon-activated microglia, Toxoplasma-infected microglia did not upregulate major histocompatibility complex (MHC) class II molecules and the costimulatory molecule CD86. Yet Toxoplasma-infected microglia and astrocytes exhibited increased sensitivity to T cell-mediated killing, leading to rapid parasite transfer to effector T cells in vitro. We hypothesize that glial cells and T cells, besides their role in triggering antiparasite immunity, may also act as "Trojan horses," paradoxically facilitating dissemination of Toxoplasma within the CNS. To our knowledge, this constitutes the first report of migratory activation of a resident CNS cell by an intracellular parasite.

Nitric oxide production increases during Toxoplasma gondii encephalitis in mice

“…However, strong immunoreactions were observed at 30 days post-infection, as at 10 days post-infection, and a comparison of the histopathological findings called into question the occurrence of reactivation. Microglia/macrophages might be responsible for both recurrent and systemic T. gondii infections, with tachyzoites and bradyzoites hidden in the cells acting as a "Trojan horse" (Da Gama et al, 2004;Barragan and Hitziger, 2008;Dellacasa-Lindberg et al, 2011). In the present study, the strong NO immunopositivity observed in the microglia/ macrophages suggested that bradyzoites were hidden in these cells, thus providing a putative explanation for the activation of the cerebral immune mechanism.…”

Brains and Brawn: Toxoplasma Infections of the Central Nervous System and Skeletal Muscle

“…Intracerebral inflammation can also contribute to the onset of seizures [84]. Given the significant number of activated microglia and astrocytes in Toxoplasma- infected brains [85], parasite-induced inflammation could contribute to seizures in infected mice. Overexpression of several cytokines that are upregulated by infection (e.g.…”

Passage of parasites across the blood-brain barrier

“…A molecule secreted by Toxoplasma gondii, cyclophilin 18, interacts with the chemokine receptor CCR5 and this results in the production of nitric oxide (NO), interleukin 12 (IL-12), and tumor necrosis factor α (TNFα) as well as attraction of macrophages to the site of infection to increase the chances of parasite-leukocyte interaction 36 , 37 . Once the parasite has invaded the immune cells it increases their motility and migratory activities via a G i -protein coupled receptor signaling pathway 38 - 40 . How the parasite activates the G i -protein coupled receptor signaling pathway is still not known.…”