Role of T cells during the cerebral infection with Trypanosoma brucei.

Gabriela C Olivera,Juan Basile,Leonie Vetter,Martin E Rottenberg,Chiara Tesoriero,Gustav Hedberg,Federico Del Gallo,Mary Ann Mcdowell

doi:10.1371/journal.pntd.0009764

Gabriela C Olivera, Juan Basile + Show 6 more

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https://doi.org/10.1371/journal.pntd.0009764

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Abstract

The infection by Trypanosoma brucei brucei (T.b.b.), a protozoan parasite, is characterized by an early-systemic stage followed by a late stage in which parasites invade the brain parenchyma in a T cell-dependent manner. Here we found that early after infection effector-memory T cells were predominant among brain T cells, whereas, during the encephalitic stage T cells acquired a tissue resident memory phenotype (TRM) and expressed PD1. Both CD4 and CD8 T cells were independently redundant for the penetration of T.b.b. and other leukocytes into the brain parenchyma. The role of lymphoid cells during the T.b.b. infection was studied by comparing T- and B-cell deficient rag1-/- and WT mice. Early after infection, parasites located in circumventricular organs, brain structures with increased vascular permeability, particularly in the median eminence (ME), paced closed to the sleep-wake regulatory arcuate nucleus of the hypothalamus (Arc). Whereas parasite levels in the ME were higher in rag1-/- than in WT mice, leukocytes were instead reduced. Rag1-/- infected mice showed increased levels of meca32 mRNA coding for a blood /hypothalamus endothelial molecule absent in the blood-brain-barrier (BBB). Both immune and metabolic transcripts were elevated in the ME/Arc of WT and rag1-/- mice early after infection, except for ifng mRNA, which levels were only increased in WT mice. Finally, using a non-invasive sleep-wake cycle assessment method we proposed a putative role of lymphocytes in mediating sleep alterations during the infection with T.b.b. Thus, the majority of T cells in the brain during the early stage of T.b.b. infection expressed an effector-memory phenotype while TRM cells developed in the late stage of infection. T cells and parasites invade the ME/Arc altering the metabolic and inflammatory responses during the early stage of infection and modulating sleep disturbances.

Highlights

The extracellular protozoan parasite Trypanosoma brucei (T.b.) is the causative agent of African trypanosomiasis, an infectious disease that affects both humans and animals
To determine the role of parasites in the maintenance of T cell infiltrates in the brain, a group of mice was treated with the trypanocidal drugs melarsoprol and suramin starting at 21 days post-infection, when parasites have penetrated into the brain parenchyma
We found that T cells in the brain increased during infection and persisted after reducing T.b.b. levels by parasiticidal treatment, recapitulating the post-treatment reactive encephalopathy occurring after a sub-curative parasiticidal treatment of the late stage of T.b.b. infection

Summary

Introduction

The extracellular protozoan parasite Trypanosoma brucei (T.b.) is the causative agent of African trypanosomiasis, an infectious disease that affects both humans and animals. In a mouse model of infection, T.b. brucei (T.b.b.) and leukocytes cross the blood-brain barrier (BBB) and enter the brain parenchyma [3]. We have previously observed that T.b.b. brain invasion depends on the presence of T cells as shown by the absence of parasites in the brain of rag1-/- mice, lacking mature T and B cells. The secretion of interferon (IFN)-γ by T cells [3], of the IFN-γ-dependent chemokine CXCL10 by astrocytes [6], and of tumor necrosis factor (TNF) by T cells and macrophages [5,7] have been shown to be required for parasite and leukocyte invasion of the brain. An unresolved question is how inflammatory cells are initially recruited into the brain parenchyma during T.b.b. infection.

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