CXCL10 and CXCR3 modulate morbidity and brain invasion by parasites and T-cells in an African Trypanosomiasis mouse model (original) (raw)
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A link between chemokine levels and disease severity in human African trypanosomiasis
International Journal for Parasitology, 2006
Trypanosoma brucei gambiense infection is an important public health challenge in sub-Saharan Africa. This parasitic disease is difficult to diagnose due to insidious clinical signs and transient parasitaemias. The clinical course is marked by two stages of increasing disease severity. An early systemic parasitic invasion is followed by the development of a progressive meningo-encephalitis. During this latter stage, a broad spectrum of neurological signs appears, which finally lead to a demyelinating and fatal stage if untreated. Treatment is toxic and difficult to administer when the CNS is invaded. Therefore, accurate diagnostic methods for stage determination are needed. The classically used criteria are not sufficiently specific and mechanisms of parasite invasion through the blood-brain barrier remain poorly understood. As cytokines/chemokines are involved in the early recruitment of leukocytes into the CNS, this study has focused on their potential value to define the onset of CNS involvement. Levels of monocyte chemoattractant protein-1/CCL-2, macrophage inflammatory protein-1a/CCL-3, IL-8/CXCL-8, regulated upon activation T cell expressed and secreted (RANTES)/CCL-5 and IL-1b were measured in paired sera and CSF from 57 patients and four controls. Patients were classified into three groups (stage 1, intermediate and stage 2) according to current field criteria for stage determination (CSF cell count, presence of trypanosomes in CSF and neurological signs). In sera, cytokine/ chemokine levels were poorly related to disease stage. Only CXCL-8 was higher in stage 1 patients when compared with stage 2 and CCL-5 was higher in controls when compared with patients. In contrast, in CSF the expression of the selected cytokines, except CCL-5, was associated with the presence of neurological signs, demonstrating their diagnostic value. We observed a relationship between the presence of trypanosomes or trypanosome-related compounds in CSF and levels of IL-1b, CXCL-8, CCL-2 and CCL-3. These cytokines and chemokines may be triggered by the parasite and hence are potential markers of CNS invasion. Ó
Role of T cells during the cerebral infection with Trypanosoma brucei
PLOS Neglected Tropical Diseases, 2021
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...
Chemokines are produced in the brain early during the course of experimental African trypanosomiasis
Journal of Neuroimmunology, 2000
. African trypanosomiasis is characterized by progressive central nervous system CNS involvement. Using single and double immunohistochemistry, we evaluated the induction of aand b-chemokines in brains of Sprague-Dawley rats infected with Try-( ) panosoma brucei brucei T. b. brucei and identified their cellular source. The results showed high production of MIP-2, RANTES and MIP-1a and to a lower extend MCP-1 in infected animals compared to controls. MIP-2, RANTES and MIP-1a were produced early by astrocytes and microglia and later by macrophages and T-cells. These findings suggest that chemokines may contribute to the immunopathogenesis that occurs in the CNS early during infections. q
A Combined CXCL10, CXCL8 and H-FABP Panel for the Staging of Human African Trypanosomiasis Patients
Plos Neglected Tropical Diseases, 2009
Background: Human African trypanosomiasis (HAT), also known as sleeping sickness, is a parasitic tropical disease. It progresses from the first, haemolymphatic stage to a neurological second stage due to invasion of parasites into the central nervous system (CNS). As treatment depends on the stage of disease, there is a critical need for tools that efficiently discriminate the two stages of HAT. We hypothesized that markers of brain damage discovered by proteomic strategies and inflammation-related proteins could individually or in combination indicate the CNS invasion by the parasite.
Immunology, 2001
The present study shows that CD8 + T lymphocytes expressing low levels of T-cell receptor (TCR)ab, CD8 and CD3 accumulate in the spleen, blood, peritoneum and liver, but not in the lymph nodes of mice chronically infected with Trypanosoma cruzi. Analysis of spleen lymphocytes reveals that most CD8 LOW TCR LOW T cells have an experienced phenotype (CD44 HIGH CD62L LOW and CD45RA,B,C LOW). These cells have small size, lack activation markers such as CD69, CD25 and CD11b (Mac-1), and do not spontaneously secrete cytokines, suggesting they are at the resting state. When stimulated in vitro with T. cruzi-infected macrophages, TCR LOW CD8 LOW T cells behave as parasite-speci®c memory cells, readily responding with interferon-c (IFN-c) production. Indeed, among parasite-activated CD8 + lymphocytes, IFN-c production was mostly due to TCR LOW CD8 LOW cells. Upon in vitro stimulation with anti-CD3/ CD28 monoclonal antibodies, down-regulated cells produce IFN-c and tumour necrosis factor-a, but not interleukin IL-10 or IL-4. Our results indicate that despite parasite persistence, most T. cruzi-speci®c experienced CD8 + cells are resting. Nevertheless, when encountering infected macrophages these cells differentiate to Tc1 effectors.