Trypanosoma cruzi-triggered meningoencephalitis is a CCR1/CCR5-independent inflammatory process
Introduction
In infectious diseases, the mounting of a prompt immune response is critical for the control of the invading microorganism. This seems to occur in the central nervous system (CNS) of immunocompetent mice infected by the intracellular protozoan Trypanosoma cruzi. The CD8-enriched T. cruzi-triggered meningoencephalitis is restricted to the acute infection and associated with parasite control (Pittella, 1993, Silva et al., 1999, Da Matta et al., 2000, Roffê et al., 2003). Immunodeficiency induced by either treatment with immunosuppressive drugs or infection with HIV-1 leads to reactivation of the chronic T. cruzi infection mostly in the CNS (Jardim and Takayanagui, 1994, Rocha et al., 1994, Antunes et al., 2002). Supporting the general acknowledges that surveillance of the CNS by immune cells is a pivotal host component, controlling parasitism and resolving inflammation in this target tissue, the CNS is the main site of T. cruzi infection reactivation in IL-12-deficient mice (Michailowsky et al., 2001).
The main route of leukocytes entry into the CNS requires the breaching of the blood–brain barrier and endothelial basal lamina. In general, the entry of leukocytes in target tissues depends on the activation status of these cells, including cell adhesion molecules expression, being mainly coordinated by chemokines (Moser and Loetscher, 2001). Chemokines and their receptors are important in activation, co-stimulation, differentiation and recruitment of inflammatory cells to injured sites (Luster et al., 2005) as well as in resistance to infection (Machado et al., 2000, Teixeira et al., 2002). Previously, we have demonstrated that VCAM-1/VLA-4-mediated interactions are crucial in T. cruzi-elicited encephalitis formation during the acute infection and in immunosuppression-induced chronic infection reactivation (Roffê et al., 2003). However, it remains to be comprehended the role of chemokines in the pathogenesis of T. cruzi-elicited meningoencephalitis. A significant increase in the frequency of CD8+ T cells bearing CCR5, a CC-chemokine receptor that binds CCL3/MIP-1α, CCL4/MIP-1β and CCL5/RANTES, was detected among the PBMC of T. cruzi-infected C3H/He mice (Marino et al., 2004), a model that develops acute CD8-enriched meningoencephalitis (Silva et al., 1999, Roffê et al., 2003). These results taken together with the data that in T. cruzi-infected mice CNS inflammatory lesions are mainly composed of macrophages and CD8+ T cells (Silva et al., 1999) led us to consider that CC-chemokines and, specially, the CC-chemokine receptor CCR5 could be involved in the immunopathogenesis of T. cruzi-triggered CNS inflammation. Therefore, we undertook this study to investigate the expression of CC-chemokines in the CNS of mice resistant and susceptible to develop T. cruzi-elicited meningoencephalitis. Additionally, we used the N-terminal-methionylated RANTES (Met-RANTES), a selective CCR1/CCR5 antagonist (Proudfoot et al., 1996), to evaluate the participation of chemokines signaling via CCR1/CCR5 in the early phase of T. cruzi-elicited meningoencephalitis.
Section snippets
Animals and experimental infection
Five- to seven-week-old female C3H/HeJ (H-2k) and C57BL/6 (H-2c) mice obtained from the animal facilities (CECAL) of the Oswaldo Cruz Foundation-Fiocruz (Rio de Janeiro, Brazil) were maintained under standard conditions and manipulated according to institutional guidelines for animal ethics of the Fiocruz (#PO161/03). All the experiments were performed twice or three times according with the protocols.
Mice were infected by intra-peritoneal via with 100 blood trypomastigotes of the Colombiana
Expression of mRNA of CC-chemokines in the CNS of T. cruzi-infected mice
Based on the presence and intensity of inflammation, C3H/He strain was previously described to be more susceptible than C57BL/6 to T. cruzi-elicited meningoencephalitis (Roffê et al., 2003). To further analyze this differential susceptibility we analyzed the expression of CC-chemokines in the brain of T. cruzi-infected C57BL/6 and C3H/He mice. In the CNS of acutely T. cruzi-infected C57BL/6 mice, there was an increased expression of CCL4/MIP-1β and CCL5/RANTES mRNA in the absence of
Discussion
The leukocyte migration to a site of tissue injury requires a multi-step process with protagonist participation of cell adhesion molecules, chemokines and their receptors. The participation of VLA-4/VCAM-1 in trafficking of inflammatory cells into the CNS was associated with susceptibility to meningoencephalitis in T. cruzi infection (Roffê et al., 2003). Based on that and trying to further understand the differential susceptibility of C57BL/6 (resistant) and C3H/He (susceptible) mice to T.
Acknowledgments
Supported in part by CNPq (501561/2004–8, 301504/2005–9, 471518/2006–9), FAPERJ (E-26/151999/2000). JLV, MMT and RTG are research fellows from CNPq. APM was a post-graduate student with scholarship from FAPERJ (Bolsa Nota 10). KKP is a student with scholarship from PIBIC-CNPq.
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