RESUMEN
Analysis of the mechanisms underlying the inflammatory response in amoebiasis is important to understand the immunopathology of the disease. Mucosal associated effector and regulatory T cells may play a role in regulating the inflammatory immune response associated to Entamoeba histolytica infection in the colon. A subpopulation of regulatory T cells has recently been identified and is characterized by the expression of the chemokine receptor CCR9. In this report, we used CCR9 deficient (CCR9(-/-)) mice to investigate the role of the CCR9(+) T cells in a murine model of E. histolytica intestinal infection. Intracecal infection of CCR9(+/+), CCR9(+/-) and CCR9(-/-) mice with E. histolytica trophozoites, revealed striking differences in the development and nature of the intestinal inflammatory response observed between these strains. While CCR9(+/+) and CCR9(+/-) mice were resistant to the infection and resolved the pathogen-induced inflammatory response, CCR9(-/-) mice developed a chronic inflammatory response, which was associated with over-expression of the cytokines IFN-γ, TNF-α, IL-4, IL-6 and IL-17, while IL-10 was not present. In addition, increased levels of CCL11, CCL20 and CCL28 chemokines were detected by qRT-PCR in CCR9(-/-) mice. E. histolytica trophozoites were identified in the lumen of the cecum of CCR9(-/-) mice at seven days post infection (pi), whereas in CCR9(+/+) mice trophozoites disappeared by day 1 pi. Interestingly, the inflammation observed in CCR9(-/-) mice, was associated with a delayed recruitment of CD4(+)CD25(+)FoxP3(+) T cells to the cecal epithelium and lamina propria, suggesting that this population may play a role in the early regulation of the inflammatory response against E. histolytica, likely through IL-10 production. In support of these data, CCR9(+) T cells were also identified in colon tissue sections obtained from patients with amoebic colitis. Our data suggest that a population of CCR9(+)CD4(+)CD25(+)FoxP3(+) T cells may participate in the control and resolution of the inflammatory immune response to E. histolytica infection.
Asunto(s)
Modelos Animales de Enfermedad , Disentería Amebiana/inmunología , Entamoeba histolytica/inmunología , Receptores CCR/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Quimiocina CCL11/genética , Quimiocina CCL11/inmunología , Quimiocina CCL11/metabolismo , Quimiocina CCL20/genética , Quimiocina CCL20/inmunología , Quimiocina CCL20/metabolismo , Quimiocinas CC/genética , Quimiocinas CC/inmunología , Quimiocinas CC/metabolismo , Disentería Amebiana/metabolismo , Disentería Amebiana/parasitología , Entamoeba histolytica/fisiología , Citometría de Flujo , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Expresión Génica , Humanos , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-17/inmunología , Interleucina-17/metabolismo , Subunidad alfa del Receptor de Interleucina-2/inmunología , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Interleucina-4/inmunología , Interleucina-4/metabolismo , Interleucina-6/inmunología , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR/genética , Receptores CCR/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trofozoítos/inmunología , Trofozoítos/fisiología , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Amoebiasis is caused by the protozoa Entamoeba histolytica and persists as one of the leading parasitic diseases affecting millions worldwide. This parasite invades the intestinal mucosa, causing amoebic colitis and ulcers. It may also spread to other organs, mainly the liver, causing amoebic liver abscess (ALA). Current research efforts have focused on the development of specific diagnostic tests and animal models searching for a better understanding of the complex physiopathology of this disease. Analysis of the inflammatory immune response during intestinal amoebiasis in both human disease and animal murine models has revealed an important regulatory role for chemokines and cytokines. Recruitment and activation of inflammatory cells can also be modulated by specific protease-mediated cleavage of cytokines and by secreted amoebic factors such as amoebapores and monocyte locomotion inhibitory factor (MLIF). Unlike intestinal amoebiasis, analysis of the immune response in ALA has mainly been done in the hamster model. This has limited our information regarding the immune response during this phase of the disease. However, even with these limitations, several Th1/2 cytokines, such as IL-6 and IL-4, and regulatory cytokines, like IL-10 and TGFbeta, have been associated to the development of this disease.