RESUMEN
Chagas disease is caused by infection with the protozoan Trypanosoma cruzi. CD8 T-lymphocytes help to control infection, but apoptosis of CD8 T cells disrupts immunity and efferocytosis can enhance parasite infection within macrophages. Here, we investigate how apoptosis of activated CD8 T cells affects M1 and M2 macrophage phenotypes. First, we found that CD8 T-lymphocytes and inflammatory monocytes/macrophages infiltrate peritoneum during acute T. cruzi infection. We show that treatment with anti-Fas ligand (FasL) prevents lymphocyte apoptosis, upregulates type-1 responses to parasite antigens, and reduces infection in macrophages cocultured with activated CD8 T cells. Anti-FasL skews mixed M1/M2 macrophage profiles into polarized M1 phenotype, both in vitro and following injection in infected mice. Moreover, inhibition of T-cell apoptosis induces a broad reprogramming of cytokine responses and improves macrophage-mediated immunity to T. cruzi. The results indicate that disposal of apoptotic CD8 T cells increases M2-macrophage differentiation and contributes to parasite persistence.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Enfermedad de Chagas/inmunología , Proteína Ligando Fas/antagonistas & inhibidores , Interacciones Huésped-Parásitos , Inmunidad Celular/efectos de los fármacos , Macrófagos/inmunología , Animales , Anticuerpos Neutralizantes/farmacología , Apoptosis/efectos de los fármacos , Asialoglicoproteínas/genética , Asialoglicoproteínas/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/parasitología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/parasitología , Comunicación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/genética , Enfermedad de Chagas/parasitología , Técnicas de Cocultivo , Proteína Ligando Fas/genética , Proteína Ligando Fas/inmunología , Regulación de la Expresión Génica , Subunidad p35 de la Interleucina-12/genética , Subunidad p35 de la Interleucina-12/inmunología , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Activación de Linfocitos , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos BALB C , Fenotipo , Trypanosoma cruzi/crecimiento & desarrollo , Trypanosoma cruzi/inmunologíaRESUMEN
Toxoplasma gondii infects many warm-blooded animals, including chickens. However, little is known about how this protozoan behaves within chicken macrophages. Thus, the microbicidal biology of HD11 and MQ-NCSU (available chicken macrophage cell lines) and the escaping mechanism of T. gondii were investigated. After infection, both cell lines were activated with lipopolysaccharide (LPS) and nitric oxide (NO), and reactive oxygen intermediates (ROI) were evaluated. T. gondii infected both cell lines, and 30 and 60% inhibition of NO production was detected in MQ-NCSU and HD11, respectively. In HD11, NO inhibition was not dependent on cyclooxygenase products. Although NO was partially inhibited, it did control T. gondii multiplication, showing the importance of this microbicidal molecule. Production of ROI was not detected in either cell line after T. gondii or yeast interaction. NADPH diaphorase (NADPH-d) activity, a histochemical marker of inducible NO synthase (iNOS), was detected at various levels in the HD11 population activated with LPS. The HD11 population infected with T. gondii showed a decrease in NADPH-d, indicating that NO production inhibition was related to iNOS disappearance in infected macrophages. These results demonstrate that in chicken macrophages T. gondii can also inhibit NO production, which suggests that an iNOS suppression mechanism might be used for better survival in macrophages.
