Transmissible spongiform encephalopathies (TSEs) or prion diseases, are subacute neurodegenerative diseases that infect humans and animals. Many of these diseases are acquired by peripheral exposure (e.g. orally). After oral exposure prion replication within the Peyer's patches (PP) in the small intestine is necessary for the efficient spread of the disease to the brain. Within the intestine, bacteria and pathogenic microorganisms can affect the status of the gut associated lymphoid tissue (GALT). GALT consists of PP and isolated lymphoid follicles (ILF) that maintain homeostasis and protect from infections. Therefore, factors which modify GALT status, might dramatically affect oral prion disease pathogenesis by influencing the uptake of prions from the gut lumen or expanding their distribution within the host. Chronic intestinal helminth infections are common in animals and in man, and can cause significant pathology within the intestine. Little is known of the effects that intestinal helminth infections may have on oral prion diseases susceptibility. Therefore, in this study the influence that co-infection with Heligmosomoides polygyrus (a natural pathogen of the mouse small intestine) may have on oral prion disease pathogenesis and susceptibility was determined. The studies consisted of groups of 4 (for H. polygyrus characterization and for early prion detection) and 8 (for H. polygyrus-prion co-infection to terminal stage) mice infected with H. polygyrus (orally) alone or subsequently infected with ME7 scrapie prions (orally) at different time-points after parasitic infection. The effects of the H. polygyrus infection alone, and on oral prion disease pathogenesis and susceptibility were then determined. Initially the characterization of H. polygyrus infection on the host intestine revealed that this parasite caused significant pathology in the small intestine and affected the GALT microarchitecture. In the PP follicles, H. polygyrus infection increased the area of follicular dendritic cell expression, altered the positioning of mononuclear phagocytes and increased M cell density. H. polygyrus infection also reduced the number of ILF in both the small and large intestines. Additional studies in mice co-infected with a low dose of prions, revealed that these pathological changes affected the survival time and disease susceptibility. Data also show that the extent of the effects on prion disease pathogenesis and susceptibility were dependent on the stage of the helminth infection at which the mice were orally-exposed to prions. Data demonstrate that co-infection with the gastrointestinal helminth H. polygyrus can influence oral prion disease pathogenesis and susceptibility. Helminth infections can significantly modify the microarchitecture of the gut and the GALT. Data presented suggest the pathological changes that pathogens such as small intestinal helminths cause, may also influence the uptake of prions from the gut lumen after oral exposure.

Made available in DSpace on 2016-12-23T13:56:03Z (GMT). No. of bitstreams: 1 HELMINtiASE INTESTINAL.pdf: 1507224 bytes, checksum: 6132aca0f1aadf166d4e2b773c982a74 (MD5) Previous issue date: 2009-04-27 / Mycobacterium tuberculosis (MTB) é um exemplo clássico de patógeno para o qual a resposta protetora depende da imunidade celular do tipo Th1, que é caracterizada pela presença de linfócitos T CD4+ produtores de IFN-g. Essa citocina ativa mecanismos microbicidas no macrófago infectado, levando à eliminação do bacilo. Evidências sugerem que a progressão para a tuberculose esteja relacionada à presença de mecanismos imunossupressores mediados por citocinas e por células T reguladoras. Acredita-se que a presença de helmintíase intestinal possa prejudicar o desenvolvimento de uma resposta adaptativa capaz de conter ou eliminar o MTB, tornando assim o indivíduo susceptível ao adoecimento. Para aquilatar a influência da infecção por helmintos intestinais na resposta celular durante a tuberculose pulmonar, neste trabalho, foram avaliados os perfis quantitativo e fenotípico de populações celulares de sangue periférico e o padrão de citocinas em culturas de sangue total estimuladas com antígenos de MTB, em pacientes portadores de tuberculose pulmonar apresentando ou não helmintíase intestinal no momento do diagnóstico e durante a terapia antituberculose. Para isso, foram arrolados 53 pacientes com diagnóstico recente de tuberculose pulmonar. Desses, 26% eram portadores de pelo menos uma espécie de helminto intestinal. Pacientes com tuberculose pulmonar apresentaram uma redução significativa nos números de linfócitos T CD8+, células NK e NKT. Os indivíduos com helmintíase intestinal associada à tuberculose apresentaram uma maior freqüência de células T reguladoras, com ambos os fenótipos CD4+CD25HIGH e CD4+CD25HIGHFoxp3+. Além disso, os resultados sugerem que a presença de infecção por helmintos intestinais tenha induzido um estado de hipoergia em pacientes portadores de tuberculose pulmonar, uma vez que esses pacientes apresentaram concentrações menores das citocinas IL-2, TNF-a, IL-4, IL-5 e IL-10 nos sobrenadantes de culturas em relação às concentrações encontradas no grupo TB e no grupo controle. Portanto, os resultados desse trabalho sugerem que a presença de infecção por helmintos intestinais tenha um impacto negativo na resposta imunitária à tuberculose em pacientes portadores de tuberculose pulmonar. / The protection against Mycobacterium tuberculosis (MTB) depends on a cellmediated Th1 type-immune response. This response is characterized by IFN-g production by CD4+ T cells, which activates macrophages to enhance microbicidal mechanisms leading to the bacillus eradication. Factors related to tuberculosis resistance or susceptibility are not completely understood. There are evidences suggesting that the progress to active disease is related to immune downregulation caused by suppressors cytokines and regulatory T cells. It is believed that the association with helminth infection can disturb the protective immune response that should contain or eliminate MTB. Here, we investigated the role of intestinal helminth infection on M. tuberculosis specific immune response during active pulmonar tuberculosis in patients with associated tuberculosis and intestinal helminth infection at the time of diagnosis and during tuberculosis therapy. Quantitative and phenotypic analyses of peripheral blood cells populations were performed and the MTBstimulated whole blood culture cytokines production was evaluated. Fifty-three patients with newly diagnosed tuberculosis were enrolled for this study. Twenty-six percent of these patients were infected with at least one intestinal helminth (TB + HELM patients). Patients with pulmonary tuberculosis presented a significant reduction in the numbers of TCD8+, NK and NKT cells. Patients with both intestinal helminth infection and tuberculosis presented higher frequency of regulatory T cells, of both phenotype CD4+CD25HIGH and CD4+CD25HIGHFoxp3+, as compared to TB group, to HELM group, and to control group. In addition, the results suggest a hipoergy status in TB + HELM patients because the production of the cytokines IL-2, TNF-a, IL-4, IL-5 and IL-10 decreased in whole blood culture of these patients as compared to both TB patients and healthy controls. The data from this study indicated that the associated intestinal helminth infection has a negative impact on immunity to tuberculosis in patients with tuberculosis.