RESUMEN
BACKGROUND: In malaria-endemic areas, a proportion of individuals becomes chronic carriers of parasites with few or no clinical signs. There is little information on cellular immune responses in asymptomatic parasite carriers. METHODS: In 80 schoolchildren residing in a malaria-endemic area of Flores Island, Indonesia, T-helper subsets, regulatory T-cell (Treg) frequencies, tumor necrosis factor receptor type II (TNFRII) expression on Tregs, and cytokine responses induced by Plasmodium falciparum-infected red blood cells (RBCs) were measured, and values for asymptomatic infected subjects were compared to those for uninfected controls. To ascertain that alterations found were due to the presence of malaria parasites, the immune responses were analyzed in 16 children before and 1 month after antimalarial treatment. RESULTS: TNFRII expression, a marker of activation on Tregs, was higher during infection but decreased upon treatment. GATA3-positive cells and the level of interleukin 13 secretion in response to P. falciparum-infected RBCs appeared to be suppressed by plasmodial infection, as both increased after antimalarial treatment. TNFRII expression on Tregs correlated positively with TNF in response to P. falciparum-infected RBCs, but this association disappeared following treatment. CONCLUSIONS: Malaria parasites associated with asymptomatic infections seem to result in increased TNFRII expression on Tregs, as well as suppressed Th2 cytokine responses, features that might be important for survival of the parasites in asymptomatic carriers.
Asunto(s)
Infecciones Asintomáticas , Malaria Falciparum/inmunología , Receptores Tipo II del Factor de Necrosis Tumoral/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Antimaláricos/uso terapéutico , Niño , Preescolar , Estudios Transversales , Eritrocitos/inmunología , Eritrocitos/parasitología , Femenino , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/metabolismo , Humanos , Inmunidad Celular/inmunología , Indonesia , Interleucina-13/sangre , Interleucina-13/inmunología , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Estudios Longitudinales , Malaria Falciparum/parasitología , Masculino , Proyectos Piloto , Plasmodium falciparum/aislamiento & purificación , Plasmodium falciparum/patogenicidad , Reacción en Cadena de la Polimerasa , Prevalencia , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Células TH1/inmunología , Células Th2 , Regulación hacia ArribaRESUMEN
Malaria parasites are characterized by a complex life cycle that is accompanied by dynamic gene expression patterns. The factors and mechanisms that regulate gene expression in these parasites have been searched for even before the advent of next generation sequencing technologies. Functional genomics approaches have substantially boosted this area of research and have yielded significant insights into the interplay between epigenetic, transcriptional and post-transcriptional mechanisms. Recently, considerable progress has been made in identifying sequence-specific transcription factors and DNA-encoded regulatory elements. Here, we review the insights obtained from these efforts including the characterization of core promoters, the involvement of sequence-specific transcription factors in life cycle progression and the mapping of gene regulatory elements. Furthermore, we discuss recent developments in the field of functional genomics and how they might contribute to further characterization of this complex gene regulatory network.
Asunto(s)
Regulación de la Expresión Génica , Genómica , Plasmodium/crecimiento & desarrollo , Plasmodium/genética , Factores de Transcripción/metabolismo , Redes Reguladoras de Genes , Estadios del Ciclo de Vida/genética , Plasmodium/metabolismo , Regiones Promotoras Genéticas , Elementos Reguladores de la Transcripción/genética , Factores de Transcripción/genéticaRESUMEN
Telomere repeat-binding factors (TRFs) are essential components of the molecular machinery that regulates telomere function. TRFs are widely conserved across eukaryotes and bind duplex telomere repeats via a characteristic MYB-type domain. Here, we identified the telomere repeat-binding protein PfTRZ in the malaria parasite Plasmodium falciparum, a member of the Alveolate phylum for which TRFs have not been described so far. PfTRZ lacks an MYB domain and binds telomere repeats via a C2H2-type zinc finger domain instead. In vivo, PfTRZ binds with high specificity to the telomeric tract and to interstitial telomere repeats upstream of subtelomeric virulence genes. Conditional depletion experiments revealed that PfTRZ regulates telomere length homeostasis and is required for efficient cell cycle progression. Intriguingly, we found that PfTRZ also binds to and regulates the expression of 5S rDNA genes. Combined with detailed phylogenetic analyses, our findings identified PfTRZ as a remote functional homologue of the basic transcription factor TFIIIA, which acquired a new function in telomere maintenance early in the apicomplexan lineage. Our work sheds unexpected new light on the evolution of telomere repeat-binding proteins and paves the way for dissecting the presumably divergent mechanisms regulating telomere functionality in one of the most deadly human pathogens.