RESUMEN
Yeast prions are atypical genetic elements that are transmitted as heritable protein conformations. [PSI+], [URE3], and [PIN+] are three well-studied prions in the budding yeast, Saccharomyces cerevisiae. In the last three years, several additional prions have been reported in yeast, including [SWI+], [OCT+], [MCA], [GAR+], [MOT3+], [ISP+], and [NSI+]. The growing number of yeast prions suggests that protein-based inheritance might be a widespread biological phenomenon. In this review, we summarize the characteristics of each prion element, and discuss their potential functional roles in yeast biology.
Asunto(s)
Amiloide/metabolismo , Priones/química , Priones/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomycetales/metabolismo , Caspasas/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Unión al ADN/metabolismo , Epigenómica , Glutatión Peroxidasa/metabolismo , Factores de Terminación de Péptidos/metabolismo , ATPasas de Translocación de Protón/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Schistosoma blood flukes, which infect over 200 million people globally, co-opt CD4+ T cell-dependent mechanisms to facilitate parasite development and egg excretion. The latter requires Th2 responses, while the mechanism underpinning the former has remained obscure. Using mice that are either defective in T cell receptor (TCR) signaling or that lack TCRs that can respond to schistosomes, we show that naïve CD4+ T cells facilitate schistosome development in the absence of T cell receptor signaling. Concurrently, the presence of naïve CD4+ T cells correlates with both steady-state changes in the expression of genes that are critical for the development of monocytes and macrophages and with significant changes in the composition of peripheral mononuclear phagocyte populations. Finally, we show that direct stimulation of the mononuclear phagocyte system restores blood fluke development in the absence of CD4+ T cells. Thus we conclude that schistosomes co-opt innate immune signals to facilitate their development and that the role of CD4+ T cells in this process may be limited to the provision of non-cognate help for mononuclear phagocyte function. Our findings have significance for understanding interactions between schistosomiasis and other co-infections, such as bacterial infections and human immunodeficiency virus infection, which potently stimulate innate responses or interfere with T cell help, respectively. An understanding of immunological factors that either promote or inhibit schistosome development may be valuable in guiding the development of efficacious new therapies and vaccines for schistosomiasis.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis/inmunología , Animales , Citocinas/biosíntesis , Ensayo de Inmunoadsorción Enzimática , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Proteínas del Helminto/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores de Antígenos de Linfocitos T/inmunologíaRESUMEN
Schistosoma blood flukes are trematode parasites with a cosmopolitan distribution that infect over 200 million people globally. We previously showed that Schistosoma mansoni growth and development in the mammalian host is dependent on signals from host CD4+ T cells. To gain insight into the mechanisms that underlie this dependence, we sought to determine the evolutionary origins and limits of this aspect of the host-pathogen relationship. By infecting RAG-1-/- mice with a range of different schistosome species and strains, we tested several hypotheses concerning the time during Schistosoma evolution at which this dependence arose, and whether this dependence is specific to Schistosoma or is also found in other blood flukes. Our data indicate that the developmental dependence on CD4+ T cells previously described for S. mansoni is conserved in the evolutionarily basal species Schistosoma japonicum, suggesting this developmental adaptation arose early in Schistosoma evolution. We also demonstrate that the development of the more evolutionarily derived species Schistosoma haematobium and Schistosoma intercalatum are dependent on adaptive immune signals. Together, these data suggest that the blood fluke parasites of humans utilise common mechanisms to infect their hosts and to co-opt immune signals in the coordination of parasite development. Thus, exploitation of host-schistosome interactions to impair or prevent parasite development may represent a novel approach to combating all of the schistosome pathogens of humans.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Schistosoma/crecimiento & desarrollo , Esquistosomiasis/inmunología , Animales , Evolución Biológica , Femenino , Proteínas de Homeodominio/fisiología , Interacciones Huésped-Parásitos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Schistosoma/clasificación , Schistosoma/inmunología , Schistosoma haematobium/crecimiento & desarrollo , Schistosoma haematobium/inmunología , Schistosoma japonicum/crecimiento & desarrollo , Schistosoma japonicum/inmunología , Esquistosomiasis/parasitología , Especificidad de la EspecieRESUMEN
Yeast prions are self-propagating protein conformations that transmit heritable phenotypes in an epigenetic manner. The recently identified yeast prion [SWI(+)] is an alternative conformation of Swi1, a component of the evolutionarily conserved SWI/SNF chromatin-remodeling complex. Formation of the [SWI(+)] prion results in a partial loss-of-function phenotype for Swi1. The amino-terminal region of Swi1 is dispensable for its normal function but is required for [SWI(+)] formation and propagation; however, the precise prion domain (PrD) of Swi1 has not been elucidated. Here, we define the minimal Swi1 PrD as the first 37 amino acids of the protein. This region is extremely asparagine rich but, unexpectedly, contains no glutamine residues. This unusually small prion domain is sufficient for aggregation, propagation, and transmission of the [SWI(+)] prion. Because of its unusual size and composition, the Swi1 prion domain defined here has important implications for describing and identifying novel prions.
Asunto(s)
Fragmentos de Péptidos/fisiología , Priones/química , Saccharomycetales/química , Asparagina , Glutamina , Fragmentos de Péptidos/químicaRESUMEN
We have recently reported that the yeast chromatin-remodeling factor Swi1 can exist as a prion, [SWI(+)], demonstrating a link between prionogenesis and global transcriptional regulation. To shed light on how the Swi1 conformational switch influences Swi1 function and to define the sequence and structural requirements for [SWI(+)] formation and propagation, we functionally dissected the Swi1 molecule. We show here that the [SWI(+)] prion features are solely attributable to the first 327 amino acid residues (N), a region that is asparagine rich. N was aggregated in [SWI(+)] cells but diffuse in [swi(-)] cells; chromosomal deletion of the N-coding region resulted in [SWI(+)] loss, and recombinant N peptide was able to form infectious amyloid fibers in vitro, enabling [SWI(+)] de novo formation through a simple transformation. Although the glutamine-rich middle region (Q) was not sufficient to aggregate in [SWI(+)] cells or essential for SWI/SNF function, it significantly modified the Swi1 aggregation pattern and Swi1 function. We also show that excessive Swi1 incurred Li(+)/Na(+) sensitivity and that the N/Q regions are important for this gain of sensitivity. Taken together, our results provide the final proof of "protein-only" transmission of [SWI(+)] and demonstrate that the widely distributed "dispensable" glutamine/asparagine-rich regions/motifs might have important and divergent biological functions.
Asunto(s)
Proteínas Cromosómicas no Histona/metabolismo , Priones/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/metabolismo , Secuencias de Aminoácidos/genética , Amiloide/metabolismo , Asparagina/genética , Asparagina/metabolismo , Proteínas Cromosómicas no Histona/genética , Deleción Cromosómica , Cromosomas Fúngicos/genética , Glutamina/genética , Glutamina/metabolismo , Immunoblotting , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Microscopía Confocal , Microscopía Electrónica , Mutación , Priones/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Factores de Transcripción/genéticaRESUMEN
The human pathogen Schistosoma mansoni exhibits a highly evolved and intricate relationship with its host, evading immune destruction while co-opting CD4(+) T cell-driven mechanisms to facilitate parasite development and egg excretion. Because the common gamma ( gamma (c)) chain cytokine interleukin (IL)-7 is also implicated in modulating schistosome development, we investigated whether this effect is mediated indirectly through the essential role that IL-7 plays in CD4(+) T cell growth and survival. We demonstrate that attenuated schistosome development in the absence of IL-7 results from dysregulated T cell homeostasis and not from disruption of direct interactions between schistosomes and IL-7. We also identify an indirect role that another gamma (c) chain cytokine plays in schistosome development, demonstrating that IL-2 expression by CD4(+) T cells is essential for normal parasite development. Thus, cytokines critical for CD4(+) T cell survival and function can mediate indirect but potent effects on developing schistosomes and underscore the importance of CD4(+) T cells in facilitating schistosome development.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Interleucina-2/inmunología , Interleucina-7/inmunología , Schistosoma mansoni/crecimiento & desarrollo , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/parasitología , Traslado Adoptivo , Animales , Homeostasis , Hígado/parasitología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Morfogénesis , Recuento de Huevos de Parásitos , Receptores de Interleucina-2/genética , Receptores de Interleucina-7/genética , Schistosoma mansoni/inmunologíaRESUMEN
Active efflux of antimicrobial substances is likely to be an important bacterial defense against inhibitory host factors inherent to different body sites. Two well-characterized multidrug resistance efflux systems (MtrCDE and FarAB-MtrE) exist in Neisseria gonorrhoeae, a bacterial pathogen of the human genital mucosae. In vitro studies suggest that the MtrCDE and FarAB-MtrE efflux systems protect the gonococcus from hydrophobic antimicrobial substances that are likely to be present on mucosal surfaces. Here we report that a functional MtrCDE efflux system, but not a functional FarAB-MtrE system, enhances experimental gonococcal genital tract infection in female mice. Specifically, the recovery of mtrD and mtrE mutants, but not a farB mutant, from mice inoculated with mutant or wild-type gonococci was reduced compared with that of the wild-type strain. Competitive-infection experiments confirmed the survival disadvantage of MtrCDE-deficient gonococci. This report is the first direct evidence that a multidrug resistance efflux system enhances survival of a bacterial pathogen in the genital tract. Additionally, experiments using ovariectomized mice showed that MtrCDE-deficient gonococci were more rapidly cleared from mice that were capable of secreting gonadal hormones. MtrCDE-deficient gonococci were more sensitive to nonphysiological concentrations of progesterone in vitro than were wild-type or FarAB-MtrE-deficient gonococci. These results suggest that progesterone may play an inhibitory role in vivo. However, hormonally regulated factors rather than progesterone itself may be responsible for the more rapid clearance of mtr-deficient gonococci from intact mice.
Asunto(s)
Proteínas Bacterianas , Proteínas de Transporte de Membrana , Neisseria gonorrhoeae/metabolismo , Animales , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Farmacorresistencia Bacteriana Múltiple , Estradiol/metabolismo , Estradiol/farmacología , Femenino , Gonorrea/inmunología , Gonorrea/metabolismo , Gonorrea/microbiología , Técnicas In Vitro , Lipoproteínas/genética , Lipoproteínas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Mutación , Neisseria gonorrhoeae/efectos de los fármacos , Neisseria gonorrhoeae/genética , Neisseria gonorrhoeae/inmunología , Progesterona/metabolismo , Progesterona/farmacologíaRESUMEN
Neisseria gonorrhoeae is capable of utilizing a variety of iron sources in vitro, including human transferrin, human lactoferrin, hemoglobin, hemoglobin-haptoglobin complexes, heme, and heterologous siderophores. Transferrin has been implicated as a critical iron store for N. gonorrhoeae in the human male urethra. The demonstration that gonococci can infect the lower genital tracts of estradiol-treated BALB/c mice in the absence of human transferrin, however, suggests that other usable iron sources are present in the murine genital tract. Here we demonstrate that gonococcal transferrin and hemoglobin receptor mutants are not attenuated in mice, thereby ruling out transferrin and hemoglobin as essential for murine infection. An increased frequency of phase variants with the hemoglobin receptor "on" (Hg(+)) occurred in ca. 50% of infected mice; this increase was temporally associated with an influx of neutrophils and detectable levels of hemoglobin in the vagina, suggesting that the presence of hemoglobin in inflammatory exudates selects for Hg(+) phase variants during infection. We also demonstrate that commensal lactobacilli support the growth of N. gonorrhoeae in vitro unless an iron chelator is added to the medium. We hypothesize that commensal lactobacilli may enhance growth of gonococci in vivo by promoting the solubilization of iron on mucosal surfaces through the production of metabolic intermediates. Finally, transferrin-binding lipoprotein (TbpB) was detected on gonococci in vaginal smears, suggesting that although gonococci replicate within the genital tracts of mice, they may be sufficiently iron-stressed to express iron-repressible proteins. In summary, these studies support the potential role of nontransferrin, nonhemoglobin iron sources during gonococcal infection of the female genital tract.