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International journal for parasitology [journal]
- Hc-daf-2 encodes an insulin-like receptor kinase in the barber's pole worm, Haemonchus contortus, and restores partial dauer regulation. [JOURNAL ARTICLE]
- Int J Parasitol 2014 Apr 10.
Infective L3s (iL3s) of parasitic nematodes share common behavioural, morphological and developmental characteristics with the developmentally arrested (dauer) larvae of the free-living nematode Caenorhabditis elegans. It is proposed that similar molecular mechanisms regulate entry into or exit from the dauer stage in C. elegans, and the transition from free-living to parasitic forms of parasitic nematodes. In C. elegans, one of the key factors regulating the dauer transition is the insulin-like receptor (designated Ce-DAF-2) encoded by the gene Ce-daf-2. However, nothing is known about DAF-2 homologues in most parasitic nematodes. Here, using a PCR-based approach, we identified and characterized a gene (Hc-daf-2) and its inferred product (Hc-DAF-2) in Haemonchus contortus (a socioeconomically important parasitic nematode of ruminants). The sequence of Hc-DAF-2 displays significant sequence homology to insulin receptors (IRs) in both vertebrates and invertebrates, and contains conserved structural domains. A sequence encoding an important proteolytic motif (RKRR) identified in the predicted peptide sequence of Hc-DAF-2 is consistent with that of the human IR, suggesting that it is involved in the formation of the IR complex. The Hc-daf-2 gene was transcribed in all life stages of H. contortus, with a significant up-regulation in the iL3 compared with other stages. To compare patterns of expression between Hc-daf-2 and Ce-daf-2, reporter constructs fusing the Ce-daf-2 or Hc-daf-2 promoter to sequence encoding GFP were microinjected into the N2 strain of C. elegans, and transgenic lines were established and examined. Both genes showed similar patterns of expression in amphidial (head) neurons, which relate to sensation and signal transduction. Further study by heterologous genetic complementation in a daf-2-deficient strain of C. elegans (CB1370) showed partial rescue of function by Hc-daf-2. Taken together, these findings provide a first insight into the roles of Hc-daf-2/Hc-DAF-2 in the biology and development of H. contortus, particularly in the transition to parasitism.
- Natural killer cell intrinsic toll-like receptor MyD88 signaling contributes to IL-12-dependent IFN-γ production by mice during infection with Toxoplasma gondii. [JOURNAL ARTICLE]
- Int J Parasitol 2014 Apr 9.
Myeloid differentiation factor 88 (MyD88)-dependent IL-12 secretion by dendritic cells (DCs) is critical for natural killer (NK) cell-mediated IFN-γ production and innate resistance to Toxoplasma gondii. Although MyD88(-/-) mice challenged with T. gondii have defective IL-12 responses and succumb to infection, administration of IL-12 to MyD88(-/-) mice fails to prevent acute mortality, suggesting that MyD88 may mediate signals within NK cells important for IL-12-dependent IFN-γ production and innate resistance to this parasite. In this study, we found that T. gondii antigens and IL-12 could synergistically trigger IFN-γ secretion by NK cells, which was dependent on toll-like receptor (TLR)-MyD88 signaling. Further analysis showed that p38 MAPK, ERK, JNK and NF-κB multiple pathways downstream of MyD88 contributed to IFN-γ production by NK cells. Moreover, the well-established TLR agonists, T. gondii profilin (Tgprofilin) and T. gondii heat shock protein 70 (TgHSP70) could evoke a similar IFN-γ secretory response in NK cells to that evoked by T. gondii antigens. In vivo adoptive transfer experiments showed that, upon challenge with T. gondii, NOD/SCID-β2 microglobulin null (NOD/SCID-β2m(-/-)) mice injected i.v. with MyD88(-/-) NK cells had reduced serum IFN-γ levels and increased splenic tachyzoite burdens compared with those injected i.v. with wild-type NK cells. Taken together, these findings demonstrate a critical role for NK cell intrinsic TLR-MyD88 signaling in IL-12-dependent early IFN-γ production and innate resistance to T. gondii.
- Population genetics of Cryptosporidium meleagridis in humans and birds: evidence for cross-species transmission. [JOURNAL ARTICLE]
- Int J Parasitol 2014 Apr 9.
Population genetic studies have been used to understand the transmission of pathogens in humans and animals, especially the role of zoonotic infections and evolution and dispersal of virulent subtypes. In this study, we analyzed the genetic diversity and population structure of Cryptosporidium meleagridis, the only known Cryptosporidium species that infects both avian and mammalian hosts and is responsible for approximately 10% of human cryptosporidiosis in some areas. A total of 62 C. meleagridis specimens from children, AIDS patients, and birds in Lima, Peru were characterized by sequence analysis of the ssrRNA gene and five minisatellite, microsatellite and polymorphic markers in chromosome 6, including the 60 kDa glycoprotein (gp60), 47 kDa glycoprotein (CP47), a serine repeat antigen (MSC6-5), retinitis pigmentosa GTPase regulator (RPGR) and thrombospondin protein 8 (TSP8). The multilocus sequence analysis identified concurrent infections with Cryptosporidium hominis in four AIDS patients and three children. Unique subtypes of C. meleagridis ranged from eight at the gp60 locus (gene diversity -Hd = 0.651), three at the RPGR (Hd = 0.556), three at the MSC6-5 locus (Hd = 0.242), two at TSP8 (Hd = 0.198), to one at CP47 (monomorphic), much lower than that of C. hominis in the same area. Intragenic linkage disequilibrium (LD) was strong and complete at all gene loci. Intergenic LD was highly significant (P < 0.001) for all pairs of polymorphic loci. Two major groups of subtypes were seen, with most subtypes belonging to group 1. Within group 1, there was no clear population segregation, and two of the 14 multilocus subtypes of C. meleagridis were found in both AIDS patients and birds. We believe that these results provide the first evidence of a clonal population structure of C. meleagridis and the likely occurrence of cross-species transmission of C. meleagridis between birds and humans.
- DNA from pre-erythrocytic stage malaria parasites is detectable by PCR in the faeces and blood of hosts. [JOURNAL ARTICLE]
- Int J Parasitol 2014 Apr 3.
Following the bite of an infective mosquito, malaria parasites first invade the liver where they develop and replicate for a number of days before being released into the bloodstream where they invade red blood cells and cause disease. The biology of the liver stages of malaria parasites is relatively poorly understood due to the inaccessibility of the parasites to sampling during this phase of their life cycle. Here we report the detection in blood and faecal samples of malaria parasite DNA throughout their development in the livers of mice and before the parasites begin their growth in the blood circulation. It is shown that parasite DNA derived from pre-erythrocytic stage parasites reaches the faeces via the bile. We then show that different primate malaria species can be detected by PCR in blood and faecal samples from naturally infected captive macaque monkeys. These results demonstrate that pre-erythrocytic parasites can be detected and quantified in experimentally infected animals. Furthermore, these results have important implications for both molecular epidemiology and phylogenetics of malaria parasites. In the former case, individuals who are malaria parasite negative by microscopy, but PCR positive for parasite DNA in their blood, are considered to be "sub-microscopic" blood stage parasite carriers. We now propose that PCR positivity is not necessarily an indicator of the presence of blood stage parasites, as the DNA could derive from pre-erythrocytic parasites. Similarly, in the case of molecular phylogenetics based on DNA sequences alone, we argue that DNA amplified from blood or faeces does not necessarily come from a parasite species that infects the red blood cells of that particular host.
- The reliability of observational approaches for detecting interspecific parasite interactions: comparison with experimental results. [JOURNAL ARTICLE]
- Int J Parasitol 2014 Apr 3.
Interactions among coinfecting parasites have the potential to alter host susceptibility to infection, the progression of disease and the efficacy of disease control measures. It is therefore essential to be able to accurately infer the occurrence and direction of such interactions from parasitological data. Due to logistical constraints, perturbation experiments are rarely undertaken to directly detect interactions, therefore a variety of approaches are commonly used to infer them from patterns of parasite association in observational data. However, the reliability of these various approaches is not known. We assess the ability of a range of standard analytical approaches to detect known interactions between infections of nematodes and intestinal coccidia (Eimeria) in natural small-mammal populations, as revealed by experimental perturbations. We show that correlation-based approaches are highly unreliable, often predicting strong and highly significant associations between nematodes and Eimeria in the opposite direction to the underlying interaction. The most reliable methods involved longitudinal analyses, in which the nematode infection status of individuals at one month is related to the infection status by Eimeria the next month. Even then, however, we suggest these approaches are only viable for certain types of infections and datasets. Overall we suggest that, in the absence of experimental approaches, careful consideration be given to the choice of statistical approach when attempting to infer interspecific interactions from observational data.
- Identification and pharmacological induction of autophagy in the larval stages of Echinococcus granulosus: an active catabolic process in calcareous corpuscles. [JOURNAL ARTICLE]
- Int J Parasitol 2014 Apr 1.
Autophagy is a fundamental catabolic pathway conserved from yeast to mammals, but which remains unknown in parasite cestodes. In this work, the pharmacological induction of autophagy was cellularly and molecularly analysed in the larval stages of Echinococcus granulosus. Metacestode sensitivity to rapamycin and TORC1 expression in protoscoleces and metacestodes were shown. Ultrastructural studies showed that treated parasites had an isolation membrane, autophagosomes and autolysosomes, all of which evidenced the autophagic flux. Genes coding for key autophagy-related proteins were also identified in the Echinococcus genome. These genes were involved in autophagosome formation and transcriptional over-expression of Eg-atg5, Eg-atg6, Eg-atg8, Eg-atg12, Eg-atg16 and Eg-atg18 was shown in presence of rapamycin or arsenic trioxide. Thus, Echinococcus autophagy could be regulated by non-transcriptional inhibition through TOR and by transcription-dependent up-regulation via FoxO-like transcription factors and/or TFEB proteins. An increase in the punctate pattern and Eg-Atg8 polypeptide level in the tegument, parenchyma cells and excretory system of protoscoleces and in vesicularised parasites was detected after rapamycin treatment. This suggests the occurrence of basal autophagy in the larval stages and during vesicular development. In arsenic-treated protoscoleces, high Eg-Atg8 polypeptide levels within the free cytoplasmic matrix of calcareous corpuscles were observed, thus verifying the occurrence of autophagic events. These experiments also confirmed that the calcareous corpuscles are sites of arsenic trioxide accumulation. The detection of the autophagic machinery in this parasite represents a basic starting point to unravel the role of autophagy under both physiological and stress conditions which will allow identification of new strategies for drug discovery against neglected parasitic diseases caused by cestodes.
- Modelling parasite aggregation: disentangling statistical and ecological approaches. [JOURNAL ARTICLE]
- Int J Parasitol 2014 Apr 1.
The overdispersion in macroparasite infection intensity among host populations is commonly simulated using a constant negative binomial aggregation parameter. We describe an alternative to utilising the negative binomial approach and demonstrate important disparities in intervention efficacy projections that can come about from opting for pattern-fitting models which are not process-explicit. We present model output in the context of the epidemiology and control of soil-transmitted helminths due to the significant public health burden imposed by these parasites, but our methods are applicable to other infections with demonstrable aggregation in parasite numbers among hosts.
- Resistance of Biomphalaria glabrata 13-16-R1 snails to Schistosoma mansoni PR1 is a function of haemocyte abundance and constitutive levels of specific transcripts in haemocytes. [JOURNAL ARTICLE]
- Int J Parasitol 2014 Mar 28.
Continuing transmission of human intestinal schistosomiasis depends on the parasite's access to susceptible snail intermediate hosts (often Biomphalaria glabrata). Transmission fails when parasite larvae enter resistant individuals in wild snail populations. The genetic basis for differences in snail susceptibility/resistance is being intensively investigated as a means to devise novel control strategies based on resistance genes. Reactive oxygen species produced by the snail's defence cells (haemocytes) are effectors of resistance. We hypothesised that genes relevant to production and consumption of reactive oxygen species would be expressed differentially in the haemocytes of snail hosts with different susceptibility/resistance phenotypes. By restricting the genetic diversity of snails, we sought to facilitate identification of resistance genes. By inbreeding, we procured from a 13-16-R1 snail population with both susceptible and resistant individuals, comprising 52 lines of B. glabrata (expected homozygosity ∼87.5%), and determined the phenotype of each in regard to susceptibility/resistance to Schistosoma mansoni. The inbred lines were found to have line-specific differences in numbers of spreading haemocytes; these were enumerated in both juvenile and adult snails. Lines with high cell numbers were invariably resistant to S. mansoni, whereas lines with lower cell numbers could be resistant or susceptible. Transcript levels in haemocytes were quantified for 18 potentially defence-related genes. Among snails with low cell numbers, the different susceptibility/resistance phenotypes correlated with differences in transcript levels for two redox-relevant genes: an inferred phagocyte oxidase component and a peroxiredoxin. Allograft inflammatory factor (potentially a regulator of leucocyte activation) was expressed at higher levels in resistant snails regardless of spread cell number. Having abundant spreading haemocytes is inferred to enable a snail to kill parasite sporocysts. In contrast, snails with fewer spreading haemocytes seem to achieve resistance only if specific genes are expressed constitutively at levels that are high for the species.
- From ancient to contemporary molecular eco-epidemiology of Chagas disease in the Americas. [JOURNAL ARTICLE]
- Int J Parasitol 2014 Mar 24.
One of the best-studied populations with regard to Chagas disease is from the coastal area of northern Chile at the foot of the western Andean slopes. The extremely arid climate here generates rapid, spontaneous desiccation of buried bodies, arresting the decay process. The absence of rainfall then preserves these dried bodies (mummies) for millennia. The aim of the present study was to perform the first molecular paleoepidemiological study on a set of 43 mummified human remains from the Atacama Desert in Northern Chile in order to elucidate the transmission dynamics and determinants of ancient genotypes, to try to unravel the natural history of the Trypanosoma cruzi taxon and Chagas disease. Interestingly, TcBat, a recently described Discrete Taxonomic Unit, emerges as the plausible ancestor of T. cruzi. The findings herein presented allow us to present a plausible model of T. cruzi transmission in pre-Columbian civilisations.
- Analysis of trait mean and variability versus temperature in trematode cercariae: is there scope for adaptation to global warming? [JOURNAL ARTICLE]
- Int J Parasitol 2014 Mar 24.
The potential of species for evolutionary adaptation in the context of global climate change has recently come under scrutiny. Estimates of phenotypic variation in biological traits may prove valuable for identifying species, or groups of species, with greater or lower potential for evolutionary adaptation, as this variation, when heritable, represents the basis for natural selection. Assuming that measures of trait variability reflect the evolutionary potential of these traits, we conducted an analysis across trematode species to determine the potential of these parasites as a group to adapt to increasing temperatures. Firstly, we assessed how the mean number of infective stages (cercariae) emerging from infected snail hosts as well as the survival and infectivity of cercariae are related to temperature. Secondly and importantly in the context of evolutionary potential, we assessed how coefficients of variation for these traits are related to temperature, in both cases controlling for other factors such as habitat, acclimatisation, latitude and type of target host. With increasing temperature, an optimum curve was found for mean output and mean infectivity, and a linear decrease for survival of cercariae. For coefficients of variation, temperature was only an important predictor in the case of cercarial output, where results indicated that there is, however, no evidence for limited trait variation at the higher temperature range. No directional trend was found for either variation of survival or infectivity. These results, characterising general patterns among trematodes, suggest that all three traits considered may have potential to change through adaptive evolution.