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1.
Sci Rep ; 9(1): 16207, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31700040

RESUMO

Modulating the tumor microenvironment to promote an effective immune response is critical in managing any type of tumor. Melanoma is an aggressive skin cancer and the incidence rate is increasing worldwide. Potent protease inhibitors have recently been extensively researched as potential therapeutic agents against various cancers. EgKI-1 is a potent Kunitz type protease inhibitor identified from the canine tapeworm Echinococcus granulosus that has shown anti-cancer activities in vivo. In this study we show that EgKI-1 significantly reduced the growth of melanoma in the B16-F0 mouse model and was not toxic to normal surrounding tissue. Moreover, EgKI-1 treatment significantly reduced survivin expression levels and increased the CD8+ T cell population in draining axillary lymph nodes. Therefore, EgKI-1 potentially reduces tumor growth by inducing apoptosis and modulating the tumor microenvironment, and has potential for development as an intra-lesional treatment for melanoma.

2.
Parasit Vectors ; 12(1): 452, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31521183

RESUMO

BACKGROUND: Schistosomiasis is a harmful neglected tropical disease caused by infection with Schistosoma spp., such as Schistosoma mansoni. Schistosoma must transition within a molluscan host to survive. Chemical analyses of schistosome-molluscan interactions indicate that host identification involves chemosensation, including naïve host preference. Proteomic technique advances enable sophisticated comparative analyses between infected and naïve snail host proteins. This study aimed to compare resistant, susceptible and naïve Biomphalaria glabrata snail-conditioned water (SCW) to identify potential attractants and deterrents. METHODS: Behavioural bioassays were performed on S. mansoni miracidia to compare the effects of susceptible, F1 resistant and naïve B. glabrata SCW. The F1 resistant and susceptible B. glabrata SCW excretory-secretory proteins (ESPs) were fractionated using SDS-PAGE, identified with LC-MS/MS and compared to naïve snail ESPs. Protein-protein interaction (PPI) analyses based on published studies (including experiments, co-expression, text-mining and gene fusion) identified S. mansoni and B. glabrata protein interaction. Data are available via ProteomeXchange with identifier PXD015129. RESULTS: A total of 291, 410 and 597 ESPs were detected in the susceptible, F1 resistant and naïve SCW, respectively. Less overlap in ESPs was identified between susceptible and naïve snails than F1 resistant and naïve snails. F1 resistant B. glabrata ESPs were predominately associated with anti-pathogen activity and detoxification, such as leukocyte elastase and peroxiredoxin. Susceptible B. glabrata several proteins correlated with immunity and anti-inflammation, such as glutathione S-transferase and zinc metalloproteinase, and S. mansoni sporocyst presence. PPI analyses found that uncharacterised S. mansoni protein Smp_142140.1 potentially interacts with numerous B. glabrata proteins. CONCLUSIONS: This study identified ESPs released by F1 resistant, susceptible and naïve B. glabrata to explain S. mansoni miracidia interplay. Susceptible B. glabrata ESPs shed light on potential S. mansoni miracidia deterrents. Further targeted research on specific ESPs identified in this study could help inhibit B. glabrata and S. mansoni interactions and stop human schistosomiasis.

3.
Exp Parasitol ; 204: 107725, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306646

RESUMO

Characterisation of the cellular immune response to schistosomiasis is well established for Schistosoma mansoni but a comprehensive description of T cell-mediated immune responses against S. japonicum infection is lacking. Accordingly, 20 CBA mice were infected with cercariae of S. japonicum and the immune response at different time points was determined. Mouse spleen and liver lymphocytes were isolated from the mice and stimulated with schistosomal adult worm antigen preparation (SWAP) and schistosomal soluble egg antigen (SEA). There was a relatively higher Th1 immune response to SWAP compared to SEA at the early phase of infection (up to week 5 post challenge). However, a Th2 immune response directed against SEA was dominant at week 6 post-infection, a time point when the highest IgG response against both SWAP and, especially, SEA was generated. The regulatory immune response was highest at the early phase of the immune response (up to week 5 post challenge) followed by a rapid decline at week 6-post infection. Before egg-laying, S. japonicum induced a regulatory T cell immune response which may limit the early Th1-mediated immune response that is believed to be protective in murine schistosomiasis. Following egg laying, the immune response was polarized to a Th2 immune response mainly directed against the eggs and this may contribute to parasite survival.


Assuntos
Imunidade Celular , Schistosoma japonicum/imunologia , Esquistossomose Japônica/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Helmintos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Fígado/citologia , Fígado/imunologia , Fígado/parasitologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos CBA , Óvulo/imunologia , Contagem de Ovos de Parasitas , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Caramujos/parasitologia , Baço/citologia , Baço/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th2/imunologia
4.
Front Immunol ; 10: 645, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31001264

RESUMO

Despite significant progress, China faces the challenge of re-emerging schistosomiasis transmission in currently controlled areas due, in part, to the presence of a range of animal reservoirs, notably water buffalo and cattle, which can harbor Schistosoma japonicum infections. Environmental, ecological and social-demographic changes in China, shown to affect the distribution of oncomelanid snails, can also impact future schistosomiasis transmission. In light of their importance in the S. japonicum, lifecycle, vaccination has been proposed as a means to reduce the excretion of egg from cattle and buffalo, thereby interrupting transmission from these reservoir hosts to snails. A DNA-based vaccine (SjCTPI) our team developed showed encouraging efficacy against S. japonicum in Chinese water buffaloes. Here we report the results of a double-blind cluster randomized trial aimed at determining the impact of a combination of the SjCTPI bovine vaccine (given as a prime-boost regimen), human mass chemotherapy and snail control on the transmission of S. japonicum in 12 selected administrative villages around the Dongting Lake in Hunan province. The trial confirmed human praziquantel treatment is an effective intervention at the population level. Further, mollusciciding had an indirect ~50% efficacy in reducing human infection rates. Serology showed that the SjCTPI vaccine produced an effective antibody response in vaccinated bovines, resulting in a negative correlation with bovine egg counts observed at all post-vaccination time points. Despite these encouraging outcomes, the effect of the vaccine in preventing human infection was inconclusive. This was likely due to activities undertaken by the China National Schistosomiasis Control Program, notably the treatment, sacrifice or removal of bovines from trial villages, over which we had no control; as a result, the trial design was compromised, reducing power and contaminating outcome measures. This highlights the difficulties in undertaking field trials of this nature and magnitude, particularly over a long period, and emphasizes the importance of mathematical modeling in predicting the potential impact of control intervention measures. A transmission blocking vaccine targeting bovines for the prevention of S. japonicum with the required protective efficacy would be invaluable in tandem with other preventive intervention measures if the goal of eliminating schistosomiasis from China is to become a reality.

5.
Parasit Vectors ; 12(1): 173, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992086

RESUMO

BACKGROUND: Schistosome parasites lay up to a thousand eggs per day inside the veins of their mammalian hosts. The immature eggs deposited by females against endothelia of venules will embryonate within days. Approximately 30% of the eggs will migrate to the lumen of the intestine to continue the parasite life-cycle. Many eggs, however, are trapped in the liver and intestine causing the main pathology associated with schistosomiasis mansoni and japonica, the liver granulomatous response. Excretory-secretory egg proteins drive much of egg-induced pathogenesis of schistosomiasis mansoni, and Schistosoma japonicum induce a markedly distinct granulomatous response to that of S. mansoni. METHODS: To explore the basis of variations in this responsiveness, we investigated the proteome of eggs of S. japonicum. Using mass spectrometry qualitative and quantitative (SWATH) analyses, we describe the protein composition of S. japonicum eggs secretory proteins (ESP), and the differential expression of proteins by fully mature and immature eggs, isolated from faeces and ex vivo adults. RESULTS: Of 957 egg-related proteins identified, 95 were exclusively found in S. japonicum ESP which imply that they are accessible to host immune system effector elements. An in-silico analysis implies that ESP are able of stimulating the innate and adaptive immune system through several different pathways. While quantitative SWATH analysis revealed 124 proteins that are differentially expressed by mature and immature S. japonicum eggs, illuminating some important aspects of eggs biology and infection, we also show that mature eggs are more likely than immature eggs to stimulate host immune responses. CONCLUSIONS: Here we present a list of potential targets that can be used to develop better strategies to avoid severe morbidity during S. japonicum infection, as well as improving diagnosis, treatment and control of schistosomiasis japonica.


Assuntos
Proteínas do Ovo/metabolismo , Proteínas de Helminto/metabolismo , Óvulo/metabolismo , Proteoma , Schistosoma japonicum/metabolismo , Animais , Sobrevivência Celular , Proteínas do Ovo/genética , Feminino , Perfilação da Expressão Gênica , Proteínas de Helminto/genética , Camundongos , Schistosoma japonicum/citologia
6.
PLoS Negl Trop Dis ; 13(3): e0007228, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30830925

RESUMO

BACKGROUND: Zoonotic schistosomiasis in Asia, caused by Schistosoma japonicum, remains a major public health concern in China and the Philippines. The developing epidemiological and socio-economic picture of the disease in endemic areas necessitates the development of affordable and highly accurate field diagnostics as an important component in evaluating ongoing integrated control and elimination efforts. METHODS: Three diagnostic methods, namely Kato-Katz (KK) stool microscopy, ELISA and droplet digital (dd) PCR assays, were compared by detecting infection in a total of 412 participants from an area moderately endemic for schistosomiasis in the Philippines. RESULTS: This comprehensive comparison further defined the diagnostic performance and features for each assay. Compared with the ddPCR assay analysing DNA from faeces (F_ddPCR), which exhibited the highest sensitivity, the SjSAP4 + Sj23-LHD-ELISA had the best accuracy (67.2%) among all five ELISA assays assessed. Schistosomiasis prevalence determined by the SjSAP4 + Sj23-LHD-ELISA and ddPCRs was similar and was at least 2.5 times higher than obtained with the KK method. However, the agreement between these assays was low. In terms of cost and logistical convenience, the SjSAP4 + Sj23-LHD-ELISA represents a cost-effective assay with considerable diagnostic merits. In contrast, although the ddPCR assays exhibited a high level of diagnostic performance, the high cost and the need for specialized equipment presents a major obstacle in their application in screening campaigns. CONCLUSION: The SjSAP4 + Sj23-LHD-ELISA represents a cost-effective tool for the diagnosis of schistosomiasis that could prove an important component in the monitoring of integrated control measures as elimination draws closer, whereas the ddPCR assays, in addition to their high sensitivity and specificity, are capable of quantifying infection intensity. However, the high cost of ddPCR hinders its wider application in screening programs, although it could be a valuable reference in the development and improvement of other diagnostic assays.


Assuntos
Doenças Endêmicas , Ensaio de Imunoadsorção Enzimática , Reação em Cadeia da Polimerase , Schistosoma japonicum/isolamento & purificação , Esquistossomose Japônica/diagnóstico , Adulto , Idoso , Animais , Anticorpos Anti-Helmínticos/imunologia , Criança , Estudos de Coortes , Fezes/parasitologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Filipinas/epidemiologia , Prevalência , Schistosoma japonicum/imunologia , Esquistossomose Japônica/sangue , Esquistossomose Japônica/epidemiologia , Esquistossomose Japônica/parasitologia , Sensibilidade e Especificidade
7.
Int J Mol Sci ; 20(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925781

RESUMO

We showed previously that the Schistosoma japonicum insulin-like peptide (SjILP) binds the worm insulin receptors, thereby, activating the parasite's insulin pathway and emphasizing its important role in regulating uptake of glucose, a nutrient essential for parasite survival. Here we show that SjILP is differentially expressed in the schistosome life cycle and is especially highly transcribed in eggs, miracidia, and adult female worms. RNA inference was employed to knockdown SjILP in adults in vitro, with suppression confirmed by significantly reduced protein production, declined adenosine diphosphate levels, and reduction in glucose consumption. Immunolocalization showed that SjILP is located to lateral gland cells of mature intra-ovular miracidia in the schistosome egg, and is distributed on the ciliated epithelium and internal cell masses of newly transformed miracidia. In schistosomula, SjILP is present on the tegument in two antero-lateral points, indicating highly polarized expression during cercarial transformation. Analysis of serum from S. japonicum-infected mice by ELISA using a recombinant form of SjILP as an antigen revealed IgG immunoreactivity to this molecule at 7 weeks post-infection indicating it is likely secreted from mature eggs into the host circulation. These findings provide further insights on ILP function in schistosomes and its essential roles in parasite survival and growth in different development stages.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Helminto/genética , Insulina/genética , Schistosoma japonicum/crescimento & desenvolvimento , Schistosoma japonicum/genética , Esquistossomose Japônica/parasitologia , Animais , Feminino , Proteínas de Helminto/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Insulina/imunologia , Estágios do Ciclo de Vida , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Schistosoma japonicum/imunologia , Esquistossomose Japônica/sangue , Esquistossomose Japônica/imunologia
8.
Clin Microbiol Rev ; 32(2)2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30760475

RESUMO

Echinococcosis is a zoonosis caused by cestodes of the genus Echinococcus (family Taeniidae). This serious and near-cosmopolitan disease continues to be a significant public health issue, with western China being the area of highest endemicity for both the cystic (CE) and alveolar (AE) forms of echinococcosis. Considerable advances have been made in the 21st century on the genetics, genomics, and molecular epidemiology of the causative parasites, on diagnostic tools, and on treatment techniques and control strategies, including the development and deployment of vaccines. In terms of surgery, new procedures have superseded traditional techniques, and total cystectomy in CE, ex vivo resection with autotransplantation in AE, and percutaneous and perendoscopic procedures in both diseases have improved treatment efficacy and the quality of life of patients. In this review, we summarize recent progress on the biology, epidemiology, diagnosis, management, control, and prevention of CE and AE. Currently there is no alternative drug to albendazole to treat echinococcosis, and new compounds are required urgently. Recently acquired genomic and proteomic information can provide a platform for improving diagnosis and for finding new drug and vaccine targets, with direct impact in the future on the control of echinococcosis, which continues to be a global challenge.


Assuntos
Equinococose/epidemiologia , Equinococose/terapia , Zoonoses/parasitologia , Albendazol/uso terapêutico , Animais , China/epidemiologia , Ensaios Clínicos como Assunto , Cistectomia , Gerenciamento Clínico , Humanos , Qualidade de Vida , Transplante Autólogo , Zoonoses/epidemiologia , Zoonoses/terapia
9.
Am J Trop Med Hyg ; 100(3): 584-587, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628570

RESUMO

Mitochondrial genome analysis of Schistosoma japonicum suggests that diversity of intermediate host snails drove intra-species divergence during its expansion in Asia. We applied the knowledge of this genomic variation to study an unusual patient we recently diagnosed with schistosomiasis. The patient had not visited any schistosomiasis-endemic countries for more than 35 years and had no idea where she became infected. Unusual clinical features of this patient included the absence of egg granulomas in tissue and persistent noncalcified eggs despite multiple praziquantel (PZQ) treatments over 7 years. A digital droplet polymerase chair reaction (PCR) assay that specifically targets the schistosome 1,4 dihydronicotinamide adenine dinucleotide-1 (NADH1) dehydrogenase-1 mitochondrial gene successfully amplified parasite DNA extracted from colon biopsies. DNA sequence analysis of parasite DNA revealed that it was a Philippine strain of S. japonicum. Future molecular studies using stored DNA from patients such as this may provide new insight into why some persons do not respond well to PZQ treatment.

10.
PLoS Negl Trop Dis ; 13(1): e0006948, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668561

RESUMO

The human disease schistosomiasis (or bilharzia) is caused by the helminth blood fluke parasite Schistosoma mansoni, which requires an intermediate host, the freshwater gastropod snail Biomphalaria glabrata (the most common intermediate host). The free-swimming parasite miracidia utilise an excellent chemosensory sense to detect and locate an appropriate host. This study investigated the biomolecules released by the snail that stimulate changes in the behaviour of the aquatic S. mansoni miracidia. To achieve this, we have performed an integrated analysis of the snail-conditioned water, through chromatography and bioassay-guided behaviour observations, followed by mass spectrometry. A single fraction containing multiple putative peptides could stimulate extreme swimming behaviour modifications (e.g. velocity, angular variation) similar to those observed in response to crude snail mucus. One peptide (P12;-R-DITSGLDPEVADD-KR-) could replicate the stimulation of miracidia behaviour changes. P12 is derived from a larger precursor protein with a signal peptide and multiple dibasic cleavage sites, which is synthesised in various tissues of the snail, including the central nervous system and foot. P12 consists of an alpha helix secondary structure as indicated by circular dichroism spectroscopy. This information will be helpful for the development of approaches to manipulate this parasites life cycle, and opens up new avenues for exploring other parasitic diseases which have an aquatic phase using methods detailed in this investigation.


Assuntos
Agentes de Controle Biológico/farmacologia , Biomphalaria/química , Descoberta de Drogas/métodos , Peptídeos/farmacologia , Feromônios/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Anti-Helmínticos/farmacologia , Humanos , Esquistossomose/tratamento farmacológico
11.
PLoS Pathog ; 15(1): e1007513, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30673782

RESUMO

Mesenteric infection by the parasitic blood fluke Schistosoma bovis is a common veterinary problem in Africa and the Middle East and occasionally in the Mediterranean Region. The species also has the ability to form interspecific hybrids with the human parasite S. haematobium with natural hybridisation observed in West Africa, presenting possible zoonotic transmission. Additionally, this exchange of alleles between species may dramatically influence disease dynamics and parasite evolution. We have generated a 374 Mb assembly of the S. bovis genome using Illumina and PacBio-based technologies. Despite infecting different hosts and organs, the genome sequences of S. bovis and S. haematobium appeared strikingly similar with 97% sequence identity. The two species share 98% of protein-coding genes, with an average sequence identity of 97.3% at the amino acid level. Genome comparison identified large continuous parts of the genome (up to several 100 kb) showing almost 100% sequence identity between S. bovis and S. haematobium. It is unlikely that this is a result of genome conservation and provides further evidence of natural interspecific hybridization between S. bovis and S. haematobium. Our results suggest that foreign DNA obtained by interspecific hybridization was maintained in the population through multiple meiosis cycles and that hybrids were sexually reproductive, producing viable offspring. The S. bovis genome assembly forms a highly valuable resource for studying schistosome evolution and exploring genetic regions that are associated with species-specific phenotypic traits.


Assuntos
Hibridização Genética/genética , Schistosoma/genética , África , África Ocidental , Animais , Sequência de Bases/genética , Bovinos , Mapeamento Cromossômico/métodos , DNA/genética , Genoma/genética , Genoma Mitocondrial/genética , Hibridização Genética/fisiologia , Oriente Médio , Filogenia , Proteoma/genética , Especificidade da Espécie , Trematódeos/genética , Sequenciamento Completo do Genoma/métodos
12.
Gigascience ; 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30520948

RESUMO

Background: Foodborne infections caused by lung flukes of the genus Paragonimus are a significant and widespread public health problem in tropical areas. Around 50 Paragonimus species have been reported to infect animals and humans, but Paragonimus westermani is responsible for the bulk of human disease. Despite their medical and economic importance, no genome sequence for any Paragonimus species is available. Results: We sequenced and assembled the genome of P. westermani, which is among the largest of the known pathogen genomes with an estimated size of 1.1 Gb. A 922.8 Mb genome assembly was generated from Illumina and PacBio sequence data, covering 84% of the estimated genome size. The genome has a high proportion (45%) of repeat-derived DNA, particularly of the LINE and LTR subtypes, and the expansion of these elements may explain some of the large size. We predicted 12,852 protein coding genes, showing a high level of conservation with related trematode species. The majority of proteins (80%) had homologs in the human liver fluke Opisthorchis viverrini with an average sequence identity of 64.1%. Assembly of the P. westermani mitochondrial genome from long PacBio reads resulted in a single high-quality circularized 20.6 kb contig. The contig harboured a 6.9 kb region of non-coding repetitive DNA comprised of three distinct repeat units. Our results suggest that the region is highly polymorphic in P. westermani, possibly even within single worm isolates. Conclusions: The generated assembly represents the first Paragonimus genome sequence and will facilitate future molecular studies of this important, but neglected, parasite group.

13.
Infect Dis Poverty ; 7(1): 121, 2018 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-30526666

RESUMO

BACKGROUND: Co-parasitism is a frequent occurrence in impoverished communities in the tropics resulting in a considerable disease burden. While there are extensive reports of intestinal helminthiases, including schistosomiasis japonica, the occurrence and extent of diseases caused by intestinal protozoa (IP) have yet to be investigated in depth in the Philippines. We present a detailed analysis of polyparasitism in a rural community of Northern Samar, focusing on co-infections of IP with Schistosoma japonicum. METHODS: A descriptive cross sectional study was carried out in 2015 across 18 barangays (villages) endemic for S. japonicum in Northern Samar, the Philippines to assess the burden of human schistosomiasis and IP infections. Faecal samples collected from 412 participants from the 18 barangays were included in the final molecular analysis. A multiplex quantitative PCR assay was developed and used for the detection of Blastocystis spp., Entamoeba histolytica, Cryptosporidium spp. and Giardia duodenalis in stool samples. The findings were combined with previous results of droplet digital PCR diagnosis of individuals from the same 18 barangays infected with S. japonicum determined using the same stool samples for analysis. RESULTS: Mean age of the study participants was 40.3 years (95% CI: 38.8-41.8) with 53% (n = 218) being males. Prevalence of S. japonicum (74.5%) and Blastocystis spp. (58.7%) was significantly higher compared to other infections, with E. histolytica having the lowest prevalence (12.1%). A majority of individuals were infected with more than one parasite with two infections being most common (n = 175, 42.5%). The prevalence of individuals with two parasites was significantly higher than all others with 27.9% (n = 115) subjects harbouring a single parasite species. Of individuals with two infections, S. japonicum and Blastocystis spp. were the most common combination (n = 110, 62.9%). Examining age within the population, 58.5% (n = 38) of school-aged children and 60.1% (n = 14) of women of child bearing age harboured at least two parasite species. CONCLUSIONS: The study revealed that polyparasitism with IP infections and schistosomiasis japonica is highly prevalent in individuals in Northern Samar which likely contributes to the significant public health and socio-economic burden suffered by this population. More generally, the findings are of relevance when considering implementation of integrated control strategies for intestinal parasites.


Assuntos
Coinfecção , Enteropatias Parasitárias/complicações , Infecções por Protozoários/complicações , População Rural , Esquistossomose Japônica/complicações , Adolescente , Adulto , Criança , Feminino , Humanos , Enteropatias Parasitárias/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Filipinas , Prevalência , Infecções por Protozoários/epidemiologia , Fatores de Risco , Esquistossomose Japônica/epidemiologia , Adulto Jovem
14.
Lab Invest ; 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30401957

RESUMO

Hepatic fibrosis is the central cause of chronic clinical pathology resulting from infection by the blood flukes Schistosoma japonicum or S. mansoni. Much has been elucidated regarding the molecular, cellular and immunological responses that correspond to the formation of the granulomatous response to trapped schistosome eggs. A central feature of this Th2 response is the deposition of collagen around the periphery of the granuloma. To date, traditional histology and transcriptional methods have been used to quantify the deposition of collagen and to monitor the formation of the hepatic granuloma during experimental animal models of schistosomiasis. We have investigated the dynamic nature of granuloma formation through the use of a transgenic mouse model (B6.Collagen 1(A) luciferase mice (B6.Coll 1A-luc+)). With this model and whole-animal bioluminescence imaging, we followed the deposition of collagen during an active schistosome infection with Chinese and Philippines geographical strains of S. japonicum and after clearance of the adult parasites by the drug praziquantel. Individual mice were re-imaged over the time course to provide robust real-time quantitation of the development of chronic fibrotic disease. This model provides an improved method to follow the course of hepatic schistosomiasis-induced hepatic pathology and effectively supports the current dogma of the formation of hepatic fibrosis, originally elucidated from static traditional histology. This study demonstrates the first use of the B6.Coll 1A-luc+ mouse to monitor the dynamics of disease development and the treatment of pathogen-induced infection with the underlying pathology of fibrosis.

15.
EBioMedicine ; 37: 334-343, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30482723

RESUMO

BACKGROUND: Chronic infection with Schistosoma japonicum or S. mansoni results in hepatic fibrosis of the human host. Staging fibrosis is crucial for the prognosis and to determine the rapid need of treatment in patients with schistosomiasis. METHODS: To establish whether there is a correlation between circulating microRNA (miRNA) level and fibrosis progression in schistosomiasis, ten miRNAs were selected to assess their potential in grading schistosomiasis liver fibrosis. This was done firstly in two mouse strains (C57BL/6 and BALB/c) to determine the temporal expression profiles in serum over the course of S. japonicum infection, and then within a cohort of 163 schistosomiasis japonica patients with different grades of liver fibrosis. FINDING: Four miRNAs (miR-150-5p, let-7a-5p, let-7d-5p and miR-146a-5p) were able to distinguish patients with mild versus severe fibrosis. The level of serum miR-150-5p showed the most promising potential for grading hepatic fibrosis in schistosomiasis. The diagnostic performance of miR-150-5p in discriminating mild from severe fibrosis is comparable with that of the ELF test and serum HA level. In addition, the serum levels of the four miRNAs rebounded in infected C57BL/6 mice, after 6 months post treatment, following the regression of liver fibrosis, thereby providing further support for the utility of these miRNAs in grading schistosomal hepatic fibrosis. INTERPRETATION: Circulating miRNAs can be a supplementary tool for assessing hepatic fibrosis in human schistosomiasis. FUND: National Health and Medical Research Council (NHMRC) of Australia (APP1102926, APP1037304 and APP1098244).

16.
Biochem Soc Trans ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420417

RESUMO

In eukaryotes, effective calcium homeostasis is critical for many key biological processes. There is an added level of complexity in parasites, particularly multicellular helminth worms, which modulate calcium levels while inhabiting the host microenvironment. Parasites ensure efficient calcium homeostasis through gene products, such as the calmodulin-dependent kinases (CaMK), the main focus of this review. The importance of CaMK is becoming increasingly apparent from recent functional studies of helminth and protozoan parasites. Investigations on the molecular regulation of calcium and the role of CaMK are important for both supplementing current drug regimens and finding new antiparasitic compounds. Whereas calcium regulators, including CaMK, are well characterised in mammalian systems, knowledge of their functional properties in parasites is increasing but is still in its infancy.

17.
Int J Mol Sci ; 19(10)2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30304851

RESUMO

There is a pressing need to develop vaccines for schistosomiasis given the current heavy dependency on praziquantel as the only available drug for treatment. We previously showed the ligand domain of the Schistosoma japonicum insulin receptor 1 and 2 (rSjLD1 and 2) fusion proteins conferred solid protection in mice against challenge infection with S. japonicum. To improve vaccine efficacy, we compared the immunogenicity and protective efficacy of rSjLD1 on its own and in combination with S. japonicum triose-phosphate isomerase (SjTPI), formulated with either of two adjuvants (QuilA and montanide ISA 720VG) in murine vaccine trials against S. japonicum challenge. The level of protection was higher in mice vaccinated only with rSjLD1 formulated with either adjuvant; rSjTPI or the rSjTPI-rSjLD1 combination resulted in a lower level of protection. Mirroring our previous results, there were significant reductions in the number of female worms (30⁻44%), faecal eggs (61⁻68%), liver eggs (44⁻56%), intestinal eggs (46⁻48%) and mature intestinal eggs (58⁻63%) in the rSjLD1-vaccinated mice compared with the adjuvant only groups. At 6-weeks post-cercarial challenge, a significantly increased production of interferon gamma (IFNγ) in rSjLD1-stimulated splenic CD4⁺ T cells was observed in the rSjLD1-vaccinated mice suggesting a Th1-type response is associated with the generated level of protective efficacy.

18.
Trop Med Infect Dis ; 3(2)2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-30274454

RESUMO

Lymphatic filariasis (LF) infects an estimated 120 million people worldwide, with a further 856 million considered at risk of infection and requiring preventative chemotherapy. The majority of LF infections are caused by Wuchereria bancrofti, named in honour of the Australian physician Joseph Bancroft, with the remainder due to Brugia malayi and B. timori. Infection with LF through the bite of an infected mosquito, can lead to the development of the condition known as elephantiasis, where swelling due to oedema leads to loss of function in the affected area and thickening of the skin, 'like an elephant'. LF has previously been endemic in Australia, although currently, no autochthonous cases occur there. Human immigration to Australia from LF-endemic countries, including those close to Australia, and the presence of susceptible mosquitoes that can act as suitable vectors, heighten the possibility of the reintroduction of LF into this country. In this review, we examine the history of LF in Australia and Oceania and weigh up the potential risk of its re-occurrence on mainland Australia.

19.
Trop Med Infect Dis ; 3(2)2018 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-30274464

RESUMO

Schistosomiasis is recognized as a tropical disease of considerable public health importance, but domestic livestock infections due to Schistosoma japonicum, S. bovis, S. mattheei and S. curassoni are often overlooked causes of significant animal morbidity and mortality in Asia and Africa. In addition, whereas schistosomiasis japonica is recognized as an important zoonosis in China and the Philippines, reports of viable schistosome hybrids between animal livestock species and S. haematobium point to an underappreciated zoonotic component of transmission in Africa as well. Anti-schistosome vaccines for animal use have long been advocated as part of the solution to schistosomiasis control, benefitting humans and animals and improving the local economy, features aligning with the One Health concept synergizing human and animal health. We review the history of animal vaccines for schistosomiasis from the early days of irradiated larvae and then consider the recombinant DNA technology revolution and its impact in developing schistosome vaccines that followed. We evaluate the major candidates tested in livestock, including the glutathione S-transferases, paramyosin and triose-phosphate isomerase, and summarize some of the future challenges that need to be overcome to design and deliver effective anti-schistosome vaccines that will complement current control options to achieve and sustain future elimination goals.

20.
Trop Med Infect Dis ; 3(3)2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30274477

RESUMO

Despite extensive efforts over the last few decades, the global disease burden of schistosomiasis still remains unacceptably high. This could partly be attributed to the lack of accurate diagnostic tools for detecting human and animal schistosome infections in endemic areas. In low transmission and low prevalence areas where schistosomiasis elimination is targeted, case detection requires a test that is highly sensitive. Diagnostic tests with low sensitivity will miss individuals with low infection intensity and these will continue to contribute to transmission, thereby interfering with the efficacy of the control measures operating. Of the many diagnostic approaches undertaken to date, the detection of schistosome DNA using DNA amplification techniques including polymerase chain reaction (PCR) provide valuable adjuncts to more conventional microscopic and serological methods, due their accuracy, high sensitivity, and the capacity to detect early pre-patent infections. Furthermore, DNA-based methods represent important screening tools, particularly in those endemic areas with ongoing control where infection prevalence and intensity have been reduced to very low levels. Here we review the role of DNA diagnostics in the path towards the control and elimination of schistosomiasis.

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