Magda Ellis | The University of Sydney (original) (raw)

Papers by Magda Ellis

Brain

Childhood dementia is a devastating and under-recognized group of disorders with a high level of ... more Childhood dementia is a devastating and under-recognized group of disorders with a high level of unmet need. Typically monogenic in origin, this collective of individual neurodegenerative conditions are defined by a progressive impairment of neurocognitive function, presenting in childhood and adolescence. This scoping review aims to clarify definitions and conceptual boundaries of childhood dementia and quantify the collective disease burden. A literature review identified conditions that met the case definition. An expert clinical working group reviewed and ratified inclusion. Epidemiological data were extracted from published literature and collective burden modelled. One hundred and seventy genetic childhood dementia disorders were identified. Of these, 25 were analysed separately as treatable conditions. Collectively, currently untreatable childhood dementia was estimated to have an incidence of 34.5 per 100 000 (1 in 2900 births), median life expectancy of 9 years and prevalen...

Molecular Genetics and Metabolism, 2021

Clinical & Translational Immunology, 2021

Objectives. Non-sputum-based tests to accurately identify active tuberculosis (TB) disease and mo... more Objectives. Non-sputum-based tests to accurately identify active tuberculosis (TB) disease and monitor response to therapy are urgently needed. This study examined the biomarker capacity of a panel of plasma proteins alone, and in conjunction with a previously identified miRNA signature, to identify active TB disease. Methods. The expression of nine proteins (IP-10, MCP-1, sTNFR1, RANTES, VEGF, IL-6, IL-10, TNF and Eotaxin) was measured in the plasma of 100 control subjects and 100 TB patients, at diagnosis (treatment na€ ıve) and over the course of treatment (1-, 2-and 6month intervals). The diagnostic performance of the nine proteins alone, and with the miRNA, was assessed. Results. Six proteins were significantly up-regulated in the plasma of TB patients at diagnosis compared to controls. Receiver operator characteristic curve analysis demonstrated that IP-10 with an AUC = 0.874, sensitivity of 75% and specificity of 87% was the best single biomarker candidate to distinguish TB patients from controls. IP-10 and IL-6 levels fell significantly within one month of commencing treatment and may have potential as indicators of a positive response to therapy. The combined protein and miRNA panel gave an AUC of 1.00. A smaller panel of only five analytes (IP-10, miR-29a, miR-146a, miR-99b and miR-221) showed an AUC = 0.995, sensitivity of 96% and specificity of 97%. Conclusions. A novel combination of miRNA and proteins significantly improves the sensitivity and specificity as a biosignature over single biomarker candidates and may be useful for the development of a nonsputum test to aid the diagnosis of active TB disease.

The American Journal of Tropical Medicine and Hygiene, 2006

We have identified a significant focus and unusual clustering of human cases of cystic echinococc... more We have identified a significant focus and unusual clustering of human cases of cystic echinococcosis (CE) and alveolar echinococcosis (AE) in the village of Nanwan, Xiji County, Ningxia Hui Autonomous Region, in one of the most highly endemic areas for both diseases in China. The village, a Chinese Hui Islamic community, is composed of 167 members of four extended families. A total of 28 people died (12 of echinococcosis) since the village was first settled in the 1950s. Despite similar life patterns, the number of AE and CE cases occurring in each family was different. Overall, the prevalences of AE and CE were 9% (20 cases) and 5.9% (13 cases), with a combined prevalence of 14.9%. In contrast to CE, a comparison of the prevalence of AE indicated significant differences between the four family clusters. Although suggestive that host genotype might play a role in susceptibility to AE, this hypothesis requires further investigation.

The Journal of infection, Jan 7, 2018

microRNA expression profiles are of interest as a biomarker of tuberculosis (TB). How anti-TB the... more microRNA expression profiles are of interest as a biomarker of tuberculosis (TB). How anti-TB therapy effects miRNA profiles is unknown and was examined. We identified 87 plasma miRNAs that were significantly modified in an exploratory group of 19 Chinese pulmonary TB (PTB) patients compared to 14 healthy controls. We selected 10 of these miRNAs for analysis in a cohort of 100 PTB patients prior to, and at one, two and six months during treatment. Five miRNAs were differentially expressed in PTB patients compared to controls at diagnosis; miRs -29a and -99b were up-regulated, whilst miRs -21, -146a and -652 were down-regulated. A combination of 5 miRNA distinguished TB from healthy controls with a sensitivity of 94%, a specificity of 88%, and an AUC of 0.976. Within one month of treatment, significant changes in miRs -29a, -99b, -26a and 146a levels occurred in successfully treated patients, although not all miRNAs returned to baseline by treatment completion. A 5-miRNA signature sh...

Nature communications, Jan 8, 2018

Type I interferons (IFN), best known for their anti-viral functions, have been shown to impair ho... more Type I interferons (IFN), best known for their anti-viral functions, have been shown to impair host resistance to intracellular bacteria in mice. However, the precise role of type I IFN signaling in bacterial infection in humans is unclear. Here, we show that genetic variation in the human IFNAR1 gene is associated with decreased susceptibility to tuberculosis and an increased risk of viral hepatitis in Chinese populations. Receptor mutagenesis and cell signaling studies establish that the IFNAR1 mutation corresponding to a proline deletion in the hinge region of the membrane-proximal domain of IFNAR1 decreases the binding affinity of IFNAR1 to IFN-β, impeding type I IFN signaling. Our findings suggest that IFNAR1 signaling underlies an increased risk of tuberculosis in humans and reveals a function for the IFNAR1 inter-domain region in cytokine-cytokine receptor interaction and signal transduction.

Parasitology, Jan 28, 2015

Schistosomiasis is a significant cause of human morbidity and mortality. We performed a genome-wi... more Schistosomiasis is a significant cause of human morbidity and mortality. We performed a genome-wide transcriptional survey of liver biopsies obtained from Chinese patients with chronic schistosomiasis only, or chronic schistosomiasis with a current or past history of viral hepatitis B. Both disease groups were compared with patients with no prior history or indicators of any liver disease. Analysis showed in the main, downregulation in gene expression, particularly those involved in signal transduction via EIF2 signalling and mTOR signalling, as were genes associated with cellular remodelling. Focusing on immune associated pathways, genes were generally downregulated. However, a set of three genes associated with granulocytes, MMP7, CLDN7, CXCL6 were upregulated. Differential gene profiles unique to schistosomiasis included the gene Granulin which was decreased despite being generally considered a marker for liver disease, and IGBP2 which is associated with increased liver size, and...

PLOS ONE, 2015

Although rare variants within the Toll-like receptor signalling pathway genes have been found to ... more Although rare variants within the Toll-like receptor signalling pathway genes have been found to underlie human primary immunodeficiencies associated with selective predisposition to invasive pneumococcal disease (IPD), the contribution of variants in these genes to IPD susceptibility at the population level remains unknown. Complete re-sequencing of IRAK4, MYD88 and IKBKG genes was undertaken in 164 IPD cases from the UK and 164 geographically-matched population-based controls. 233 single-nucleotide variants (SNVs) were identified, of which ten were in coding regions. Four rare coding variants were predicted to be deleterious, two variants in MYD88 and two in IRAK4. The predicted deleterious variants in MYD88 were observed as two heterozygote cases but not seen in controls. Frequencies of predicted deleterious IRAK4 SNVs were the same in cases and controls. Our findings suggest that rare, functional variants in MYD88, IRAK4 or IKBKG do not significantly contribute to IPD susceptibility in adults at the population level.

Bulletin of the World Health Organization, 2008

To evaluate the safety and efficacy of combining artemether (AM) and praziquantel (PZQ) in differ... more To evaluate the safety and efficacy of combining artemether (AM) and praziquantel (PZQ) in different regimens for treating acute schistosomiasis japonica. We undertook a randomized, double-blind, placebo-controlled trial within four specialized schistosomiasis hospitals in the Dongting Lake region, Hunan province, China, between May 2003 and December 2005. Study participants were randomized into one of four treatment regimes: group A received 60 mg/kg PZQ + 6 mg/kg AM; group B received 60 mg/kg PZQ + AM placebo; group C received 120 mg/kg PZQ + 6 mg/kg AM; and group D received 120 mg/kg PZQ + AM placebo. All participants were followed up over a 45-day period. The primary endpoint of the trial was human infection status (determined by positive stool examination). Secondary endpoints involved clinical observations and blood biochemistry, including monitoring haemoglobin and alanine aminotransferase levels over time. Treatment efficacies of the four different treatment regimens were 98...

Journal of Cellular and Molecular Medicine, 2015

Tuberculosis (TB) remains a major public health issue. New tests to aid diagnoses and monitor the... more Tuberculosis (TB) remains a major public health issue. New tests to aid diagnoses and monitor the response to therapy are urgently required. There is growing interest in the use of microRNA (miRNA) profiles as diagnostic, prognostic or predictive markers in a range of clinical and infectious diseases, including Mycobacterium tuberculosis infection, however, challenges exist to accurately normalise miRNA levels in cohorts. This study examined the appropriateness of 12 miRs and RNU6B to normalise circulating plasma miRNA levels in individuals with active TB from 2 different geographical and ethnic regions. Twelve miRs (let-7, miR-16, miR-22, miR-26, miR-93, miR-103, miR-191, miR-192, miR-221, miR-423, miR-425 and miR-451) and RNU6B were selected based on their reported production by lung cells, expression in blood and previous use as a reference miRNA. Expression levels were analysed in the plasma of newly diagnosed TB patients from Australia and China compared with individuals with latent TB infection and healthy volunteers. Analysis with both geNorm and Norm-Finder software identified miR-93 as the most suitable reference miR in both cohorts, either when analysed separately or collectively. Interestingly, there were large variations in the expression levels of some miRs, in particular miR-192 and let-7, between the two cohorts, independent of disease status. These data identify miR-93 is a suitable reference miR for normalizing miRNA levels in TB patients, and highlight how environmental, and possibly ethnic, factors influence miRNA expression levels, demonstrating the necessity of assessing the suitability of reference miRs within the study population.

PloS one, 2014

Tuberculosis (TB) is an infectious disease that remains a major cause of morbidity and mortality ... more Tuberculosis (TB) is an infectious disease that remains a major cause of morbidity and mortality worldwide, yet the reasons why only 10% of people infected with Mycobacterium tuberculosis go on to develop clinical disease are poorly understood. Genetically determined variation in the host immune response is one factor influencing the response to M. tuberculosis. SP110 is an interferon-responsive nuclear body protein with critical roles in cell cycling, apoptosis and immunity to infection. However association studies of the gene with clinical TB in different populations have produced conflicting results. To examine the importance of the SP110 gene in immunity to TB in the Vietnamese we conducted a case-control genetic association study of 24 SP110 variants, in 663 patients with microbiologically proven TB and 566 unaffected control subjects from three tertiary hospitals in northern Vietnam. Five SNPs within SP110 were associated with all forms of TB, including four SNPs at the C term...

Trends in Parasitology, 2012

Public health implications Currently, over three million people are afflicted worldwide with echi... more Public health implications Currently, over three million people are afflicted worldwide with echinococcosis, and the considerable morbidity associated with both AE and CE is estimated to result in more than 1.5 million disability-adjusted life years (DALYs) lost [12,13]. The often long period between infection and when a subject becomes symptomatic can result in late diagnosis such that, because the disease is already well established, treatment is consequently more difficult. AE is of considerable public health concern, particularly in parts of central and Eastern Europe and, especially, Northwest China [4]. Although the annual incidence of AE may appear low in many endemic areas (0.03-1.2 per 100 000 inhabitants) [4], it is estimated that many cases are undiagnosed [14]. Human CE is endemic in many pastoral communities, particularly in Eastern Europe [15] and north China [16]. In China, there are 60 million people at risk and 1.3 million cases of CE [17]. Cotransmission of both E. granulosus and E. multilocularis has been recognized in many endemic countries or regions, including northern Japan, China, North Africa, North America, and several Eurasian countries [18]. Approximately 95% of all AE cases worldwide are localized in five endemic provinces/autonomous regions of Sichuan, Qinghai, Gansu, Xinjiang and Ningxia, in north and northwest China. All five are co-endemic for AE and CE, the latter being endemic also to a further 16 of the 33 provinces in China [19].

Emerging Infectious Diseases, 2007

2 to 4,350 km 2 .The previous construction of embankments and the large silt deposits made by the... more 2 to 4,350 km 2 .The previous construction of embankments and the large silt deposits made by the Yangtze River and other connecting rivers have contributed to frequent disastrous fl ooding. As a consequence of the 2 water projects, >2 million persons and their domestic animals are being resettled. This article provides an overview of the historical background of these 2 large water management projects, the associated population movement, and their impact on future transmission and control of schistosomiasis in the Dongting Lake area. The dam will likely substantially extend the range of the snail habitats and increase schistosome transmission and schistosomiasis cases.

BMC Public Health, 2012

Background Tuberculosis is a devastating disease due to its rapid transmission and high rate of m... more Background Tuberculosis is a devastating disease due to its rapid transmission and high rate of mortality. Ningxia Hui Autonomous Region (NHAR), located in the North-west, is one of the poorest provinces in China and national surveys have shown TB has been hyper endemic in NHAR for several decades. As no active surveys had been undertaken since the initiation of the DOTS control program across all of NHAR. Methods A retrospective study was undertaken of all clinical records of TB patients registered from January 2005 to September 2009. Poisson regression was performed to investigate the change in incidence over time and accounted for age, sex and county. Length of time on treatment, disease severity and patient delay were assessed by county. Results More than 30% of patients had been on treatment for over 12 months and 10% for over 3 years, reflecting drug-resistance or failure of DOTS. More than 93% of patients had grade III disease at time of diagnosis and >15% of patients had ...

Acta Tropica, 2005

The great success in schistosomiasis control in China is attributable to a range of factors. Peri... more The great success in schistosomiasis control in China is attributable to a range of factors. Periodic epidemiological surveys (PES) used for monitoring and adapting control interventions over time are an integral feature of the national schistosomiasis control programme. PES have enabled the dynamic trends of schistosomiasis epidemics to be closely pursued and have assisted in analysing subtle changes in endemicity. The results can be summarised mathematically allowing the variation in efficacy of control measures to be readily determined and enabling control strategies to be adjusted and updated. PES have been used in both cross-sectional and longitudinal pilot studies selected by appropriate sampling methods. In the early 1990s, when the World Bank Loan Project for schistosomiasis control commenced, economic evaluations were initiated in parallel. Cost-effectiveness analysis became a necessary tool to identify the most financially feasible yet effective options among a range of alternative control strategies. There was, however, a lack of standardised approaches rendering study comparisons across sites difficult. The global burden of disease study established the disability adjusted life year (DALY) as a measure of population health, combining in a single indicator years lost from premature death and years of life lived with disability. However, a recent meta-analysis reveals that the burden of schistosomiasis is underestimated, and hence, needs to be revised. It is envisaged that after the revision of DALYs lost due to schistosomiasis japonica, they will become an essential measure in future schistosomiasis control assessments in China and in other schistosome-endemic areas of the world.

The Journal of Immunology, 2007

Genetic studies of human susceptibility to Schistosoma (blood fluke) infections have previously i... more Genetic studies of human susceptibility to Schistosoma (blood fluke) infections have previously identified a genetic locus determining infection intensity with the African species, Schistosoma mansoni, in the 5q31-33 region of the human genome that is known to contain the Th2 immune response cluster, including the genes encoding the IL-4, IL-5, and IL-13 cytokines. These cytokines are key players in inflammatory immune responses and have previously been implicated in human susceptibility to infection with the Asian species, S. japonicum. In a nested case control study, we genotyped 30 HapMap tagging single nucleotide polymorphisms (SNPs) across these three genes in 159 individuals identified as putatively susceptible to reinfection with S. japonicum and in 133 putatively resistant individuals. A third group comprising 113 individuals demonstrating symptomatic infection was also included. The results provided no significant association at a global level between reinfection predisposition and any of the individual SNPs or haplotype blocks. However, two tagging SNPs in IL-5 demonstrated globally significant association with susceptibility to symptomatic infection. They were in strong linkage disequilibrium with each other and were found to belong to the same haplotype block that also provided a significant association after permutation testing. This haplotype was located in the 3-untranslated region of IL-5, suggesting that variants in this region of IL-5 may modulate the immune response in these individuals with symptomatic infection.

Schistosomiasis is a significant cause of human morbidity and mortality. We performed a genome-wi... more Schistosomiasis is a significant cause of human morbidity and mortality. We performed a genome-wide transcriptional survey of liver biopsies obtained from Chinese patients with chronic schistosomiasis only, or chronic schistosomiasis with a current or past history of viral hepatitis B. Both disease groups were compared with patients with no prior history or indicators of any liver disease. Analysis showed in the main, downregulation in gene expression, particularly those involved in signal transduction via EIF2 signalling and mTOR signalling, as were genes associated with cellular remodelling. Focusing on immune associated pathways, genes were generally downregulated. However, a set of three genes associated with granulocytes, MMP7, CLDN7, CXCL6 were upregulated. Differential gene profiles unique to schistosomiasis included the gene Granulin which was decreased despite being generally considered a marker for liver disease, and IGBP2 which is associated with increased liver size, and was the most upregulated gene in schistosomiasis only patients, all of which presented with hepatomegaly. The unique features of gene expression, in conjunction with previous reports in the murine model of the cellular composition of granulomas, granuloma formation and recovery, provide an increased understanding of the molecular immunopathology and general physiological processes underlying hepatic schistosomiasis.

Although rare variants within the Toll-like receptor signalling pathway genes have been found to ... more Although rare variants within the Toll-like receptor signalling pathway genes have been found to underlie human primary immunodeficiencies associated with selective predisposition to invasive pneumococcal disease (IPD), the contribution of variants in these genes to IPD susceptibility at the population level remains unknown. Complete re-sequencing of IRAK4, MYD88 and IKBKG genes was undertaken in 164 IPD cases from the UK and 164 geographically-matched population-based controls. 233 single-nucleotide variants (SNVs) were identified, of which ten were in coding regions. Four rare coding variants were predicted to be deleterious, two variants in MYD88 and two in IRAK4. The predicted deleterious variants in MYD88 were observed as two heterozygote cases but not seen in controls. Frequencies of predicted deleterious IRAK4 SNVs were the same in cases and controls. Our findings suggest that rare, functional variants in MYD88, IRAK4 or IKBKG do not significantly contribute to IPD susceptibility in adults at the population level.

Tuberculosis (TB) remains a major public health issue. New tests to aid diagnoses and monitor the... more Tuberculosis (TB) remains a major public health issue. New tests to aid diagnoses and monitor the response to therapy are urgently required. There is growing interest in the use of microRNA (miRNA) profiles as diagnostic, prognostic or predictive markers in a range of clinical and infectious diseases, including Mycobacterium tuberculosis infection, however, challenges exist to accurately normalise miRNA levels in cohorts. This study examined the appropriateness of 12 miRs and RNU6B to normalise circulating plasma miRNA levels in individuals with active TB from 2 different geographical and ethnic regions. Twelve miRs (let-7, miR-16, miR-22, miR-26, miR-93, miR-103, miR-191, miR-192, miR-221, miR-423, miR-425 and miR-451) and RNU6B were selected based on their reported production by lung cells, expression in blood and previous use as a reference miRNA. Expression levels were analysed in the plasma of newly diagnosed TB patients from Australia and China compared with individuals with latent TB infection and healthy volunteers. Analysis with both geNorm and NormFinder software identified miR-93 as the most suitable reference miR in both cohorts, either when analysed separately or collectively. Interestingly, there were large variations in the expression levels of some miRs, in particular miR-192 and let-7, between the two cohorts, independent of disease status. These data identify miR-93 is a suitable reference miR for normalizing miRNA levels in TB patients, and highlight how environmental, and possibly ethnic, factors influence miRNA expression levels, demonstrating the necessity of assessing the suitability of reference miRs within the study population.

Brain

Childhood dementia is a devastating and under-recognized group of disorders with a high level of ... more Childhood dementia is a devastating and under-recognized group of disorders with a high level of unmet need. Typically monogenic in origin, this collective of individual neurodegenerative conditions are defined by a progressive impairment of neurocognitive function, presenting in childhood and adolescence. This scoping review aims to clarify definitions and conceptual boundaries of childhood dementia and quantify the collective disease burden. A literature review identified conditions that met the case definition. An expert clinical working group reviewed and ratified inclusion. Epidemiological data were extracted from published literature and collective burden modelled. One hundred and seventy genetic childhood dementia disorders were identified. Of these, 25 were analysed separately as treatable conditions. Collectively, currently untreatable childhood dementia was estimated to have an incidence of 34.5 per 100 000 (1 in 2900 births), median life expectancy of 9 years and prevalen...

Molecular Genetics and Metabolism, 2021

Clinical & Translational Immunology, 2021

Objectives. Non-sputum-based tests to accurately identify active tuberculosis (TB) disease and mo... more Objectives. Non-sputum-based tests to accurately identify active tuberculosis (TB) disease and monitor response to therapy are urgently needed. This study examined the biomarker capacity of a panel of plasma proteins alone, and in conjunction with a previously identified miRNA signature, to identify active TB disease. Methods. The expression of nine proteins (IP-10, MCP-1, sTNFR1, RANTES, VEGF, IL-6, IL-10, TNF and Eotaxin) was measured in the plasma of 100 control subjects and 100 TB patients, at diagnosis (treatment na€ ıve) and over the course of treatment (1-, 2-and 6month intervals). The diagnostic performance of the nine proteins alone, and with the miRNA, was assessed. Results. Six proteins were significantly up-regulated in the plasma of TB patients at diagnosis compared to controls. Receiver operator characteristic curve analysis demonstrated that IP-10 with an AUC = 0.874, sensitivity of 75% and specificity of 87% was the best single biomarker candidate to distinguish TB patients from controls. IP-10 and IL-6 levels fell significantly within one month of commencing treatment and may have potential as indicators of a positive response to therapy. The combined protein and miRNA panel gave an AUC of 1.00. A smaller panel of only five analytes (IP-10, miR-29a, miR-146a, miR-99b and miR-221) showed an AUC = 0.995, sensitivity of 96% and specificity of 97%. Conclusions. A novel combination of miRNA and proteins significantly improves the sensitivity and specificity as a biosignature over single biomarker candidates and may be useful for the development of a nonsputum test to aid the diagnosis of active TB disease.

The American Journal of Tropical Medicine and Hygiene, 2006

We have identified a significant focus and unusual clustering of human cases of cystic echinococc... more We have identified a significant focus and unusual clustering of human cases of cystic echinococcosis (CE) and alveolar echinococcosis (AE) in the village of Nanwan, Xiji County, Ningxia Hui Autonomous Region, in one of the most highly endemic areas for both diseases in China. The village, a Chinese Hui Islamic community, is composed of 167 members of four extended families. A total of 28 people died (12 of echinococcosis) since the village was first settled in the 1950s. Despite similar life patterns, the number of AE and CE cases occurring in each family was different. Overall, the prevalences of AE and CE were 9% (20 cases) and 5.9% (13 cases), with a combined prevalence of 14.9%. In contrast to CE, a comparison of the prevalence of AE indicated significant differences between the four family clusters. Although suggestive that host genotype might play a role in susceptibility to AE, this hypothesis requires further investigation.

The Journal of infection, Jan 7, 2018

microRNA expression profiles are of interest as a biomarker of tuberculosis (TB). How anti-TB the... more microRNA expression profiles are of interest as a biomarker of tuberculosis (TB). How anti-TB therapy effects miRNA profiles is unknown and was examined. We identified 87 plasma miRNAs that were significantly modified in an exploratory group of 19 Chinese pulmonary TB (PTB) patients compared to 14 healthy controls. We selected 10 of these miRNAs for analysis in a cohort of 100 PTB patients prior to, and at one, two and six months during treatment. Five miRNAs were differentially expressed in PTB patients compared to controls at diagnosis; miRs -29a and -99b were up-regulated, whilst miRs -21, -146a and -652 were down-regulated. A combination of 5 miRNA distinguished TB from healthy controls with a sensitivity of 94%, a specificity of 88%, and an AUC of 0.976. Within one month of treatment, significant changes in miRs -29a, -99b, -26a and 146a levels occurred in successfully treated patients, although not all miRNAs returned to baseline by treatment completion. A 5-miRNA signature sh...

Nature communications, Jan 8, 2018

Type I interferons (IFN), best known for their anti-viral functions, have been shown to impair ho... more Type I interferons (IFN), best known for their anti-viral functions, have been shown to impair host resistance to intracellular bacteria in mice. However, the precise role of type I IFN signaling in bacterial infection in humans is unclear. Here, we show that genetic variation in the human IFNAR1 gene is associated with decreased susceptibility to tuberculosis and an increased risk of viral hepatitis in Chinese populations. Receptor mutagenesis and cell signaling studies establish that the IFNAR1 mutation corresponding to a proline deletion in the hinge region of the membrane-proximal domain of IFNAR1 decreases the binding affinity of IFNAR1 to IFN-β, impeding type I IFN signaling. Our findings suggest that IFNAR1 signaling underlies an increased risk of tuberculosis in humans and reveals a function for the IFNAR1 inter-domain region in cytokine-cytokine receptor interaction and signal transduction.

Parasitology, Jan 28, 2015

Schistosomiasis is a significant cause of human morbidity and mortality. We performed a genome-wi... more Schistosomiasis is a significant cause of human morbidity and mortality. We performed a genome-wide transcriptional survey of liver biopsies obtained from Chinese patients with chronic schistosomiasis only, or chronic schistosomiasis with a current or past history of viral hepatitis B. Both disease groups were compared with patients with no prior history or indicators of any liver disease. Analysis showed in the main, downregulation in gene expression, particularly those involved in signal transduction via EIF2 signalling and mTOR signalling, as were genes associated with cellular remodelling. Focusing on immune associated pathways, genes were generally downregulated. However, a set of three genes associated with granulocytes, MMP7, CLDN7, CXCL6 were upregulated. Differential gene profiles unique to schistosomiasis included the gene Granulin which was decreased despite being generally considered a marker for liver disease, and IGBP2 which is associated with increased liver size, and...

PLOS ONE, 2015

Although rare variants within the Toll-like receptor signalling pathway genes have been found to ... more Although rare variants within the Toll-like receptor signalling pathway genes have been found to underlie human primary immunodeficiencies associated with selective predisposition to invasive pneumococcal disease (IPD), the contribution of variants in these genes to IPD susceptibility at the population level remains unknown. Complete re-sequencing of IRAK4, MYD88 and IKBKG genes was undertaken in 164 IPD cases from the UK and 164 geographically-matched population-based controls. 233 single-nucleotide variants (SNVs) were identified, of which ten were in coding regions. Four rare coding variants were predicted to be deleterious, two variants in MYD88 and two in IRAK4. The predicted deleterious variants in MYD88 were observed as two heterozygote cases but not seen in controls. Frequencies of predicted deleterious IRAK4 SNVs were the same in cases and controls. Our findings suggest that rare, functional variants in MYD88, IRAK4 or IKBKG do not significantly contribute to IPD susceptibility in adults at the population level.

Bulletin of the World Health Organization, 2008

To evaluate the safety and efficacy of combining artemether (AM) and praziquantel (PZQ) in differ... more To evaluate the safety and efficacy of combining artemether (AM) and praziquantel (PZQ) in different regimens for treating acute schistosomiasis japonica. We undertook a randomized, double-blind, placebo-controlled trial within four specialized schistosomiasis hospitals in the Dongting Lake region, Hunan province, China, between May 2003 and December 2005. Study participants were randomized into one of four treatment regimes: group A received 60 mg/kg PZQ + 6 mg/kg AM; group B received 60 mg/kg PZQ + AM placebo; group C received 120 mg/kg PZQ + 6 mg/kg AM; and group D received 120 mg/kg PZQ + AM placebo. All participants were followed up over a 45-day period. The primary endpoint of the trial was human infection status (determined by positive stool examination). Secondary endpoints involved clinical observations and blood biochemistry, including monitoring haemoglobin and alanine aminotransferase levels over time. Treatment efficacies of the four different treatment regimens were 98...

Journal of Cellular and Molecular Medicine, 2015

Tuberculosis (TB) remains a major public health issue. New tests to aid diagnoses and monitor the... more Tuberculosis (TB) remains a major public health issue. New tests to aid diagnoses and monitor the response to therapy are urgently required. There is growing interest in the use of microRNA (miRNA) profiles as diagnostic, prognostic or predictive markers in a range of clinical and infectious diseases, including Mycobacterium tuberculosis infection, however, challenges exist to accurately normalise miRNA levels in cohorts. This study examined the appropriateness of 12 miRs and RNU6B to normalise circulating plasma miRNA levels in individuals with active TB from 2 different geographical and ethnic regions. Twelve miRs (let-7, miR-16, miR-22, miR-26, miR-93, miR-103, miR-191, miR-192, miR-221, miR-423, miR-425 and miR-451) and RNU6B were selected based on their reported production by lung cells, expression in blood and previous use as a reference miRNA. Expression levels were analysed in the plasma of newly diagnosed TB patients from Australia and China compared with individuals with latent TB infection and healthy volunteers. Analysis with both geNorm and Norm-Finder software identified miR-93 as the most suitable reference miR in both cohorts, either when analysed separately or collectively. Interestingly, there were large variations in the expression levels of some miRs, in particular miR-192 and let-7, between the two cohorts, independent of disease status. These data identify miR-93 is a suitable reference miR for normalizing miRNA levels in TB patients, and highlight how environmental, and possibly ethnic, factors influence miRNA expression levels, demonstrating the necessity of assessing the suitability of reference miRs within the study population.

PloS one, 2014

Tuberculosis (TB) is an infectious disease that remains a major cause of morbidity and mortality ... more Tuberculosis (TB) is an infectious disease that remains a major cause of morbidity and mortality worldwide, yet the reasons why only 10% of people infected with Mycobacterium tuberculosis go on to develop clinical disease are poorly understood. Genetically determined variation in the host immune response is one factor influencing the response to M. tuberculosis. SP110 is an interferon-responsive nuclear body protein with critical roles in cell cycling, apoptosis and immunity to infection. However association studies of the gene with clinical TB in different populations have produced conflicting results. To examine the importance of the SP110 gene in immunity to TB in the Vietnamese we conducted a case-control genetic association study of 24 SP110 variants, in 663 patients with microbiologically proven TB and 566 unaffected control subjects from three tertiary hospitals in northern Vietnam. Five SNPs within SP110 were associated with all forms of TB, including four SNPs at the C term...

Trends in Parasitology, 2012

Public health implications Currently, over three million people are afflicted worldwide with echi... more Public health implications Currently, over three million people are afflicted worldwide with echinococcosis, and the considerable morbidity associated with both AE and CE is estimated to result in more than 1.5 million disability-adjusted life years (DALYs) lost [12,13]. The often long period between infection and when a subject becomes symptomatic can result in late diagnosis such that, because the disease is already well established, treatment is consequently more difficult. AE is of considerable public health concern, particularly in parts of central and Eastern Europe and, especially, Northwest China [4]. Although the annual incidence of AE may appear low in many endemic areas (0.03-1.2 per 100 000 inhabitants) [4], it is estimated that many cases are undiagnosed [14]. Human CE is endemic in many pastoral communities, particularly in Eastern Europe [15] and north China [16]. In China, there are 60 million people at risk and 1.3 million cases of CE [17]. Cotransmission of both E. granulosus and E. multilocularis has been recognized in many endemic countries or regions, including northern Japan, China, North Africa, North America, and several Eurasian countries [18]. Approximately 95% of all AE cases worldwide are localized in five endemic provinces/autonomous regions of Sichuan, Qinghai, Gansu, Xinjiang and Ningxia, in north and northwest China. All five are co-endemic for AE and CE, the latter being endemic also to a further 16 of the 33 provinces in China [19].

Emerging Infectious Diseases, 2007

2 to 4,350 km 2 .The previous construction of embankments and the large silt deposits made by the... more 2 to 4,350 km 2 .The previous construction of embankments and the large silt deposits made by the Yangtze River and other connecting rivers have contributed to frequent disastrous fl ooding. As a consequence of the 2 water projects, >2 million persons and their domestic animals are being resettled. This article provides an overview of the historical background of these 2 large water management projects, the associated population movement, and their impact on future transmission and control of schistosomiasis in the Dongting Lake area. The dam will likely substantially extend the range of the snail habitats and increase schistosome transmission and schistosomiasis cases.

BMC Public Health, 2012

Background Tuberculosis is a devastating disease due to its rapid transmission and high rate of m... more Background Tuberculosis is a devastating disease due to its rapid transmission and high rate of mortality. Ningxia Hui Autonomous Region (NHAR), located in the North-west, is one of the poorest provinces in China and national surveys have shown TB has been hyper endemic in NHAR for several decades. As no active surveys had been undertaken since the initiation of the DOTS control program across all of NHAR. Methods A retrospective study was undertaken of all clinical records of TB patients registered from January 2005 to September 2009. Poisson regression was performed to investigate the change in incidence over time and accounted for age, sex and county. Length of time on treatment, disease severity and patient delay were assessed by county. Results More than 30% of patients had been on treatment for over 12 months and 10% for over 3 years, reflecting drug-resistance or failure of DOTS. More than 93% of patients had grade III disease at time of diagnosis and >15% of patients had ...

Acta Tropica, 2005

The great success in schistosomiasis control in China is attributable to a range of factors. Peri... more The great success in schistosomiasis control in China is attributable to a range of factors. Periodic epidemiological surveys (PES) used for monitoring and adapting control interventions over time are an integral feature of the national schistosomiasis control programme. PES have enabled the dynamic trends of schistosomiasis epidemics to be closely pursued and have assisted in analysing subtle changes in endemicity. The results can be summarised mathematically allowing the variation in efficacy of control measures to be readily determined and enabling control strategies to be adjusted and updated. PES have been used in both cross-sectional and longitudinal pilot studies selected by appropriate sampling methods. In the early 1990s, when the World Bank Loan Project for schistosomiasis control commenced, economic evaluations were initiated in parallel. Cost-effectiveness analysis became a necessary tool to identify the most financially feasible yet effective options among a range of alternative control strategies. There was, however, a lack of standardised approaches rendering study comparisons across sites difficult. The global burden of disease study established the disability adjusted life year (DALY) as a measure of population health, combining in a single indicator years lost from premature death and years of life lived with disability. However, a recent meta-analysis reveals that the burden of schistosomiasis is underestimated, and hence, needs to be revised. It is envisaged that after the revision of DALYs lost due to schistosomiasis japonica, they will become an essential measure in future schistosomiasis control assessments in China and in other schistosome-endemic areas of the world.

The Journal of Immunology, 2007

Genetic studies of human susceptibility to Schistosoma (blood fluke) infections have previously i... more Genetic studies of human susceptibility to Schistosoma (blood fluke) infections have previously identified a genetic locus determining infection intensity with the African species, Schistosoma mansoni, in the 5q31-33 region of the human genome that is known to contain the Th2 immune response cluster, including the genes encoding the IL-4, IL-5, and IL-13 cytokines. These cytokines are key players in inflammatory immune responses and have previously been implicated in human susceptibility to infection with the Asian species, S. japonicum. In a nested case control study, we genotyped 30 HapMap tagging single nucleotide polymorphisms (SNPs) across these three genes in 159 individuals identified as putatively susceptible to reinfection with S. japonicum and in 133 putatively resistant individuals. A third group comprising 113 individuals demonstrating symptomatic infection was also included. The results provided no significant association at a global level between reinfection predisposition and any of the individual SNPs or haplotype blocks. However, two tagging SNPs in IL-5 demonstrated globally significant association with susceptibility to symptomatic infection. They were in strong linkage disequilibrium with each other and were found to belong to the same haplotype block that also provided a significant association after permutation testing. This haplotype was located in the 3-untranslated region of IL-5, suggesting that variants in this region of IL-5 may modulate the immune response in these individuals with symptomatic infection.

Schistosomiasis is a significant cause of human morbidity and mortality. We performed a genome-wi... more Schistosomiasis is a significant cause of human morbidity and mortality. We performed a genome-wide transcriptional survey of liver biopsies obtained from Chinese patients with chronic schistosomiasis only, or chronic schistosomiasis with a current or past history of viral hepatitis B. Both disease groups were compared with patients with no prior history or indicators of any liver disease. Analysis showed in the main, downregulation in gene expression, particularly those involved in signal transduction via EIF2 signalling and mTOR signalling, as were genes associated with cellular remodelling. Focusing on immune associated pathways, genes were generally downregulated. However, a set of three genes associated with granulocytes, MMP7, CLDN7, CXCL6 were upregulated. Differential gene profiles unique to schistosomiasis included the gene Granulin which was decreased despite being generally considered a marker for liver disease, and IGBP2 which is associated with increased liver size, and was the most upregulated gene in schistosomiasis only patients, all of which presented with hepatomegaly. The unique features of gene expression, in conjunction with previous reports in the murine model of the cellular composition of granulomas, granuloma formation and recovery, provide an increased understanding of the molecular immunopathology and general physiological processes underlying hepatic schistosomiasis.

Although rare variants within the Toll-like receptor signalling pathway genes have been found to ... more Although rare variants within the Toll-like receptor signalling pathway genes have been found to underlie human primary immunodeficiencies associated with selective predisposition to invasive pneumococcal disease (IPD), the contribution of variants in these genes to IPD susceptibility at the population level remains unknown. Complete re-sequencing of IRAK4, MYD88 and IKBKG genes was undertaken in 164 IPD cases from the UK and 164 geographically-matched population-based controls. 233 single-nucleotide variants (SNVs) were identified, of which ten were in coding regions. Four rare coding variants were predicted to be deleterious, two variants in MYD88 and two in IRAK4. The predicted deleterious variants in MYD88 were observed as two heterozygote cases but not seen in controls. Frequencies of predicted deleterious IRAK4 SNVs were the same in cases and controls. Our findings suggest that rare, functional variants in MYD88, IRAK4 or IKBKG do not significantly contribute to IPD susceptibility in adults at the population level.

Tuberculosis (TB) remains a major public health issue. New tests to aid diagnoses and monitor the... more Tuberculosis (TB) remains a major public health issue. New tests to aid diagnoses and monitor the response to therapy are urgently required. There is growing interest in the use of microRNA (miRNA) profiles as diagnostic, prognostic or predictive markers in a range of clinical and infectious diseases, including Mycobacterium tuberculosis infection, however, challenges exist to accurately normalise miRNA levels in cohorts. This study examined the appropriateness of 12 miRs and RNU6B to normalise circulating plasma miRNA levels in individuals with active TB from 2 different geographical and ethnic regions. Twelve miRs (let-7, miR-16, miR-22, miR-26, miR-93, miR-103, miR-191, miR-192, miR-221, miR-423, miR-425 and miR-451) and RNU6B were selected based on their reported production by lung cells, expression in blood and previous use as a reference miRNA. Expression levels were analysed in the plasma of newly diagnosed TB patients from Australia and China compared with individuals with latent TB infection and healthy volunteers. Analysis with both geNorm and NormFinder software identified miR-93 as the most suitable reference miR in both cohorts, either when analysed separately or collectively. Interestingly, there were large variations in the expression levels of some miRs, in particular miR-192 and let-7, between the two cohorts, independent of disease status. These data identify miR-93 is a suitable reference miR for normalizing miRNA levels in TB patients, and highlight how environmental, and possibly ethnic, factors influence miRNA expression levels, demonstrating the necessity of assessing the suitability of reference miRs within the study population.