Papers by Paul Van Helden
Classification of<i> Schindleria</i> In the classification of Schindleriidae as a jun... more Classification of<i> Schindleria</i> In the classification of Schindleriidae as a junior synonym of Gobiidae we follow Thacker (2009), a view adopted by several authors ( Gill & Mooi 2010; Betancur-R<i> et al.</i> 2017). Six nominal species of Schindler's fishes are documented, four from the Pacific and two from the Indian Ocean (Red Sea) ( Ahnelt & Sauberer 2018). But the number of species is obviously underestimated. Kon<i> et al.</i> (2007, 2011) found more than 30 cryptic species just in the western Pacific. Separation of these extremely paedomorphic species based on morphological characters is challenging ( Kon<i> et al</i>. 2007; Ahnelt & Sauberer 2018; Ahnelt 2019). The most striking difference between the first described species of<i> Schindleria</i>,<i> S. praematura</i> ( Schindler 1930) and<i> S. pietschmanni</i> ( Schindler 1931), was the relative positions of the dorsal and anal fins...
The Lancet. Respiratory medicine, Jan 15, 2017
Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis rema... more Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbi...
Veterinary microbiology, Jan 8, 2015
Mycobacterium bovis has global public-health and socio-economic significance and can infect a wid... more Mycobacterium bovis has global public-health and socio-economic significance and can infect a wide range of species including the lion (Panthera leo) resulting in tuberculosis. Lions are classified as vulnerable under the IUCN Red List of Threatened Species and have experienced a 30% population decline in the past two decades. However, no attempt has been made to collate and critically evaluate the available knowledge of M. bovis infections in lions and potential effects on population. In this review we set out to redress this. Arguments suggesting that ingestion of infected prey animals are the main route of infection for lions have not been scientifically proven and research is needed into other possible sources and routes of infection. The paucity of knowledge on host susceptibility, transmission directions and therefore host status, manifestation of pathology, and epidemiology of the disease in lions also needs to be addressed. Advances have been made in diagnosing the presence ...
New England Journal of Medicine, 2009
Journal of Wildlife Diseases, 2015
Warthogs (Phacochoerus africanus) have been implicated as potential maintenance hosts of Mycobact... more Warthogs (Phacochoerus africanus) have been implicated as potential maintenance hosts of Mycobacterium bovis. Our preliminary investigation of bovine tuberculosis in three warthogs describes pathologic findings and associated positive serologic results in two infected animals. This demonstrates the potential use of serodiagnostic tests for M. bovis infection in this species.
Journal of medicinal chemistry, Jan 9, 2015
High throughput screening of a library of small polar molecules against Mycobacterium tuberculosi... more High throughput screening of a library of small polar molecules against Mycobacterium tuberculosis led to the identification of a phthalimide-containing ester hit compound (1), which was optimized for metabolic stability by replacing the ester moiety with a methyl oxadiazole bioisostere. A route utilizing polymer-supported reagents was designed and executed to explore structure activity relationships with respect to the N-benzyl substituent, leading to compounds with nanomolar activity. The frontrunner compound (5h) from these studies was well tolerated in mice. A M. tuberculosis cytochrome bd oxidase deletion mutant (∆cydKO) was hyper-susceptible to compounds from this series, and a strain carrying a single point mutation in qcrB, the gene encoding a subunit of the menaquinol cytochrome c oxidoreductase, was resistant to compounds in this series. In combination, these observations indicate that this novel class of anti-mycobacterial compounds inhibits the cytochrome bc1 complex, a ...
The Journal of antimicrobial chemotherapy, Jan 15, 2015
The emergence of drug resistance continues to plague TB control, with a global increase in the pr... more The emergence of drug resistance continues to plague TB control, with a global increase in the prevalence of MDR-TB. This acts as a gateway to XDR-TB and thus emphasizes the urgency for drug development and optimal treatment options. Bedaquiline is the first new anti-TB drug approved by the FDA in 40 years and has been shown to be an effective treatment option for MDR Mycobacterium tuberculosis infection. Bedaquiline has also recently been included in clinical trials for new regimens with the aim of improving and shortening treatment periods. Alarmingly, efflux-mediated bedaquiline resistance, as well as efflux-mediated cross-resistance to clofazimine, has been identified in treatment failures. This mechanism of resistance results in efflux of a variety of anti-TB drugs from the bacterial cell, thereby decreasing the intracellular drug concentration. In doing so, the bacillus is able to render the antibiotic treatment ineffective. Recent studies have explored strategies to reverse t...
Clinical Chemistry and Laboratory Medicine, 2000
Different phenotypes are displayed by Mycobacterium tuberculosis (M. tuberculosis) strains, fuell... more Different phenotypes are displayed by Mycobacterium tuberculosis (M. tuberculosis) strains, fuelling speculation that certain strains are &amp;amp;amp;amp;amp;amp;quot;hypervirulent&amp;amp;amp;amp;amp;amp;quot; and able to evade host defenses better than others. Furthermore, differential antigen expression by M. tuberculosis strains may explain why certain patients are susceptible to a repeat episode of tuberculosis. The objective of this study was to compare protein expression by M. tuberculosis H37Rv and clinical isolates in order to determine whether differential protein expression contributes to the different phenotypes expressed by these strains. Expression of alpha-crystallin, the antigen 85 complex, PstS-1, L-alanine dehydrogenase and the 65 kDa antigen was analysed by Western blotting and enzyme-linked immunosorbent assays, using mouse monoclonal antibodies. We found no significant difference in the growth rate of the M. tuberculosis strains in vitro, and although M. tuberculosis protein expression showed phase variation during growth, expression seemed to be qualitatively, but not quantitatively, conserved in the strains investigated. These results have potentially important implications for vaccine development and serodiagnosis.
Mediators of inflammation, 2015
Elevated antibody responses to Mycobacterium tuberculosis antigens in individuals with latent inf... more Elevated antibody responses to Mycobacterium tuberculosis antigens in individuals with latent infection (LTBI) have previously been linked to an increased risk for progression to active disease. Studies in the field focussed mainly on IgG antibodies. In the present study, IgA and/or IgG responses to the mycobacterial protein antigens AlaDH, NarL, 19 kDa, PstS3, and MPT83 were determined in a blinded fashion in sera from 53 LTBI controls, 14 healthy controls, and 42 active TB subjects. Among controls, we found that elevated IgA levels against all investigated antigens were not randomly distributed but concentrated on a subgroup of <30%-with particular high levels in a small subgroup of ~5% comprising one progressor to active TB. Based on a specificity of 100%, anti-NarL IgA antibodies achieved with 78.6% sensitivity the highest accuracy for the detection of active TB compared to healthy controls. In conclusion, the consistently elevated IgA levels in a subgroup of controls suggest...
The Journal of infectious diseases, Jan 7, 2015
The study aimed to determine whether tuberculosis patients who suffer relapse have different imm... more The study aimed to determine whether tuberculosis patients who suffer relapse have different immune responses to mycobacteria in vitro compared to patients who remain cured for two years, as currently no tools to accurately predict tuberculosis relapse exist. First episode pulmonary tuberculosis patients were recruited in South Africa. Diluted blood, collected at diagnosis and after two and four weeks of treatment, was cultured with live Mycobacterium tuberculosis for six days and cellular RNA frozen. Gene expression in ten patients who subsequently relapsed, confirmed by strain genotyping, was compared to those who remained cured using microarrays. At diagnosis, expression of 668 genes was significantly different in relapse patients' samples compared to successfully cured patients: these differences persisted for at least four weeks. Gene Ontology and biological pathways analyses revealed significant up-regulation of genes involved in cytotoxic cell-mediated killing. Results...
Journal of Clinical Microbiology, 2015
word count = 48 31 Text word count = 1051 32 33 Abstract 34 Sequencing of the Mycobacterium tuber... more word count = 48 31 Text word count = 1051 32 33 Abstract 34 Sequencing of the Mycobacterium tuberculosis pncA gene allows for pyrazinamide 35 susceptibility testing. We summarize data on pncA polymorphisms which do not confer 36 resistance at a susceptibility breakpoint of 100 µg/ml pyrazinamide in MGIT within a cohort 37 of isolates from South Africa and the US Centre for Disease Control.
Journal of Wildlife Diseases, 2015
Complete blood counts (n = 115) and red blood cell analytes (n = 80) were assessed in free-rangin... more Complete blood counts (n = 115) and red blood cell analytes (n = 80) were assessed in free-ranging white rhinoceros (Ceratotherium simum) from Kruger National Park (KNP), South Africa. Blood was collected from healthy animals immobilized between February and September 2009-11 for management purposes. Our objectives were to establish baselines for KNP&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s white rhinoceros population and to compare results based on sex and age group. Significant differences in total white blood cells, total eosinophils, and hemoglobin were found between adult and subadult rhinoceros. Female rhinoceros had significantly higher total white blood cells and lower hemoglobin compared with males. Hematologic analytes were similar to those published for other rhinoceros populations, although the impact of capture and sampling methods, nutritional status, and habitat should be considered when comparing data. This baseline hematology for healthy free-ranging white rhinoceros in KNP may be useful in assessing health status for translocation and medical interventions, including treatment of poaching cases.
PloS one, 2015
Pyrazinamide (PZA) is crucial for tuberculosis (TB) treatment, given its unique ability to eradic... more Pyrazinamide (PZA) is crucial for tuberculosis (TB) treatment, given its unique ability to eradicate persister bacilli. The worldwide burden of PZA resistance remains poorly described. Systematic PubMed, Science Direct and Scopus searches for articles reporting phenotypic (liquid culture drug susceptibility testing or pyrazinamidase activity assays) and/or genotypic (polymerase chain reaction or DNA sequencing) PZA resistance. Global and regional summary estimates were obtained from random-effects meta-analysis, stratified by presence or risk of multidrug resistant TB (MDR-TB). Regional summary estimates were combined with regional WHO TB incidence estimates to determine the annual burden of PZA resistance. Information on single nucleotide polymorphisms (SNPs) in the pncA gene was aggregated to obtain a global summary. Pooled PZA resistance prevalence estimate was 16.2% (95% CI 11.2-21.2) among all TB cases, 41.3% (29.0-53.7) among patients at high MDR-TB risk, and 60.5% (52.3-68.6)...
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, Jan 6, 2015
Toll-like receptors (TLRs) are involved in the recognition of conserved microbial structures, lea... more Toll-like receptors (TLRs) are involved in the recognition of conserved microbial structures, leading to activation of an inflammatory response and formation of an adaptive immune response. Twenty-three polymorphisms in five TLR genes were genotyped in 729 tuberculosis cases and 487 healthy controls in a population-based case-control association study in a South African population. We detected sex-specific associations for TLR8 polymorphisms, with rs3761624 (OR=1.54, p<0.001), rs3764879 (OR=1.41, p=0.011) and rs3764880 (OR=1.42, p=0.011) associated in females and rs3764879 (OR=0.72, p=0.013) and rs3764880 (OR=0.75, p=0.036) associated in males. Epistatic interactions between the TLR genes were investigated and the TLR1_rs4833095 polymorphism was shown to interact with TLR2_rs3804100 and (GT)n microsatellite (p=0.002) and alter susceptibility to TB. We also studied the role of TLRs in disease caused by different Mycobacterium tuberculosis genotypes in 257 tuberculosis cases, and i...
Clinical and vaccine immunology : CVI, Jan 24, 2015
African buffaloes (Syncerus caffer) are maintenance hosts of Mycobacterium bovis, the causative a... more African buffaloes (Syncerus caffer) are maintenance hosts of Mycobacterium bovis, the causative agent of bovine tuberculosis. They act as reservoirs of this infection for a wide range of wildlife and domestic species and the detection of infected animals is important to control the geographic spread and transmission of the disease. Interferon-gamma (IFN-γ) release assays utilizing pathogen-derived peptide antigens are highly specific tests of M. bovis infection; however, the diagnostic sensitivities of these assays are suboptimal. We evaluated the diagnostic utility of measuring antigen-dependent interferon gamma-induced protein 10 (IP-10) release as an alternative to measuring IFN-γ. M. bovis-exposed buffaloes were tested using the Bovigam PC-EC and Bovigam PC-HP assays and a modified QuantiFERON TB-Gold (mQFT) assay. IP-10 was measured in the harvested plasma and was produced in significantly greater abundance in response to M. bovis antigens in Bovigam-positive than in Bovigam-ne...
BioMed Research International, 2015
Background. The clinical relevance of nontuberculous mycobacteria (NTM), detected by liquid more ... more Background. The clinical relevance of nontuberculous mycobacteria (NTM), detected by liquid more than solid culture in sputum specimens from a South African mining workforce, is uncertain. We aimed to describe the current spectrum and relevance of NTM in this population. Methods. An observational study including individuals with sputum NTM isolates, recruited at workforce tuberculosis screening and routine clinics. Symptom questionnaires were administered at the time of sputum collection and clinical records and chest radiographs reviewed retrospectively. Results. Of 232 individuals included (228 (98%) male, median age 44 years), M. gordonae (60 individuals), M. kansasii (50), and M. avium complex (MAC: 38) were the commonest species. Of 38 MAC isolates, only 2 (5.3%) were from smear-positive sputum specimens and 30/38 grew in liquid but not solid culture. MAC was especially prevalent among symptomatic, HIV-positive individuals. HIV prevalence was high: 57/74 (77%) among those tested. No differences were found in probability of death or medical separation by NTM species. Conclusions. M. gordonae, M. kansasii, and MAC were the commonest NTM among miners with suspected tuberculosis, with most MAC from smear-negative specimens in liquid culture only. HIV testing and identification of key pathogenic NTM in this setting are essential to ensure optimal treatment.
PLOS ONE, 2015
Tuberculosis (TB) is the second leading cause of mortality from infectious disease worldwide. One... more Tuberculosis (TB) is the second leading cause of mortality from infectious disease worldwide. One of the factors involved in developing disease is the genetics of the host, yet the field of TB susceptibility genetics has not yielded the answers that were expected. A commonly posited explanation for the missing heritability of complex disease is gene-gene interactions, also referred to as epistasis. In this study we investigate the role of gene-gene interactions in genetic susceptibility to TB using a cohort recruited from a high TB incidence community from Cape Town, South Africa. Our discovery data set incorporates genotypes from a large a number of candidate gene studies as well as genome-wide data. After limiting our search space to pairs of putative TB susceptibility genes, as well as pairs of genes that have been curated in online databases as potential interactors, we use statistical modelling to identify pairs of interacting SNPs. We attempt to validate the top models identified in our discovery data set using an independent genome-wide TB case-control data set from The Gambia. A number of models were successfully validated, indicating that interplay between the NRG1 -NRG3, GRIK1 -GRIK3 and IL23R -ATG4C gene pairs may modify susceptibility to TB. Gene pairs involved in the NF-κB pathway were also identified in the discovery data set (SFTPD -NOD2, ISG15 -TLR8 and NLRC5 -IL12RB1), but could not be tested in the Gambian study group due to lack of overlapping data.
PLOS ONE, 2015
We have previously developed a diagnostic test for tuberculosis based on detection of mycobacteri... more We have previously developed a diagnostic test for tuberculosis based on detection of mycobacterial lipoarabinomannan (LAM) in urine. The method depended on a laborious concentration step. We have now developed an easy to perform test based on a magnetic immunoassay platform, utilizing high avidity monoclonal antibodies for the detection of LAM in urine. With this method the analytical sensitivity of the assay was increased 50-100-fold compared to conventional ELISA. In a pilot study of HIV-negative patients with microbiologically verified TB (n=17) and healthy controls (n=22) the sensitivity of the test was 82% and the specificity 100%. This is in stark positive contrast to a range of studies using available commercial tests with polyclonal anti-LAM Abs where the sensitivity of the tests in HIVnegative TB patients was very low.
PloS one, 2015
There are limited data about the epidemiology and treatment-related outcomes associated with capr... more There are limited data about the epidemiology and treatment-related outcomes associated with capreomycin resistance in patients with XDR-TB. Capreomycin achieves high serum concentrations relative to MIC but whether capreomycin has therapeutic benefit despite microbiological resistance remains unclear. We reviewed the susceptibility profiles and outcomes associated with capreomycin usage in patients diagnosed with XDR-TB between August 2002 and October 2012 in two provinces of South Africa. Patients whose isolates were genotypically tested for capreomycin resistance were included in the analysis. Of 178 XDR-TB patients 41% were HIV-infected. 87% (154/178) isolates contained a capreomycin resistance-conferring mutation [80% (143/178) rrs A1401G and 6% (11/178) were heteroresistant (containing both the rrs A1401G mutation and wild-type sequences)]. Previous MDR-TB treatment, prior usage of kanamycin, or strain type was not associated with capreomycin resistance. 92% (163/178) of XDR-T...
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Papers by Paul Van Helden