ORCID Profile
0000-0003-3305-0533
Current Organisation
University of Melbourne
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Publisher: Springer Science and Business Media LLC
Date: 18-09-2017
DOI: 10.1038/S41598-017-11814-9
Abstract: Plasmodium falciparum causes a spectrum of malarial disease from asymptomatic to uncomplicated through to severe. Investigations of parasite virulence have associated the expression of distinct variants of the major surface antigen of the blood stages known as Pf EMP1 encoded by up to 60 var genes per genome. Looking at the population genomics of var genes in cases of uncomplicated malaria, we set out to determine if there was any evidence of a selective sweep of specific var genes or clonal epidemic structure related to the incidence of uncomplicated disease in children. By sequencing the conserved DBLα domain of var genes from six sentinel sites in Uganda we found that the parasites causing uncomplicated P. falciparum disease in children were highly erse and that every child had a unique var DBLα repertoire. Despite extensive var DBLα ersity and minimal overlap between repertoires, specific DBLα types and groups were conserved at the population level across Uganda. This pattern was the same regardless of the geographic distance or malaria transmission intensity. These data lead us to propose that any parasite can cause uncomplicated malarial disease and that these erse parasite repertoires are composed of both upsA and non-upsA var gene groups.
Publisher: Public Library of Science (PLoS)
Date: 18-05-2022
DOI: 10.1371/JOURNAL.PGPH.0000285
Abstract: High-malaria burden countries in sub-Saharan Africa are shifting from malaria control towards elimination. Hence, there is need to gain a contemporary understanding of how indoor residual spraying (IRS) with non-pyrethroid insecticides when combined with long-lasting insecticidal nets (LLINs) impregnated with pyrethroid insecticides, contribute to the efforts of National Malaria Control Programmes to interrupt transmission and reduce the reservoir of Plasmodium falciparum infections across all ages. Using an interrupted time-series study design, four age-stratified malariometric surveys, each of ~2,000 participants, were undertaken pre- and post-IRS in Bongo District, Ghana. Following the application of three-rounds of IRS, P . falciparum transmission intensity declined, as measured by a % reduction in the monthly entomological inoculation rate. This decline was accompanied by reductions in parasitological parameters, with participants of all ages being significantly less likely to harbor P . falciparum infections at the end of the wet season post-IRS (aOR = 0.22 [95% CI: 0.19–0.26], p-value 0.001). In addition, multiplicity of infection (MOI var ) was measured using a parasite fingerprinting tool, designed to capture within-host genome ersity. At the end of the wet season post-IRS, the prevalence of multi-genome infections declined from 75.6% to 54.1%. This study demonstrates that in areas characterized by high seasonal malaria transmission, IRS in combination with LLINs can significantly reduce the reservoir of P . falciparum infection. Nonetheless despite this success, 41.6% of the population, especially older children and adolescents, still harboured multi-genome infections. Given the persistence of this erse reservoir across all ages, these data highlight the importance of sustaining vector control in combination with targeted chemotherapy to move high-transmission settings towards pre-elimination. This study also points to the benefits of molecular surveillance to ensure that incremental achievements are not lost and that the goals advocated for in the WHO’s High Burden to High Impact strategy are realized.
Publisher: Public Library of Science (PLoS)
Date: 08-10-2013
Publisher: Cold Spring Harbor Laboratory
Date: 22-12-2020
DOI: 10.1101/2020.12.22.423749
Abstract: In high-transmission endemic regions, local populations of Plasmodium falciparum exhibit vast ersity of the var genes encoding its major surface antigen, with each parasite comprising multiple copies from this erse gene pool. This strategy to evade the immune system through large combinatorial antigenic ersity is common to other hyper erse pathogens. It underlies a series of fundamental epidemiological characteristics, including large reservoirs of transmission from high prevalence of asymptomatics and long-lasting infections. Previous theory has shown that negative frequency-dependent selection (NFDS) mediated by the acquisition of specific immunity by hosts structures the ersity of var gene repertoires (strains), in a pattern of limiting similarity that is both non-random and non-neutral. A combination of stochastic agent-based models and network analyses has enabled the development and testing of theory in these complex adaptive systems, where assembly of local parasite ersity occurs under frequency-dependent selection and large pools of variation. We show here the application of these approaches to theory comparing the resilience of the malaria transmission system to intervention when strain ersity is assembled under (competition-based) selection vs. a form of neutrality, where immunity depends only on the number but not the genetic identity of previous infections. The transmission system is considerably more resilient under NFDS, exhibiting a lower extinction probability despite comparable prevalence during intervention. We explain this pattern on the basis of the structure of strain ersity, in particular the more pronounced fraction of highly dissimilar parasites. For simulations that survive intervention, prevalence under specific immunity is lower than under neutrality, because the recovery of ersity is considerably slower than that of prevalence and decreased var gene ersity reduces parasite transmission. A Principal Component Analysis of network features describing parasite similarity reveals that despite lower overall ersity, NFDS is quickly restored after intervention constraining strain structure and maintaining patterns of limiting similarity important to parasite persistence. Given the resulting resilience to perturbations, intervention efforts will likely require longer times than the usual practice to eliminate P. falciparum populations. We discuss implications of our findings and potential analogies for ecological communities with non-neutral assembly processes involving frequency-dependence.
Publisher: Wiley
Date: 16-07-2021
DOI: 10.1111/MEC.16029
Abstract: Here, we report the first population genetic study to examine the impact of indoor residual spraying (IRS) on Plasmodium falciparum in humans. This study was conducted in an area of high seasonal malaria transmission in Bongo District, Ghana. IRS was implemented during the dry season (November–May) in three consecutive years between 2013 and 2015 to reduce transmission and attempt to bottleneck the parasite population in humans towards lower ersity with greater linkage disequilibrium. The study was done against a background of widespread use of long‐lasting insecticidal nets, typical for contemporary malaria control in West Africa. Microsatellite genotyping with 10 loci was used to construct 392 P . falciparum multilocus infection haplotypes collected from two age‐stratified cross‐sectional surveys at the end of the wet seasons pre‐ and post‐IRS. Three‐rounds of IRS, under operational conditions, led to a % reduction in transmission intensity and a 35.7% reduction in the P . falciparum prevalence ( p .001). Despite these declines, population genetic analysis of the infection haplotypes revealed no dramatic changes with only a slight, but significant increase in genetic ersity ( H e : pre‐IRS = 0.79 vs. post‐IRS = 0.81, p = .048). Reduced relatedness of the parasite population ( p .001) was observed post‐IRS, probably due to decreased opportunities for outcrossing. Spatiotemporal genetic differentiation between the pre‐ and post‐IRS surveys ( D = 0.0329 [95% CI: 0.0209 – 0.0473], p = .034) was identified. These data provide a genetic explanation for the resilience of P. falciparum to short‐term IRS programmes in high‐transmission settings in sub‐Saharan Africa.
Publisher: Proceedings of the National Academy of Sciences
Date: 05-2017
Abstract: This paper aims to discover how erse malaria parasites are in children from an African village. DNA sequencing shows that they are highly erse with respect to the genes encoding the surface coat. Indeed, every child has a malaria infection with a different set of these genes. Importantly, this paper shows by computational methods that the pattern of this ersity is not random but structured to enhance the parasites’ chance to evade host immunity and has implications for the success of malaria control programs.
Publisher: Springer Science and Business Media LLC
Date: 08-05-2018
DOI: 10.1038/S41467-018-04219-3
Abstract: Pathogens compete for hosts through patterns of cross-protection conferred by immune responses to antigens. In Plasmodium falciparum malaria, the var multigene family encoding for the major blood-stage antigen Pf EMP1 has evolved enormous genetic ersity through ectopic recombination and mutation. With 50–60 var genes per genome, it is unclear whether immune selection can act as a dominant force in structuring var repertoires of local populations. The combinatorial complexity of the var system remains beyond the reach of existing strain theory and previous evidence for non-random structure cannot demonstrate immune selection without comparison with neutral models. We develop two neutral models that encompass malaria epidemiology but exclude competitive interactions between parasites. These models, combined with networks of genetic similarity, reveal non-neutral strain structure in both simulated systems and an extensively s led population in Ghana. The unique population structure we identify underlies the large transmission reservoir characteristic of highly endemic regions in Africa.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 12-07-2017
Publisher: Cold Spring Harbor Laboratory
Date: 15-04-2021
DOI: 10.1101/2021.04.12.21255093
Abstract: To better understand the factors underlying the continued incidence of clinical episodes of falciparum malaria in E-2020 countries targeting elimination, we have characterised Plasmodium falciparum disease transmission dynamics after a clonal outbreak on the northwest coast of Ecuador over a period of two years. We apply a novel, high-resolution genotyping method, the “ var code” based on a single PCR to fingerprint the DBLα region of the 40-60 members of the variant surface antigen-encoding var multigene family. Var genes are highly polymorphic within and between genomes, with var repertoires rapidly evolving by outcrossing during the obligatory sexual phase of P. falciparum in the mosquito. The continued incidence of clinical malaria after the outbreak in Ecuador provided a unique opportunity to use var codes to document parasite microevolution and explore signatures of local disease transmission on the time scale of months to two years post-outbreak. We identified nine genetic var codes circulating locally with spatiotemporal parasite genetic relatedness networks revealing that ersification of the clonal outbreak parasites by sexual recombination was associated with increased incidence of clinical episodes of malaria. Whether this was due to chance, immune selection or sexual recombination per se is discussed. Comparative analyses to other South American parasite populations where P. falciparum transmission remains endemic elucidated the possible origins of Ecuadorian var codes. This analysis demonstrated that the majority of clinical cases were due to local transmission and not importation. Nonetheless, some of the var codes that were unrelated to the outbreak var code were found to be genetically related to other South American parasites. Our findings demonstrate the utility of the var code as a high-resolution surveillance tool to spatiotemporally track disease outbreaks using variant surface antigen genes and resolve signatures of recombination in an E-2020 setting nearing elimination.
Publisher: Oxford University Press (OUP)
Date: 27-05-2020
Abstract: The majority of Plasmodium falciparum infections, constituting the reservoir in all ages, are asymptomatic in high-transmission settings in Africa. The role of this reservoir in the evolution and spread of drug resistance was explored. Population genetic analyses of the key drug resistance–mediating polymorphisms were analyzed in a cross-sectional survey of asymptomatic P. falciparum infections across all ages in Bongo District, Ghana. Seven years after the policy change to artemisinin-based combination therapies in 2005, the pfcrt K76 and pfmdr1 N86 wild-type alleles have nearly reached fixation and have expanded via soft selective sweeps on multiple genetic backgrounds. By constructing the pfcrt-pfmdr1-pfdhfr-pfdhps multilocus haplotypes, we found that the alleles at these loci were in linkage equilibrium and that multidrug-resistant parasites have not expanded in this reservoir. For pfk13, 32 nonsynonymous mutations were identified however, none were associated with artemisinin-based combination therapy resistance. The prevalence and selection of alleles/haplotypes by antimalarials were similar to that observed among clinical cases in Ghana, indicating that they do not represent 2 subpopulations with respect to these markers. Thus, the P. falciparum reservoir in all ages can contribute to the maintenance and spread of antimalarial resistance.
Publisher: Public Library of Science (PLoS)
Date: 25-02-2021
DOI: 10.1371/JOURNAL.PGEN.1009269
Abstract: Malaria remains a major public health problem in many countries. Unlike influenza and HIV, where ersity in immunodominant surface antigens is understood geographically to inform disease surveillance, relatively little is known about the global population structure of PfEMP1, the major variant surface antigen of the malaria parasite Plasmodium falciparum . The complexity of the var multigene family that encodes PfEMP1 and that ersifies by recombination, has so far precluded its use in malaria surveillance. Recent studies have demonstrated that cost-effective deep sequencing of the region of var genes encoding the PfEMP1 DBLα domain and subsequent classification of within host sequences at 96% identity to define unique DBLα types, can reveal structure and strain dynamics within countries. However, to date there has not been a comprehensive comparison of these DBLα types between countries. By leveraging a bioinformatic approach (jumping hidden Markov model) designed specifically for the analysis of recombination within var genes and applying it to a dataset of DBLα types from 10 countries, we are able to describe population structure of DBLα types at the global scale. The sensitivity of the approach allows for the comparison of the global dataset to ape s les of Plasmodium Laverania species. Our analyses show that the evolution of the parasite population emerging out of Africa underlies current patterns of DBLα type ersity. Most importantly, we can distinguish geographic population structure within Africa between Gabon and Ghana in West Africa and Uganda in East Africa. Our evolutionary findings have translational implications in the context of globalization. Firstly, DBLα type ersity can provide a simple diagnostic framework for geographic surveillance of the rapidly evolving transmission dynamics of P . falciparum . It can also inform efforts to understand the presence or absence of global, regional and local population immunity to major surface antigen variants. Additionally, we identify a number of highly conserved DBLα types that are present globally that may be of biological significance and warrant further characterization.
Publisher: WHO Press
Date: 03-2012
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.NEUINT.2010.06.001
Abstract: This review discusses the role of beta-alanine as a neurotransmitter. Beta-alanine is structurally intermediate between alpha-amino acid (glycine, glutamate) and gamma-amino acid (GABA) neurotransmitters. In general, beta-alanine satisfies a number of the prerequisite classical criteria for being a neurotransmitter: beta-alanine occurs naturally in the CNS, is released by electrical stimulation through a Ca(2+) dependent process, has binding sites, and inhibits neuronal excitability. beta-Alanine has 5 recognized receptor sites: glycine co-agonist site on the NMDA complex (strychnine-insensitive) glycine receptor site (strychnine sensitive) GABA-A receptor GABA-C receptor and blockade of GAT protein-mediated glial GABA uptake. Although beta-alanine binding has been identified throughout the hippoc us, limbic structures, and neocortex, unique beta-alaninergic neurons with no GABAergic properties remain unidentified, and it is impossible to discriminate between beta-alaninergic and GABAergic properties in the CNS. Nevertheless, a variety of data suggest that beta-alanine should be considered as a small molecule neurotransmitter and should join the ranks of the other amino acid neurotransmitters. These realizations open the door for a more comprehensive evaluation of beta-alanine's neurochemistry and for its exploitation as a platform for drug design.
Publisher: Cold Spring Harbor Laboratory
Date: 30-06-2022
DOI: 10.1101/2022.06.27.497801
Abstract: At a time when effective tools for monitoring malaria control and eradication efforts are crucial, the increasing availability of molecular data motivates their application to epidemiology. The multiplicity of infection (MOI), defined as the number of genetically distinct parasite strains co-infecting a host, is one key epidemiological parameter for evaluating malaria interventions. Estimating MOI remains a challenge for high-transmission settings where in iduals typically carry multiple co-occurring infections. Several quantitative approaches have been developed to estimate MOI, including two cost-effective ones relying on molecular data: i) THE REAL McCOIL method is based on putatively neutral single nucleotide polymorphism loci, and ii) the var coding method is a fingerprinting approach that relies on the ersity and limited repertoire overlap of the var multigene family encoding the major Plasmodium falciparum blood-stage antigen PfEMP1 and is therefore under selection. In this study, we assess the robustness of the MOI estimates generated with these two approaches by simulating P. falciparum malaria dynamics under three transmission conditions using an extension of a previously developed stochastic agent-based model. We demonstrate that these approaches are complementary and best considered across distinct transmission intensities. While var coding can underestimate MOI, it allows robust estimation, especially under high-transmission where repertoire overlap is extremely limited from frequency-dependent selection. In contrast, THE REAL McCOIL often considerably overestimates MOI, but still provides reasonable estimates for low- and moderate-transmission. As many countries pursue malaria elimination targets, defining the most suitable approach to estimate MOI based on s le size and local transmission intensity is highly recommended for monitoring the impact of intervention programs. Despite control and elimination efforts, malaria continues to be a serious public health threat especially in high-transmission regions. Molecular tools for evaluating these efforts include those seeking to estimate multiplicity (or complexity) of infection (MOI), the number of genetically distinct parasite strains co-infecting a host, a key epidemiological parameter. MOI estimation remains challenging in high-transmission regions where hosts typically carry multiple co-infections by Plasmodium falciparum . THE REAL McCOIL and the var coding are two cost-effective methods relying on distinct parts of the parasite genome, those respectively under neutrality and selection. The more recent var coding approach relies on the var multigene family encoding for the major blood-stage antigen and contributing to a complex immune evasion strategy of the parasite. We compare the performance of the two methods by simulating disease dynamics under different transmission intensities with a stochastic agent-based model tracking infection by different parasite genomes and immune memory in in idual hosts, then s ling resulting infections to estimate MOI. Although THE REAL McCOIL provides reasonable estimates for low- and moderate-transmission, var coding allows more robust estimates especially under high-transmission. Defining the most suitable approach to estimate MOI based on local transmission intensity is highly recommended for hyper- erse pathogens such as malaria.
Publisher: Wiley
Date: 08-10-2017
DOI: 10.1002/ECE3.3425
No related grants have been discovered for Kathryn E Tiedje.