NIHRDataInsights/HRCSData huggingface dataset:
Title: Mathematical modelling of the emergence and spread of antibiotic resistant bacteria in healthcare settings: a stochastic approach
Funder: Medical Research Council

Abstract: See Case for Support document for abbreviations and references. This fellowship focusses on the mathematical modelling of the emergence and spread of DRB in HCSs. Due to the small population sizes involved in HCSs, the stochastic approach is considered. Main aims of this research amount to: (i) to develop intra-host models for the emergence of DRB; (ii) to relate the quantitative information obtained from these models with new epidemiological models in the population level for the spread of these bacteria strains among individuals in HCSs. These new models will address at the same time a number of open questions in the area (e.g., competition between different strains, or consideration of HCSs different than hospitals); (iii) to develop new stochastic models and tools for analysing the efficacy of intervention measures for controlling the spread of DRB in HCSs; (iv) to adapt tools that I already developed [P7,P10], and develop new mathematical/statistical tools, to address the intrinsic heterogeneity among individuals in HCSs; and (v) to relate models with clinical data. In order to attain the objectives listed above, I will make use of a wide range of techniques in which I have expertise. Among others, these techniques amount to: study of stochastic descriptors, analysis of first-passage times and absorption probabilities, use of auxiliary Markov chains, Laplace-Stieltjes transforms and probability generating functions, consideration of phase-type distributions, and algorithmic approaches within the matrix-analytic techniques [17]. On the other hand, particular skills development objectives within this fellowship are to widen my clinical knowledge in DRB, and to apply statistical techniques in order to relate the stochastic models developed within this fellowship with clinical data provided by clinical collaborators. To this end, different statistical techniques (the ABC algorithm, the Gibbs sampler or Monte Carlo Markov Chain methods) will be considered.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Genetic data as a signal of changing malaria transmission
Funder: Medical Research Council

Abstract: Malaria is declining on a worldwide scale, with many countries now setting their sites on elimination. A major challenge in the future of malaria control and elimination efforts will be monitoring transmission intensity once prevalence reaches low levels, and hence traditional surveillance methods begin to lose statistical power. Genetic data constitutes a rich and underutilised source of information here. The fact that sexual recombination between genetically distinct strains can only occur when an individual receives multiple infections simultaneously (for example by receiving bites from two separate infectious mosquitoes) means that parasite population genetics are intimately linked to ongoing levels of transmission. The handful of studies that have attempted to infer levels of transmission directly from genetic data have shown promising results, but so far lack generalisability and efficiency. I will develop the statistical and computational machinery needed to turn these fledgeling ideas into a rigorous methodology. By making use of recent developments in coalescent theory, and further extending these methods to account for recombination, I will create efficient algorithms for simulating genetic data from complex malaria transmission models. I will then use approximate Bayesian computation (ABC) to turn this simulation-based method into an inferential tool, using machine learning techniques to maximise statistical power. Finally, I will dedicate time to accessibility, making sure that newly developed methods are available to a wide audience, and not just those used to dealing with mathematical models.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Ecology of insecticide resistant vectors: consequences for the effectiveness of malaria control strategies
Funder: Medical Research Council

Abstract: Despite substantial progress with malaria control, transmission persists throughout much of Africa due to a combination of complex vector ecology, parasite and vector resistance, and poor health infrastructure. Malaria is thus an archetypal example of a complex infectious disease. Epidemiologists increasingly recognize that no single methodological approach or data type is sufficient to understand such complex disease systems and inform evidence-based policy decisions. Instead, a more holistic approach incorporating diverse data on pathogens, hosts and (where applicable) vectors will be needed. Enabling the integration of numerous sources of data remains one of the outstanding challenges for modern medical sciences but potentially game-changing advances in this area are now possible through recent innovations at the intersection of applied biology, ecology and statistics. Armed with these new modelling tools, namely a state-space model, this proposal will borrow strength from all the available types of malaria vector surveillance techniques as well as host data such as clinical incidence from a large-scale intervention trial to understand one of the most impending threats for malaria control: insecticide resistance (IR). The overall objective is to determine if the fundamental assumption that IR mosquitoes are identical to susceptible ones in all aspects other than their response to insecticides is true. We hypothesise that vector ecology may also be altered in these IR mosquitoes. In this proposal will apply these new tools to estimate the values of latent life-history traits of IR mosquitoes that could modulate the epidemiological outcome of vector control methods. Specifically, I propose to investigate the population dynamics and ecology of malaria vectors in an area of high IR (Banfora region of Burkina Faso), and to quantify the impacts of both traditional and novel control methods on mosquito life history.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: INFECTION
Title: Building resilient health systems: lessons from international, national and local emergency responses to the Ebola epidemic in Sierra Leone.
Funder: Medical Research Council

Abstract: The response to the Ebola epidemic has challenged the dominant paradigm of gradual health systems strengthening, led by national governments and supported by international actors. It poses difficult questions about what kind of responses are helpful in situations when sudden shocks appear to overwhelm already fragile health systems and deplete limited resources. Over the last 12 months, the Ebola epidemic has revealed a lack of resilience in the health systems of affected countries, demonstrating an inability to recover from shocks and mount effective responses. We ask: In what ways has the international Ebola-response affected Sierra Leone's health system and its ability to withstand future shocks? How can international, national and local emergency response mechanisms be utilised to build a resilient health system in Sierra Leone, and what lessons emerge? Our findings will offer the potential to promote a major shift in the global health systems debate, from one narrowly focused on health system strengthening, to a focus on building health systems that are strong as well as resilient. The study will explore what needs to happen at each systems level, what capacities need to be created at local, district and national level, and what role international actors should play. To address these questions, we bring together a multidisciplinary team with extensive expertise in a range of highly relevant, but currently largely separate, bodies of scientific scholarship: health systems/health systems strengthening; policy and implementation science; disaster risk reduction/emergency preparedness; and the anthropology of global health and medical humanitarianism. Explicitly bringing together these often separate bodies of learning will enable us to more fully and effectively answer our principal research questions, identify transferable lessons and contribute to generating substantive health systems research evidence relating to what promotes resilient health systems.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFECTION
Title: Evaluation of effect of social determinants and of impact of social programs on incidence, frequency of disability and treatment outcomes of leprosy
Funder: Medical Research Council

Abstract: Leprosy remains a public health problem in Brazil. The epidemiology of leprosy is not fully understood: little is known about risk factors for infection, for disease, for delayed diagnosis and for treatment interruption. Large social inequalities and poverty are historical characteristics of Brazil; major improvements in the last 2 decades, with considerable expansion of programs in education, housing, social security and social development, make this an ideal setting for investigation. We propose a novel strategy to investigate the effect of social determinants and the impact of the Brazilian cash-transfer program "Bolsa Familia" (BFP), on incidence, frequency of disabilities and treatment outcomes of leprosy by linking records from the database, "Cadastro Único para Programas Sociais" (CadÚnico), of applications for social programs, with detailed socio-economic information on over 100 million individuals, to two databases: individual payments of BFP, and the leprosy component of the National Notification Database, with information on notifications, disability, treatment and outcomes for all cases of leprosy. Statistical methods will include standard statistical methods for longitudinal data to estimate the effect of social determinants and regression discontinuity design and propensity scores to investigate the impact of BFP on notifications, disability, treatment and outcomes for all cases of leprosy. The project will produce strong and specific evidence of the impact of social interventions and social deprivation on leprosy, advance our understanding of leprosy and will strengthen the case for implementation of social interventions- in addition to biomedical interventions- to promote effective leprosy control. There is a strong drive for structural social protection interventions for poverty related infectious diseases and evidence to support these policies can play an essential role in progress towards implementation.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Leishmania virulence factors and host peptidases associated with visceral leishmaniasis
Funder: Medical Research Council

Abstract: In Brazil, visceral leishmaniasis (VL) is caused by Leishmania chagasi. In this proposal we aim to investigate virulence factors and pathways contributing to pathology in visceral leishmaniasis by comparing organ specific responses to infection using animal models (UFRJ and UK) with natural infection in a clinical setting (UFPI). It is well established that neutrophils are important in establishment of infection with Leishmania and we have preliminary data indicating that the parasite virulence factor inhibitor of serine peptidase (ISP2) and the host serine peptidase neutrophil elastase (NE) influence infection of macrophages with L. donovani and that NE might link to bone marrow failure. We hypothesize that serine peptidases of the host are important for disease outcome in experimental VL. We aim to: (1) identify the underlying molecular mechanisms using L. chagasi and L. donovani mutants lacking ISP2 and gene deficient mice lacking NE and cathepsin G. (2) test if clinical L. chagasi isolates modulate host serine peptidases to influence infection in a similar way to L. donovani; (3) investigate the possible association between parasite genotype and disease presentation in Brazilian patients with VL, with a view to understanding whether the interaction between serine peptidases and parasite ISP2 plays a role in pathogenesis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Structure - Function Relationships in Protozoan Parasites Utilising High Resolution 3D Bioimaging
Funder: Medical Research Council

Abstract: There are 4 main research areas covered by this partnership. The partners will collaborate to produce an in-depth analysis of the flagellar pocket of T. cruzi and T. brucei. We think this is important as it is becoming clear from work that has been carried out by the UK and Brazilian partners that there are important differences, such as the presence of the contractile vacuole in T. cruzi, but also to share our knowledge on potential similarities such as the discovery of microtubule connections with the kinetoplast and this will be important to understand as the kinetoplast has been a focus for potential drug therapy. We will use a range of 3D microscopy techniques that are available at both partners including cellular electron tomography to produce a high resolution map of flagellar pocket structure and biogenesis. Serial block face scanning electron microscopy (SBF-SEM) and FIB-SEM will also be used to produce whole individual cell reconstructions, which is a very recent application development by the UK-PI, so that we can map division into the context of the whole cell (SBF-SEM) and obtain larger areas of the flagellar pocket at higher resolution (FIB-SEM). The UK-PI discovered 3 sets of microtubule connections to the kinetoplast and this will be investigated in both parasites to analyse if this is a common mechanism for the maintenance of the kinetoplast in these parasites. The UK partners will also develop new molecular tools for use in T. cruzi that has already been developed in T. brucei for high through-put endogenous tagging of cells and a novel genetic tag (APEX) for use in both parasites. In T. cruzi the contractile vacuole is associated with the flagellar pocket and undergoes dynamic changees during osmotic stress and is assoociated to acidocalcisomes. These 3D microscopy techniques also allow a dissection of the spatial organisation and quantification of acidocalcisomes following osmotic stress.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Discovering genes and functional pathways associated with American cutaneous leishmaniasis (ACL) caused by Leishmania brasiliensis.
Funder: Medical Research Council

Abstract: The study is designed to discover genetic risk factors for American cutaneous leishmaniasis (ACL) caused by Leishmania braziliensis in Brazil. A genome wide association study (GWAS) is proposed as follows: 1. A stage 1 discovery GWAS will be performed by genotyping 1123 ACL cases and 1122 unaffected controls for 547,644 single nucleotide polymorphisms (SNPs) using the Illumina HumanCoreExome beadchip, enhancing SNP information by imputation against a 1000 genomes reference panel, and carrying out association analysis using mixed models to control for relatedness and population substructure. 2. A stage 2 discovery GWAS will be performed by genotyping a second set of 1000 ACL cases and 1000 controls for 547,644 SNPs using the Illumina HumanCoreExome beadchip, enhancing SNP information by imputation against a 1000 genomes reference panel, and carrying out association analysis using mixed models to control for relatedness and population substructure. 3. Detailed immunological profiling and sample banking during prospective collection of a subset of stage 2 samples. 4. A meta-analysis of the data from the two discovery cohorts will be undertaken to formalise evidence for replication and enhance ability to detect weaker and/or rarer effects. 5. Second wave analyses of the GWAS output to look for evidence of pathways of genes acting as risk factors for disease will be validated functionally using data and samples acquired during phase 2 sample collection, including transcriptional profiling of lesion biopsy samples from individuals with risk genotypes. Overall, this proposal provides the first adequately powered study of genetic risk factors for American cutaneous leishmaniasis. Genes and pathways identified as risk factors for ACL may provide novel insights in pathogenesis of disease, seeding further research into the identification of novel therapeutic targets and with the potential to inform development of vaccines against this debilitating parasitic disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Dissecting the role of mycobacterial cell envelope components and DNA in leprosy reactions
Funder: Medical Research Council

Abstract: The aim of this UK-Brazil joint research grant is to delineate the molecular basis of reactional episodes in leprosy patients. We will specifically examine the potential role of the inflammasome pathways and the involvement of M. leprae cell envelope components and DNA in triggering the reactional episodes. The main objectives of the study are: Objective I: The UK Team (UoB) will define diagnostic lipid and cell envelope component profiles of standard M. leprae, surrogate M. haemophilum and leprosy biopsy material and assess the persistence of these in leprosy biopsies. Objective II: The Brazil Team (FIOCRUZ) will investigate in biopsies of reactional skin lesions levels of M. leprae DNA, the phenotype of immune cells composing the inflammatory infiltrate and markers of inflammasome activation. Objective III: To use well-established extraction and purification protocols at UoB to provide specific cell envelope components for further studies in Objective IV by collaborators at FIOCRUZ. This will include M. leprae components (e.g. PGL, PDIM, mycolic acids, muropeptides), including available previously purified material by the UK team and through BEI Resources (e.g. whole cells, LAM). Since, leprosy bacilli are uncultivable, M. haemophilum, a related surrogate of M. leprae, will also be used as a source of structurally-related M. leprae-type lipids and LAM for bulk purification. Objective IV: To investigate by multiplex analysis the profile of inflammatory mediators secreted by whole blood samples of reactional patients in response to mycobacterial components identified in Objective I and prepared in Objective III. Use functional in vitro studies with purified mycobacterial components in order to investigate their capacity to activate inflammasome pathways in in vitro differentiated macrophages and dendritic cells. Truncated versions of the active molecules will also be tested to map their functional moieties.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The Dengue vector Aedes aegypti: Microbiota and the Chemical Ecology of Oviposition sites
Funder: Medical Research Council

Abstract: Estimates of population boundaries and mosquito dispersal have previously required mark-release-recapture experiments, where thousands of mosquitoes are radioactively labelled or marked with fluorescent dye before release. Often only a handful of mosquitoes are recaptured and this technique is plagued by a plethora of technical problems, and massive releases of vectors of disease bring ethical issues, often producing poor data. In contrast, from preliminary data obtained in a study of malaria vectors in Burkina Faso, it has been demonstrated that we can clearly assess the spatial dynamics in population distributions of An. gambiae mosquitoes. On the basis of the bacterial flora obtained from 30 mosquitoes from 3 villages within flight distance (2 km) we found clear patterns of movement of individuals in local populations within a meta-population network. We now want to expand and verify the technology developed in one country by performing a follow-up study in another country. Knowing the movement patterns of vectors will provide new knowledge which better allows control measures to be focused and applied. The development of ovitraps has been an area of interest in the control of malaria vector mosquitoes. The techniques of headspace collection and the use of odour dispensers are well developed, particularly within NRI labs. The tight spatial arrangement of hosts, breeding sites and resting sites for Dengue vectors presents a different scenario to the pattern for Anopheles species, which move through much larger areas. It is likely that the patterns of movement of Ae aegypti may be even more amenable to control than An. gambiae. Also, the successful application of techniques to identify malaria mosquito oviposition stimuli to Dengue vectors is highly attractive, and the urban setting of these species makes ovitraps a realistic tool to deploy within integrated vector control systems. These are techniques that are mature and are ripe for wider application.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Metabolic adaptation and nutrient acquisition of Paracoccidioides spp. during host interactions: Search for targets and new therapeutic approaches
Funder: Medical Research Council

Abstract: Previous proteomic analyses on strains from four different P. brasiliensis subspecies (S1, PS2, PS3 and 01-like) implied significant differences in metabolic physiology. As an example, Pb01 tends to display increased fermentative capacity. Resistance to oxidative stress appears more developed in Pb01, Pb2 and Pb339, whereas the pentose phosphate pathway is strongly represented in Pb2. Furthermore, antigenic proteins, such as GP43 and a 27-kDa antigenic protein were less abundant in Pb01 and Pb2. These data and their impact on virulence will be analysed in more detail. Transcription profiles will be recorded by qRT-PCR from selected strains during the dimorphic switch and data will be correlated with determination of enzymatic activities. Key enzymes will be heterologously expressed either in prokaryotic or eukaryotic expression system. These enzymes will be used for comparative biochemical characterisations to identify species-specific differences and will subsequently be used to screen for specific inhibitors from natural product libraries. To test for the importance of distinct metabolic pathways antisense constructs will be generated to silence these pathways in P. brasiliensis. Transformation will involve a DNA transfer via Agrobacterium tumefaciens. Furthermore, a constitutive luciferase expression system will be simultaneously integrated. By flanking the silencing construct at one border with the resistance marker and at the second border with the luciferase construct a rapid assessment of clones with integration of the complete transformation cassette will be possible. Proteome profiles will be recorded to determine the changes induced by gene silencing. The transformation procedure will generate bioluminescent strains that will be suitable for in vivo imaging of disease progression in murine infection models. This allows assessment of attenuated virulence and enables drug efficacy studies in murine infection models.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION