NIHRDataInsights/HRCSData huggingface dataset:
Title: The effect of population structure on the evolutionary dynamics of HIV.
Funder: Wellcome Trust

Abstract: AIDS has a devastating effect on communities around the world. A major obstacle in our fight against the disease is the incredibly fast rate that HIV evolves. Whatever drugs we use, the virus eventually evolves a way to escape their effect. Another obstacle, the importance of which has only recently been appreciated, is the way in which the virus is structured within the body. Although a large proportion of the viral population is vulnerable to the patient s immune system and the drugs she t akes, some virus particles reside in areas of the body where the drugs don t reach them. Consequently, although viral numbers might get very low during a course of antiretroviral therapy, the virus is never eradicated and can bide its time until a new drug resistant mutant emerges. During the Fellowship I will develop mathematical models of HIV evolution that take this kind of population structure into account, something that has been missing from almost all models so far. By doing so my goa l is to better understand how the virus will evolve in the face of different drug therapy and prevention regimes, ultimately enabling us to make better informed public health decisions.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Community-wide TB case-finding linked to a nested cluster-randomised trial of promotion of HIV-testing and prevention of HIV-related TB in Blantyre, Malawi.
Funder: Wellcome Trust

Abstract: The key goal is to identify public health interventions that are able to achieve rapid reductions in the incidence of TB within a few years in high HIV prevalence urban setting. We will be investigating two ways of controlling TB: first providing access to TB diagnosis at community-level through outreach services once every 6 months, which gave promising results on control of undiagnosed TB in a previous trial. Secondly we will investigate whether or not HIV-related TB can be controlled by targeted interventions to provide treatment of latent TB infection through a 6 month course of drugs, and prompt referral to routine HIV care services for treatment of HIV with antiretroviral therapy. This will require a community-based HIV testing strategy as well. A cluster randomised trial deign will be used, including 16,800 individual in the intervention arm. Services will be delivered by community workers and will include the option of supervised self-testing for HIV. We will provide community-distribution targeted interventions to prevent TB and referral for facility-based antiretroviral therapy. The key goals will be to reduce the incidence of TB, and define the acceptability of the HIV testing strategy.


Research activity codes: 4.4 POPULATION SCREENING;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Structural and functional analyses of the bunyavirus ribonucleoprotein complex.
Funder: Wellcome Trust

Abstract: Bunyaviruses are a group of viruses that cause serious or lethal human diseases for which treatments are not available. To develop these treatments, we need to gain a better understanding of how bunyaviruses multiply. Bunyaviruses are made from tiny building blocks that fit together precisely. One of these blocks is the nucleocapsid protein, and we know it interacts with four other blocks within the virus. These are the viral genes, the viral polymerase, other nucleocapsid proteins, and the vira l glycoproteins. These interactions are needed to allow the virus to multiply and cause disease, and we want to understand how they occur. To do this we will engineer small changes into the nucleocapsid protein, and test whether these changed proteins can still perform these interactions. To make this work more accurate, we will use a technique called X-ray crystallography to reveal the shape of the nucleocapsid protein in three dimensions and show us how best to change it. When complete, this i nformation will show how individual features of the nucleocapsid allow it to perform the four interactions described above. This information may also reveal how the interactions may be disrupted, and thus help design drugs to prevent bunyaviruses from causing disease


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Activity and structure of trypanosome metacaspases.
Funder: Wellcome Trust

Abstract: Human African trypanosomiasis is a fatal disease found in sub-Saharan Africa caused by the parasitic protozoon Trypanosoma brucei. The disease has severe costs in both health and economic terms and drain resources that could be used to promote growth of developing nations. There are no effective vaccines against the disease and chemotherapy is the prime means for reducing the disease burden. Unfortunately the existing drug treatments have many limitations and new drugs are desperately needed. One approach to developing new drug treatments is rational drug design, where chemical compounds are designed to inhibit l proteins found in the parasite, but not in humans. One possible such protein is the metacaspase, an enzyme that digests other proteins. Metacaspase proteins are not found in humans but only in parasites such trypanosomes, fungi and plants. In this project we aim to determine the three dimensional structure of a family of metacaspase proteins, using X-ray crystallography. Information gained on the 3D structure will help us understand how metacaspases enzymes work. An expected outcome would be to obtain knowledge on how chemicals prevent the activity of metacaspases, which could lead to the development of new drugs.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Genes affecting intraerythrocytic cell cycle length in Plasmodium falciparum.
Funder: Wellcome Trust

Abstract: Our aim is to identify genes in the human malaria parasite Plasmodium falciparum that determine the parasite's growth rate in erythrocytes and mosquitoes. Parasite lines differ in their rate of mitotic replication in both vertebrate and invertebrate hosts. Within erythrocytes, the intra-erythrocytic cycle time, the number of daughter cells produced per cycle, and the efficiency of invasion of daughter merozoites into new erythrocytes vary. Within mosquitoes, differences in mitotic divisio n within oocysts result in differing numbers of sporozoites. We will determine which parasite genetic loci contribute to mitotic growth rate differences. We will use quantitative trait loci (QTL) analysis of a genetic cross between two parasite clones to identify loci determining differential rates of growth, using dense genetic maps of progeny clones. Our goals are to identify how many loci contribute to growth phenotypes, their relative contributions, and if the same loci contribute to phenotypes in the vertebrate and invertebrate host. We will locate the contributing loci on a genetic map (and in the genome) of the parasite. Candidate genes will be identified within the major loci detected. Finally, we will investigate the frequency of polymorphisms within loci contributing to intraerythrocytic growth in samples taken from Kenyan patients with hyperparasitaemia.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Genetic analysis of growth rates in Plasmodium falciparum.
Funder: Wellcome Trust

Abstract: Malaria affects 40% of the world's population, and kills over a million children each year. New disease control methods are urgently required. Different strains of Plasmodium falciparum, the most lethal human malaria parasite, multiply at different rates in human hosts, and in mosquitoes. Fast growth in humans is associated with more severe forms of the disease. This project aims to find the parasite genes responsible for these differences in parasite growth rate. Our goal is to identify t he genetic differences between two parasite lines that differ in their growth rates in humans and mosquitoes. The two lines have been mated to produce many offspring. We will use a technique called linkage analysis, which identifies genes causing a particular characteristic (e.g. infectivity) by associating it with inheritance of DNA in the offspring of two parents. All offspring with the characteristic of one parent will share common DNA (genes) that cause the characteristic with each other and that parent. This DNA is not shared with the other parent, nor with any offspring without the characteristic. By comparing the DNA of offspring parasites with 'fast' and 'slow' growth, we can identify regions of parasite DNA (genes) which account for differences in growth.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Regulation of helminth-driven intestinal inflammation.
Funder: Wellcome Trust

Abstract: Infections with gut-dwelling worms are extraordinarily common. They cause feelings of ill health and represent a significant cost to society. Most infections are long term, lasting for years. During this time the parasitic worms damage the gut. As part of the immune response to infection the gut becomes inflamed and cells of the immune system enter the damaged tissue from the bloodstream. It is vital that mechanisms are in place to allow the development of inflammation, to limit the damage respo nse, and to repair the damage when the infection has gone. We have evidence showing that one of the cell types in the intestine, the macrophage, orchestrates the development of inflammation. We also have evidence that the breakdown products of vitamins and fats generated during the inflammation, signal to cells via special receptors inside cells, to limit the damage caused by infection-driven inflammation. The focus of my grant proposal is to understand the role played by macrophages and the intracellular receptors in the development, regulation and resolution of gut damage. This new knowledge will inform future treatment programmes to control the pathology associated with worm infections and other diseases which feature inflammation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: ROAD-MAP: a repository for open access data collected by the Malaria Atlas Project.
Funder: Wellcome Trust

Abstract: Malaria control is central to improving child survival in the developing world. The Malaria Atlas Project (MAP), funded by the Wellcome Trust since 2005, was founded to provide the scientific evidence-base to map the extent and intensity of malaria risk worldwide. These maps allows the assessment of whether proposed tools to control transmission are adequate and help monitor progress in countries receiving international financial support. MAP has been successful in providing this evidence throug h publications in open-access peer-reviewed scientific journals. MAP must now expand to meet the challenges of assembling new information as risks change with time and to meet increasing demand for access to the data. Making these data available will increase their scientific application and allow new areas of basic and applied epidemiological research to evolve. The MAP database resource is a unique, carefully curated and spatially-linked assembly of parasite, vector and inherited blood disorde r survey data linked to other national administrative and population information across all malarious countries. Here we propose to create a Repository of Open Access Data (ROAD) of information assembled by MAP that is rigorously assembled, documented and formatted, for use by a wide variety of scientists involved in supporting malaria control worldwide.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Development and validation of field adapted anti-infective drug assays primarily for infants and young chidlren.
Funder: Wellcome Trust

Abstract: Most of the million deaths from malaria each year occur in infants and children. Other infections such as pneumonia, TB and HIV take an even greater toll. These vulnerable patients need the very best drug treatments, but what they receive is often inadequate. This is because the doses chosen are extrapolated from studies in adults. Infants and young children are usually excluded from clinical studies to optimise dosing because of the difficulties in taking repeated blood samples in the conventi onal way. Many guardians refuse venous blood sampling on behalf of their young children. Furthermore itis often simply too difficult taking and storing venous blood samples in remote areas of the tropics. We aim to solve these problems by developing andvalidating low volume, high throughput methods for the accurate measurement ofantimalarial and other anti-infective drugs in dried blood spots. These can betaken anywhere (and at the same time as the routine malaria smear is performed). The s amples can be stored anywhere without requirement of freezers, and even sent in the ordinary post. This will allow these essential drugs to be evaluated properly and for optimal drug regimens to be developed, particularly for the very young.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: New childhood vaccines for Malawi: Impact of a national pneumococcal and rotavirus vaccine roll-out on child mortality and disease burden, in a region of sub-optimal strain coverage.
Funder: Wellcome Trust

Abstract: Acute respiratory infections and diarrhoeal diseases are leading causes of childhood illness and death worldwide. Malawi is about to introduce conjugate pneumococcal vaccine and live, oral, rotavirus vaccine into its national childhood immunization schedule. Although these vaccines have been shown to be efficacious in clinical trials, vaccine effectiveness, indirect herd protection effects, serotype replacement and synergy between the vaccines, have not been assessed in high disease-burden setti ngs in Africa. This project aims to: a) Quantify the public health impact of sequential pneumococcal and rotavirus vaccine introduction on all-cause under-one and under-five mortality and disease-specific morbidity b) Examine serotype-specific vaccine effectiveness c) Measure the extent of herd protection for unvaccinated children and adults d) Detect and quantify serotype replacement disease and e) Detect change in the epidemiology of disease (ie age of peak infection, disease sever ity). We will undertake cohort and case-control studies at three Wellcome-trust funded sites in Malawi: Blantyre (urban), Mchinji (rural high density) & Karonga (rural low density). The combined surveillance populations of Karonga and Mchinji (~440,000) will enable us to document vaccine impact on all-cause childhood mortality. This initiative will critically inform further vaccine delivery in Africa and provide a framework for further population-based research.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: An evidenced based platform for the wider utility of serological analysis in malaria control and elimination.
Funder: Wellcome Trust

Abstract: Whilst recent high-profile calls for global malaria eradication might be overly ambitious given the currently available tools, elimination of malaria from areas of low transmission ( shrinking the malaria map ) is eminently feasible. Identifying sites for elimination, and measuring the impact of elimination activities, depends on being able accurately to measure how much malaria there is. At low endemicity, which will inevitably be encountered if elimination attempts are successful, conventiona l measures of transmission intensity are highly inaccurate. We have shown that the proportion of individuals in a population with anti-malarial antibodies in their serum is a highly sensitive and specific indicator of malaria transmission intensity. The aim of this project is to develop our serological assay into a practical tool which can be readily implemented around the world to measure malaria transmission. We will refine the current assay, particularly to measure transmission rates for diff erent species of malaria - which can occur in the same communities but which may have different requirements for control; field test the revised assay across Africa and south-east Asia to extend the evidence base for this approach; and engage in dialogue with stakeholders to ensure rapid implementation of serological tools into global malaria monitoring activities.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: INFECTION
Title: TB Meningitis: intensified treatment with rifampicin and levofloxacin to reduce mortality: TBM-IT.
Funder: Wellcome Trust

Abstract: Tuberculous meningitis (TBM) is the most severe of tuberculosis with a mortality of 50%. Treatment for TBM is based on regimens used for lung TB. However, the commonly used drugs for TB have varying ability to get into the brain. Rifampicin, the key drug for the treatment of tuberculosis, penetrates into the brain poorly. We hypothesize that the high mortality of patients with TBM is due to the lack of sufficient anti-tuberculosis drugs in the brain. Increasing the dose of rifampicin is relative ly safe, will result in higher levels of the drug in the blood and in the brain. Our data show that one of the second-line drugs for the treatment of TB, levofloxacin, penetrates the brain extremely well. Levofloxacin is very well tolerated by patients. We propose to investigate an enhanced treatment regimen for TBM. In this trial the control-group will receive standard treatment for TBM, the intervention-group will receive the same standard treatment plus a higher dose of rifampicin and levoflo xacin. We will compare the survival of all patients at 9 months. Our primary aim is to improve survival and secondly to reduce disability and monitor safety of the treatment.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Does treatment of invasive and persistent non-typhoid Salmonella in HIV-infected African adults cause evolution of antibiotic resistance?
Funder: Wellcome Trust

Abstract: Multi-drug-resistant non-Typhoid-Salmonella (NTS) are a serious, emerging infection in HIV-infected African adults. In Blantyre, Malawi, NTS are a common cause of bacteraemia with a 25% case-fatality. Survivors are at high risk of recrudescence of invasive NTS (iNTS), necessitating multiple courses of ciprofloxacin, yet the sanctuary site of persistence remains unknown. Resistance (MIC) to ciprofloxacin has risen gradually since it was introduced in 2002, and threatens to spread among NTS and ot her major pathogens. Recent high-throughput whole-genome sequencing has shown that novel epidemic iNTS strains in Sub-Saharan Africa have become more human-adapted, with genetic similarities to S.Typhi. A cohort of HIV-infected adults with iNTS and their spouses will therefore be recruited to: 1) Evaluate mechanisms of persistence and clinical outcomes of iNTS, in the era of rapid anti-retroviral(ARV) roll-out 2) Investigate how iNTS persistence influences the emergence of fluoroquinolon e resistance following repeated ciprofloxacin treatment 3) Determine how iNTS persistence influences further NTS human-adaptation and microevolution. These data, including high-throughput sequencing and SNP-typing of isolates, will inform the design of alternative interventions that prevent episodes of iNTS without promoting antibiotic resistance; and generate locally-implementable molecular tools to further understand the dynamics of molecular evolution of epidemic MDR-NTS in individuals an d populations.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Mechanism and inhibition of chitin synthesis.
Funder: Wellcome Trust

Abstract: In the EU alone millions of patients are hospitalized annually for (cancer) chemotherapy, organ transplants or AIDS treatment. 25% of these people suffer during their treatment from fungi infections such as Candida albicans and Aspergillus fumigatus. Current drugs are not sufficiently treating those severe infections that can become lethal. Hence, there is a growing and urgent requirement to identify new antifungal targets. Only a few drug targets are known to tackle those fungal infections. One target is the so-called chitin synthase. This protein produces an essential component of the fungal cell wall, which is not found in humans. If we can target specifically this fungal protein, this will stop the fungi grow in the infected human tissue. Therefore this protein is a good target for the discovery of new drugs. My aim is to produce this protein (key goal) and to determine the structure and mechanism (key goal). This will help to understand how current, weak drugs work against chitin synthase. Based on structural data, these drugs could be optimised. I also aim to identify new potential lead for antifungal drugs (key goal) and to test, whether they are able to stop fungal cell growth (key goal).


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Optofluidic microscopy for portable low-cost malaria diagnostics.
Funder: Wellcome Trust

Abstract: Malaria is a devastating disease causing more than a million deaths each year, mostly among young African children. When diagnosed, it can be treated but reliable diagnostic tools to monitor a person s health are very limited in many areas affected by malaria. Microscopy of infected blood samples is the gold standard for diagnosis, but conventional microscopy requires trained personnel and lab infrastructure not available to many people who live in remote rural areas. I propose to overcome this limitation by using novel lens-free microscopes of the size of a fingertip, based on a new field of technology called optofluidics. The goal of my project is to develop optofluidic microscopes suitable for easy, portable diagnosis of malaria. I will then assess and improve the performance of such diagnostic microscopes under real-world conditions in Africa. If successful, my project will result in the development of a new portable, low-cost, easy-to-use and reliable diagnostic test for malaria in developing countries. This would enable correct treatment, prevent deaths of infants and young children and ultimately decrease the burden of malaria.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFECTION
Title: Unraveling the dynamics of rapidly evolving infectious diseases in humans with Approximate Bayesian Computations.
Funder: Wellcome Trust

Abstract: With the world-wide spread of HIV and the re-emergence of eradicated pathogens, faith in the effectiveness of public health programs has been dwindling. One crucial problem of efforts targeted at improving public health is that many viral pathogens are evolving rapidly, thus re-juvenating persistently, and turning drugs and vaccines quickly ineffective. Many variants of these viruses coexist at any time, with each variant challenged by different levels of host immunity. As time progresse s, new mutations and the history of pre-existing immunity in the population render the resulting virus dynamics extremely complicated. Recent technological advances are now delivering data on the immunogenic properties, the genetic diversity and the ancestral relationship of these variants, which together with case data hold the potential to unravel the dynamics of REIDs [1,2]. But these data are bewilderingly heterogeneous, making it difficult to write down a formula for the probability of a ll the data (the likelihood ) under specific assumptions on the nature of REID dynamics. Unfortunately, most statistical methods for the analysis of REIDs require that the likelihood can be computed. ABC circumvents likelihood evaluations altogether, relying solely on efficient simulations of REID dynamics. This should make ABC broadly applicable to study REID dynamics rigorously.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION