NIHRDataInsights/HRCSData huggingface dataset:
Title: Functional Proteomic Analysis of the Ubiquitin Pathway During Malaria Infection.
Funder: Wellcome Trust

Abstract: The ability of the malaria-causing parasite, Plasmodium falciparum, to evade the host s immune system and rapidly develop drug resistance has long plagued vaccine development and drug design for this disease. New approaches to parasite control are therefore essential. Here, I propose to study the ubiquitin pathway in both parasite and host in an effort to identify novel drug and vaccine targets. Ubiquitin is a small protein modifier that is implicated in many aspects of cell survival. The mec hanisms which control the dynamic addition and removal of ubiquitin from target proteins has been conserved throughout evolution and is important to all organisms ranging from parasites to humans. Although components of the ubiquitin cascade have been successfully targeted in humans for the treatment of cancer, this pathway has been largely overlooked in the context of infectious diseases. Since several pathogens express proteins capable of interfering with the host s ubiquitin machinery, it stands to reason that Plasmodium parasites may also encode such molecules. By using ubiquitin as a marker, my goal is to better understand the fundamental immunological changes induced in the host during infection as well as the role of ubiquitin in Plasmodium biology to identify novel drug and vaccine targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The demography, population genetics and genome evolution of viral pathogens in an innate immunity model.
Funder: Wellcome Trust

Abstract: Immune systems drive the evolution of pathogens: any pathogen strain that escapes or overcomes host immunity has an advantage over its competitors and will spread. Studying the co-evolutionary process between the immune system and pathogens is important, as it might help us to understand how, why, and when, infectious diseases occur. The effect of our adaptive immune system (which learns to recognize pathogens) is relatively well studied, but we know less about evolution in response t o other types of immunity. For example, although the fruit-fly (Drosophila melanogaster) is one of our best models for the innate immune system, we know very little about its pathogens. I will use population-based methods to study virus evolution in Drosophila, allowing me to see how viral genomes are shaped by coevolution with the innate immune system. By using a model system such as Drosophila to study disease, I hope to gain insights without the same complexity, cost, safety and ethic al concerns that comes with using human diseases. Specifically, I will ask questions relating to the population biology of Drosophila viruses, and how viral genomes evolve. I will also discover new Drosophila viruses, which will provide an important resource for future work on pathogen evolution.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Mechanisms of persistence of B. pseudomallei.
Funder: Wellcome Trust

Abstract: Melioidosis, caused by the Gram negative bacterium Burkholderia pseudomallei, is an often fatal disease of humans and animals. Human melioidosis is characterised by a profound difficulty in eradicating the pathogen either via the immune response or by antibiotics. Our hypothesis is that the ability of B. pseudomallei to establish a persistentinfection is central to the inefficiency of current antibiotic treatment, the susceptibility of individuals to re-infection and the difficulties associated with vaccine development. If the molecular basis of persistent infection was understood this would allow new pretreatments, therapies and diagnostics for melioidosis to be established and would address fundamental questions in the biology of persistent infection caused by bacteria. Our aims are to; i) Identify B. pseudomallei genes associated with chronic disease in humans and in mice ii) identify B. pseudomallei genes associated with the appearance of metabolically inactive (persister) cells in vitro which are resistant to antibiotics iii) construct bacterial mutants lacking genes identified in Aims 1&2 and assess their virulence and susceptibility to antibiotic treatment in a murine model of infection iv) investigate ways in which chronic or persistent infection might be more effectively controlled by antibiotics


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The biosynthesis of glycoproteins in Trypanosoma brucei: basic and translational research.
Funder: Wellcome Trust

Abstract: Trypanosomes and humans are both eukaryotes , which means we have a lot in common with respect to the fundamental biochemistry and cell biology that keeps us (and them) ticking. However, the huge evolutionary distance between the trypanosome parasite, that causes African sleeping sickness, and the human host means that there are also exploitable differences. We aim to establish the details of how the parasite constructs and uses molecules called glycoproteins (proteins with sugar chains att ached to them). We are interested in this because the parasite s glycoproteins are used to protect them from the human immune system. Therefore, if we can make compounds that are not toxic to humans but that selectively interfere with the assembly of the parasite glycoproteins, we should be able to produce useful and badly needed medicines for this devastating disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Therapeutic CD8+ T cell-biased vaccines for human visceral leishmaniasis.
Funder: Wellcome Trust

Abstract: The Leishmania parasite is responsible for visceral leishmaniasis, a disease largely of the world's poorest nations and responsible for an estimated 250,000 deaths annually. The development of a vaccine is a major international research priority. Although most vaccines are given to prevent infection, we aim to develop a therapeutic vaccine. Initially, this will be used together with drugs to improve how they work, reduce their side effects, and prevent drug-resistance. If successful, it may replace the drugs. From over 10 years of research, we have identified two parasite molecules which induce good protective immune responses in animals. We have also identified the type of immune response that gives best protection and from the work of others, we know that this can be stimulated in humans by using a harmless virus to deliver the vaccine. In this study, we wish to identify the best molecule / virus combination, and then to have this vaccine manufactured under the strictly controlled conditions required for a human medicine. We will then confirm that the vaccine is safe by testing it in UK volunteers. This study is an essential step in the process of developing a new vaccine, to reduce deaths from visceral leishmaniasis.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Activation of type 1 fimbriation by SlyA, NagC and NanR.
Funder: Wellcome Trust

Abstract: E.coli is a common resident of the human large intestine where most strains of the bacterium do not cause disease. However some pathogenic E.coli are also able to grow in the urinary tract, leading to diseases that range from mildly debilitating to life-threatening. Nearly all strains of E.coli - whether pathogenic or not - produce adhesins that allow them to attach to cells of the body. Although by themselves not thought to be sufficient to cause ill health normally, adhesins are nevertheless critical for pathogens to cause disease. Mammals possess defence mechanisms that recognise and respond to bacteria, and adhesins are an important bacterial component that activates these responses. In a population of bacteria, only some individuals produce a particular adhesin at any time, and we have found recently that two chemicals found naturally in animals and humans (abbreviated to Neu5Ac and GlcNAc) affect this process. We propose to investigate (i) how Neu5Ac and GlcNAc affect the produ ction of one important adhesin (the type 1 fimbriae ), and (ii) the potential importance of this process in the ability of E.coli to cause disease in humans. This will enhance our understanding of how E.coli causes infections, and could lead to new treatments.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Kinesin motor proteins in malaria.
Funder: Wellcome Trust

Abstract: Over 1 million people die from malaria every year and over 300 million are infected with the parasite that causes the disease. Very few drugs kill the malaria parasite and some parasites are completely drug-resistant, so new malaria treatments are urgently needed. We want to study an aspect of the malaria-causing parasite which is not very well understood because we think this could provide new information about ways to kill the parasite. We are interested in the parasite cytoskeleton: in the sa me way that our bodies have skeletons that support us and help us to move, parasites have a skeleton the cytoskeleton that helps perform tasks that keep the parasite alive. Tiny machines inside the parasite, called kinesins, help control and organise the cytoskeleton and we are planning to study these kinesins in malaria. We will use bacteria to prepare fragments of the kinesins so we can study their properties in the test tube. We will also try to discover where kinesins are found inside th e parasite. Together these experiments will tell us about the jobs that kinesins perform and if drugs against kinesins could be used to kill the parasite and therefore be used to treat malaria.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The Biochemistry and Cellular Role of Rv1636, a Universal Stress Protein from Mycobacterium tuberculosis.
Funder: Wellcome Trust

Abstract: Tuberculosis, resulting from infection by the bacterium Mycobacterium tuberculosis, causes approximately 3 million deaths per annum. There is a need to understand fundamental aspects of its biology to underpin attempts to find new treatments. The bacterium has a remarkable ability to endure attack by the immune system and it is able to survive in a persistent, non-infectious form in the lung for many years following infection. Subsequent changes in the patient s health can lead to reactivation of the disease. We wish to understand how these bacteria are able to remain inactive for long periods in the body without causing disease. We have identified a class of protein called Universal Stress Proteins, which we believe have a role M. tuberculosis persistence. Despite there being more than 2500 examples of USPs in nature, their role in the cell is not known. We have shown that a USP from Mtb, called Rv1636, acts on RNA. Therefore, we propose and will test in this research project wh ether Rv1636 plays a role in maintaining the function of crucial RNA molecules involved in protein synthesis and so promote the survival of Mtb when it is unable to grow, such as during its latent infection.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Genetic and phenotypic characterisation of emerging virulent Clostridium difficile.
Funder: Wellcome Trust

Abstract: The current epidemic of C. difficile-associated disease has been accompanied predominantly by the emergence of two clonal groups of 027 and A-B+ strains that are associated with increased disease severity. We recently compared genome sequence data from historical non-epidemic and contemporary epidemic 027 and A-B+ strains and identified several genetic regions of difference that could explain the emergence of the epidemic phenotype. In parallel studies, assays have identified significant pheno typic differences between non-epidemic and epidemic 027 strains. In this study we will determine the genetic and phenotypic attributes that could explain the emergence of epidemic strains. This will include the rigorous characterization of epidemic strains and respective mutants using relevant in vitro and in vivo assays. In complementary studies, comparative phylogenomics, MLST analysis and SNP typing will be used to establish an evolutionary framework for C. difficile strains. This analysis wi ll help to (i) determine the distribution of newly found virulence determinants, (ii) trace the origin of 027 and A-B+ strains and (iii) predict the emergence of further epidemic clones. The two lineages of epidemic C. difficile provide a unique opportunity to study the recent emergence of hypervirulent bacteria and improve our general understanding of the evolution of bacterial virulence


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Impact of urbanisation on malaria vectors population dynamic in two major cities of Cameroon .
Funder: Wellcome Trust

Abstract: Malaria remains a major public health problem in Africa especially in sub Saharan Africa rural areas. However, many factors linked to a rapid and uncontrolled urbanisation are increasing malaria transmission in cities across Africa. In Cameroon, unplanned urbanisation during the last decades has profoundly influenced malaria epidemiology in the two largest cities of the country. In this project, I will investigate the factors facilitating the adaptation of malaria vectors to urban environments i n Douala and Yaound , and assess the impact on malaria transmission, vector ecology and the development of resistance to pollutants and insecticides. I intend to: - Study the ecology of malaria vectors and establish a map of the spatial distribution of breeding sites to guide potential larviciding activities in these two cities. - Establish the susceptibility status of malaria vector populations to insecticides in relation to the high level of pollutants in breeding sites and also to the commo n use domestic and agricultural insecticides in these cities. - Investigate the molecular basis of insecticide resistance mechanisms and patterns of cross resistance between xenobiotics found in the breeding sites and insecticides. - Investigate the interaction between resistance to insecticides or pollutants and the vectorial capacity of malaria vectors.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Using modelling to explore the transmission dynamics of HIV among men who have sex with men in a southern Indian setting.
Funder: Wellcome Trust

Abstract: Men who have sex with men (MSM) in southern India can be divided into identities associated with whether they usually take the insertive or receptive role during anal sex. Many MSM have sex with men without exchanging money, and some identities typically either sell or buy sex from other MSM or female sex workers. Over a third of MSM also have sex with women, which is more common among some identities than others. These different behaviours affect a man s chance of becoming infected with HIV. However, little is known about the importance of these different behaviours in accelerating, sustaining or limiting the spread of HIV among MSM, or onto their female partners. The key goal of this research is to understand the importance, for HIV transmission and prevention, of the different behaviours of the MSM identities. This will be achieved by using mathematical equations and computer simulations of the spread of HIV, along with recently collected local data, to explore the role of these i dentities in accelerating, sustaining or limiting the spread of HIV among MSM themselves and, through sex with women, into the wider population. The implications for HIV prevention among MSM in this setting will be investigated.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Mechanisms and consequences of interferon induction by influenza viruses.
Funder: Wellcome Trust

Abstract: Although severe effects of influenza virus infection are usually only seen in the elderly and infirm, sometimes it causes death in young children who seemed previously healthy. Currently there is public concern because a bird flu strain, H5N1, has infected over 300 humans and more than half of them have died. The purpose of this work is to understand why some influenza infections cause more severe disease than others. We hypothesize that some strains of influenza virus can stimulate such a lar ge immune response that it does more harm than good. Using viruses isolated from real influenza cases, we will document how the host cell responds to each different strain, and ask whether that correlates with the severe outcomes. We use real human tissue as well as the best animal models for our work. The results will help decide whether immune therapies will be worthwhile if the current H5N1 bird flu transforms into a pandemic. They will also tell us what to look out for as the virus cont inually evolves that would herald a particularly bad year for flu cases. Finally, we can ensure that new vaccines are as safe as they should be.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Training Health Researchers into Vocational Excellence in East Africa
Funder: Wellcome Trust

Abstract: 1. Develop and sustain a consortium functioning as a strong network by: i. Exchange of staff ii. Developing collaborative research projects iii. Regular communication between consortium members iv. Adjunct appointments of senior research scientists v. Joint academic programmes attended by trainees from THRiVE vi. Joint annual meetings vii. Joint supervision of PhD students 2. Empower institutions to build a critical mass of well trained research scientists capable of winning competitive national and international grants i. Mount modular short courses. These will contribute towards PhD and Masters training. ii. Enhance quality of masters training at KCMC (with emphasis on epidemiology, biostatistics and clinical trials), Gulu University and National University of Rwanda iii. Establish, and model, high-quality systems for selection, supervision and mentorship of fellowships/internships: ? Undergraduate internships ? Masters fellowships ? PhD training ? Post-doctoral fellowships 3. Augment the development of a conducive institutional environment i. Improve electronic communication, maintain website and facilitate high-speed internet access ii. Ensure availability of basic and advanced laboratory facilities iii. Identify/support key senior positions for supporting research training and mentoring 4. Support systems for improved governance/management of research activities i. Strengthen research administration and resource mobilization at participating institutions ii. Establish staff development programmes


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: INFECTION
Title: African SNOWS; strengthening research capacity in environmental health.
Funder: Wellcome Trust

Abstract: To consolidate the gains of SNOWS in the internal capacity building process inresearch training, research management, proposal development, and financial management. Further refining of the SNOWS model of sustainable capacity building resulting in more African-led initiatives is envisaged to strengthen the consortium in international bids. The efforts at joint research in water supply, sanitation and environmental health shall be strengthened and the young academics mentoring process throughSNOWS scientific conference shall also be consolidated.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: One Medicine Africa- UK Research Capacity Development Partnership Programme for Infectious Diseases in Southern Africa.
Funder: Wellcome Trust

Abstract: To develop SACIDS as a Regional One Health Research Platform for Infectious Diseases in Africa through human -animal health research engagement and capacity strengthening across universities and research institutes


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFECTION
Title: Systematic analysis of essential parasite genes linked to invasion of the host cell in Toxoplasma gondii.
Funder: Wellcome Trust

Abstract: Toxoplasma gondii is an obligate intracellular parasite that is closely related to Plasmodium falciparum, the causative agent of malaria. In order to survive these parasites need to invade the host cell. These parasites evolved an unique machinery for this process. I am interested in the formation, maintenance and regulation of this complex machinery to gain more insight into the fundamental mechanisms involved in host cell invasion. Hopefully this research will also lead to the identification of novel drug targets that are urgently needed. To do so my research uses powerful genetics in T.gondii that allows a detailed functional characterisation of factors believed to play a role in host cell invasion. We previously demonstrated that parasites mutated in some of these factors are indeed unable to invade the host and can be used as experimental vaccines. In this proposal I aim to perform a systematic, functional analysis of important parasite genes. Therefore we combine bioinformati cs, reverse genetics and biochemistry to: - Generate and analyse parasite mutants unable to invade the host cell - Establish an open access database of characterised genes of interest (GOIs) as a community resource - Screen for chemical inhibitors (drug development) for the most promising GOIs


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Population genomics of the Neisseria: evolution of commensalism and virulence.
Funder: Wellcome Trust

Abstract: Many bacteria that cause human disease are very diverse, a property that makes the development of drugs or vaccines difficult. An example is the meningococcus, which causes meningitis. These differences, can however, be turned to our advantage if we make careful comparisons of bacteria with different properties. For example, comparing one bacterium that is likely to cause disease with one that does not, may identify the reasons why the virulent variant is harmful - which may be useful in deve loping a vaccine or drug. In this proposal the meningococcus and its close relatives will be analysed in this way. We shall take advantage of modern automated means of determining the entire genetic code of bacteria to collect exhaustive data from carefully made collections of bacteria that will enable specific questions to be addressed. By means of a custom made database system we shall store information from these closely related bacteria and use a variety of computational techniques based on evolutionary theory to identify the differences among them. These will help us to understand how and why some of these bacteria never cause disease, why one of them causes a sexually transmitted disease, and why only some meningococci are particularly virulent.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION