NIHRDataInsights/HRCSData huggingface dataset:
Title: The interaction of paramyxoviruses with the interferon system.
Funder: Wellcome Trust

Abstract: The interferon (IFN) system is an extremely powerful anti-viral response, which all viruses have some mechanism to counter. Viruses usually achieve this by producing products that inhibit one part of the IFN response or another. Intriguingly, different viruses do this in different ways and undoubtedly the way in which they circumvent the IFN response must influence their life-style and hence the type of disease they cause. However, viruses rarely completely overwhelm the IFN response and it rema ins critical in controlling virus infections, buying time for the generation of an adaptive immune response. In this programme of work, we will continue our studies on the nature of the interaction of paramyxoviruses with the IFN system in order to better understand how viruses trigger the IFN response, and how, in turn, the IFN response influences their replication cycles and hence the types of diseases they cause. Such studies are likely to lead to new targets for anti-viral drug design. In ad dition, we propose to develop methods for the rapid selection of IFN-sensitive viruses, both for our fundamental studies on the interaction of viruses with the IFN system and because such IFN-sensitive viruses may be developed as potential attenuated virus vaccines.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Immune regulation of viral lung disease.
Funder: Wellcome Trust

Abstract: Bronchiolitis is the commonest single cause of infantile hospital admission. It is mostly caused by RSV, a virus that causes lung inflammation, difficulty breathing and is linked with later asthma. There is no vaccine, and some vaccines actually make the disease worse. We ve been trying to understand why this is for 20 years. Recent advances in immunology have given us a completely different way to looking at inflammation: rather than just finding out what switches it on, we now want to look at what regulates it. This area of immunology has undergone explosive development over the past 5 years and we are in a perfect position to apply new concepts to RSV disease in our very well characterised mouse model. However, the mouse does not exactly predict what happens in man. We therefore plan to infect human volunteers with RSV, and directly compare what we see in the mouse with what happens in humans after RSV infection. These studies are backed up by excellent preliminary data, ar e timely, ambitious but completely feasible. We anticipate that the discoveries made in this programme will help to control the excessive inflammation in bronchiolitis and help in vaccines design.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: A high-resolution mass spectrometry and electron microscopy approach to understanding the function of the Shigella T3SS.
Funder: Wellcome Trust

Abstract: Many disease-causing bacteria attack the cells of our bodies by using a complex machine designed to inject bacterial toxins directly into the attacked cell. This machine directly contacts the targeted cell by using a tiny hollow needle that projects from the surface of the bacterium. Contact between the cell and the needle switches on the machine within the bacterium so that bacterial toxins travel through the needle and are injected into the cell. We want to study the detailed composition and s tructure of this machine, particularly its base within the outer part of the bacterium, to help us understand how the bacterium knows that the needle has touched a suitable host cell. We hope that a good understanding of this system will suggest new ways to interfere with the process. Such knowledge may lead to the eventual design of small molecules inhibiting this process at a time when antibiotic resistance is increasing ever faster.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The regulation of life cycle differentiation in African trypanosomes.
Funder: Wellcome Trust

Abstract: Trypanosomes are single-celled parasites that cause African sleeping sickness. They are spread by tsetse-flies in sub-Saharan Africa and cause fatal disease in humans and livestock. This restricts the economic development of large areas of Africa. Whilst still in the mammalian-bloodstream, trypanosomes must prepare for life in the tsetse to optimise their chances of transmission. They achieve this by regulating their proliferation, using a mechanism that detects their population-density, and pr oducing so-called stumpy -forms Stumpy-forms shut down the production of most proteins, excepting those required for their survival and establishment when taken up by tsetse-flies in a bloodmeal. When this happens, stumpy-forms generate procyclic-forms that colonise the tsetse-midgut, this requiring new genes to be expressed, as well as changes in parasite morphology, metabolism and proliferation. This proposal will investigate how trypanosomes prepare for tsetse-transmission by (i) identi fying the proteins and mechanisms that optimise their survival and transmission (ii) investigating how they signal to each other to control parasite numbers in the bloodstream and (iii) determining how they regulate the genes that are expressed when they enter the tsetse-fly. By investigating the processes underlying parasite-transmission we hope to find routes to intervene in this vulnerable step in the trypanosome life-cycle.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: microRNAs and viral pathogenesis.
Funder: Wellcome Trust

Abstract: Herpesviruses are medically relevant, causing diseases ranging from the common cold sore to more serious conditions, such as cancer. Human cytomegalovirus is one of eight herpesviruses that infect humans. It can cause serious disease in individuals with defective immune systems and is the leading cause of birth defects resulting from congenital infections. Recently, human cytomegalovirus have been found to produce small molecules, called microRNAs, which they use to regulate the production of the viruses own proteins as well as the proteins of the cells they infect. The aim of the first part of this proposal will be to determine which proteins are effected by the viral microRNAs and why. A second project concerns how cytomegaloviruses are able to spread throughout the body from the initial site of infection. It is currently unclear how the virus achieves this. One theory is that virus travels within the host by infecting particular types of blood cells. I have developed a novel system that specifically blocks replication of cytomegaloviruses in bloods cells and will ask the question - can the virus still spread within a host if it cannot infect these blood cells?


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Quadruple intervention against tuberculosis.
Funder: Wellcome Trust

Abstract: Tuberculosis is a bacterial disease that is transmitted between people by coughing. The risk of tuberculosis is greatly increased by simultaneous HIV infection. In Southern Africa high rates of HIV infection have led to an increase in tuberculosis such that it is a very common cause of death and life expectancy in many countries has decreased to below 50 years. What is needed are new ways to tackle this difficult problem within relatively simple health care programmes. Treating HIV reduces the r isk of tuberculosis and treating HIV infection earlier is becoming a priority. When people start treatment for HIV infection it is also a good opportunity to screen for tuberculosis. 'Latent' tuberculosis, infection that does not cause symptoms but able to become active, could also be treated at this time. Latent tuberculosis is usually treated for 9 months with one drug: this research will investigate whether it could be treated in 1 month using multiple drugs. We will investigate whether vitam in D deficiency contributes to the risk of tuberculosis and whether supplementation improves the immune response. Lastly we will also test whether a new vaccine against tuberculosis works equally well when administed with treatment for latent tuberculosis.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Studying the molecular interactions of Plasmodium LCCL proteins to elucidate their roles in malaria transmission.
Funder: Wellcome Trust

Abstract: Malaria is a parasitic disease responsible for over one million deaths annually, mainly in infants, and remains a major global health concern. This project proposes to study a family of malaria parasite proteins, named LCCL proteins, that are essential for transmission of the parasite by mosquitoes. If we find out more about these proteins and the molecular processes they are involved in we could develop new ways to control malaria transmission, for example by making a vaccine or developing drug s that block the action of these molecules. We will use a mouse malaria model for these studies, and mosquitoes that transmit the parasite. Malaria parasites will be genetically modified in such a way that the proteins in question are tagged with fluorescent probes so that their expression, localization and trafficking in the cell, as well as molecular interactions between the LCCL proteins, can be monitored under the microscope. Protein complexes that these LCCL proteins form in the cell will b e harvested using their fluorescent tags, purified and analyzed by mass spectrometry to discover which other parasite proteins they interact with. The results obtained will provide a platform for the identification and development of new strategies to reduce malaria transmission.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Quasispecies evolution in the progression of FIV infection.
Funder: Wellcome Trust

Abstract: Cats are often tested and found to be positive for feline immunodeficiency virus (FIV) infection and it is difficult for veterinarians to advise the owners of such infected cats since the outcome is highly variable. The life-expectancy of infected cats has been estimated to be around 2 years and yet many FIV-infected cats are euthanised following diagnosis. Infected cats may appear to be outwardly healthy with only minor clinical problems that respond to treatment, but meanwhile the virus is se quentially destroying the immune system, resulting in immunodeficiency, the development of AIDS and death. In contrast there have been reports of some cats living with FIV infection for a normal lifespan. Therefore it is important to: a.) Understand how these different outcomes may arise and b.) Develop a test to predict whether a cat has either a good prognosis or will go on to develop AIDS.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Studies of the Plasmodium falciparum EMP-1 intracellular domain: protein structures and interactions in erythrocyte cytoadherence .
Funder: Wellcome Trust

Abstract: Severe malaria is an acute form of the disease that can lead to coma and death. It is often caused by infected red blood cells forming clumps and blocking blood vessels in various organs, including the brain, which deprives tissues of oxygen. Parasite-infected cells produce a particular protein, PfEMP1, that is responsible for cell attachment to blood vessels. PfEMP1 forms clusters and links to the cell skeleton to increase the mechanical strength of attachment; disruptions in clustering render the infected cells unable to attach. Thus far, relatively little research has been done on the portion of PfEMP1 that is believed to be important in organizing clustering of this molecule, and we do not understand the molecular basis of this process. This proposal aims to provide information on how this PfEMP1 portion interacts with other parasite and native cell proteins to form PfEMP1 clusters. Our ultimate goal of is to learn how to disrupt this process, which could provide the basis for trea tment. Preliminary work on this system indicates that NMR spectroscopy, our technique of choice, is likely a good match for the questions at hand.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Intensified tuberculosis case finding and rapid detection of drug resistant disease in patients accessing antiretroviral treatment in South Africa.
Funder: Wellcome Trust

Abstract: This research will be done in a well documented HIV/AIDS treatment clinic in a township of Cape Town. A group of 600 patients joining the treatment clinic for the first time and who do not already have a TB diagnosis will be studied. They will be screened for TB at baseline and again after completion of 4 months treatment for HIV/AIDS. The proportions of these patients that have TB and drug-resistant TB will be determined using diagnostic tests for TB that are routinely available in Cape Town, i ncluding culturing TB bacteria from sputum. Such tests are often very slow, taking many weeks to produce results. These results will be compared with those obtained using two new rapid laboratory tests for TB called the MTBDRplus and Xpert MTB assays. These newer tests are able to trace the presence of the DNA of TB bacteria in sputum samples and produce results within 1-2 days. This study will find out whether these new tests can reliably detect TB and how much more quickly they can diagnose T B and detect TB drug resistance. Calculations will then be done to whether the benefits of these new tests justify the costs of using them.


Research activity codes: 4.4 POPULATION SCREENING;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Does quorum sensing diversity affect cell-cell communication, biofilm fitness and susceptibility to antimicrobials?.
Funder: Wellcome Trust

Abstract: The importance of the superbug Pseudomonas aeruginosa in lung disease is increasingly recognised. Upon infecting the lungs, rather than being a population of independent identical cells, the bacteria cooperate using signal molecules to form slime cities . These communities work collectively to survive, making them difficult to treat with conventional antibiotics. Samples of P. aeruginosa from infected patients have identified bacterial cheats which take advantage of the cooperation of o thers without contributing themselves and thus they spread in an infection. Preliminary experiments suggest that an increase in the proportion of cheats weakens an infection, potentially rendering it more susceptible to antibiotics. We will explore the idea of bacterial cooperation and conflict in the context of chronic lung infections. We will introduce bacterial cheats to infections to determine their overall effect on disease progression and test whether conventional antibiotics work more eff ectively when cheats are present. In addition, we will test new drugs which directly block the communication of the bacteria to determine whether they are effective in treating infections alone or together with conventional treatments. Our key goal is to show infections caused by superbugs can be weakened: paving the way for more effective and sustainable treatments.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The Genomics of host adaptation in Campylobacter.
Funder: Wellcome Trust

Abstract: A comparative functional genomics approach will describe the genetic basis and ecology of host specificity and niche adaptation in Campylobacter and how this relates to the emergence of virulence. Recent advances in Illumina GA resequencing technologies, specifically isolate multiplexing, enable high-throughput sequencing of multiple genomes and open the new field of population genomics . Large in-house isolate collections, genotyped at 7 loci, are the starting point for this multidisciplin ary fellowship studying the evolution and ecology of pathogens, in three major types of experiment: (i) Genome-wide association mapping in natural populations; (ii) Quantifying adaptability and generalism in in vitro experimental evolution systems; (iii) in vivo competition experiments in specific-pathogen free chickens. Genomic experiments will describe the mechanisms and nature of adaptations to host. The competition experiments will assay the absolute fitness differences of strains with diffe rent degrees of host-adaptation and allow rigorous tests of specific adaptive hypotheses. The laboratory experiments will help to elucidate variation in genome plasticity and its relationship to host adaptation. Experimental results will feed into the Genome Evolution by Recombination and Mutation (GERM) program, designed for this project to provide a systems approach to the investigation of niche adaptation and population structuring in bacteria.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Systematic Bioinformatic Discovery of 'Hidden' Virus Genes.
Funder: Wellcome Trust

Abstract: While certain viruses, such as HIV, have been intensively studied, hundreds of others have received substantially less attention. Identification of the full complement of genes in such viruses is critical to our understanding of their biology and the development of effective treatments and control strategies. Computational analyses of their genome sequences is a very time- and cost-efficient way to guide further experimental research where resources are limited. My research involves the devel opment of new software tools specifically designed for the analysis of virus sequence data and the application of these tools in order to find new virus genes and other features. I am particularly interested in identifying genes that, because of their small size or other unusual features, have been persistently overlooked by other researchers. Prior to detection, such genes can constitute a source of considerable confusion and wasted research effort, as exemplified by two recent discoveries of my own. The goal of the proposed research is to apply my software, and new software under development, to a much larger number of viruses in order to systematically identify, and experimentally verify, these 'hidden' genes. A key feature of my research strategy is close synergistic interaction between bioinformaticians and experimentalists.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Functional genetic and transcriptomic analysis of male fertility in Anopheles gambiae.
Funder: Wellcome Trust

Abstract: The failing promise of current methods of mosquito-borne disease control drives the impetus to investigate biological processes that can be targeted in novel anti-vector measures. This project focuses on the analysis of An. gambiae genes involved in sperm and testis development a virtually unexplored aspect of vector biology that may offer many targets for mosquito-specific interventions. We propose two avenues of research: first, functional analysis of the recently identified testis-expressed orphan genes to provide crucial information regarding their suitability as targets for control by chemosterilisation; second, an in-depth analysis of the testis transcriptome to define a more complete map of testis biology in An. gambiae and broaden the list of potential targets. The key goals are to: - Determine the cellular/subcellular localisation of Ams, AAms and mts orphan gene expression - Determine the role of these orphan genes in the male reproductive success using combined gene silencing and mating experiments - Identify and molecularly characterize additional orphan and rapidly evolving testis-specific genes in An. gambiae as potential target molecules in novel control strategies.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Chromosomal recombination and repair in African trypanosomes
Funder: Wellcome Trust

Abstract: The genome is the ultimate information source for the functioning of all organisms During growth, damage afflicts the genome, which is countered by repair pathways. Several organisms have co-opted these pathways to generate adaptive genetic diversity. Our own immune system is a good example, allowing us to eradicate infections , while several parasites use similar mechanisms to evade that immune system. Thus, antigenic variation in the Affrican trypanosome, an important parasite of humans and animals, relies upon genetic reassortment, close to chromosome ends, of the genes that encode abundant surface proteins. We developed a system that allows controlled induction of DNA breaks in specific regions of trypanosome chromosomes and observed robust repair when the break was in the core of the chromosome. We now propose to use cell and molecular biology techniques to compare repair pathways following DNA breaks introduced around the genomeand determine when repair takes place during the cell-cycle. We will determine which proteins are required for repair and how they interact. our findings will reveal how DNA repair contributes to immune invasion in this important pathogen.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Defining the role of primaquine in malaria elimination.
Funder: Wellcome Trust

Abstract: There is renewed enthusiasm for the enormous challenge of eliminating malaria. Elimination may not be possible without greatly increased use of primaquine. This is an old and underused drug with unusual properties. It is the only available antimalarial which specifically stops transmission of falciparum malaria from one person to another. It is also the only drug which kills the dormant stages of P.vivax and P.ovale in the liver that make these malarias so difficult to eliminate. Primaquine is u nderused is because it causes potentially dangerous loss of red blood cells in people with inherited enzyme deficiencies which are very common in the tropics (up to 15% of the population). Consequently primaquine is often not prescribed for fear of causing a more serious illness than it cures. Children suffer particularly from vivax malaria, but we do not know the correct dose in this vulnerable group. We propose a series of epidemiological, clinical and pharmacological studies in Thailand to de termine the best primaquine treatment regimens, characterise its safety profile and in particular define the risks in people with these common hereditary deficiencies. If we can define the risks and the benefits better, then greater use of primaquine will help to eliminate malaria.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: The impact of murine norovirus infection on the innate immune system.
Funder: Wellcome Trust

Abstract: We propose that the activation of innate immune responses become altered upon infection with persistent versus non-persistent strains of MNV. We further propose that persistent MNV infection affects subsequent immune responses to other pathogens such as Salmonella. 1. To identify the signaling pathways of the innate immune system involved in the response to persistent and non-persistent variants of murine norovirus, focusing particularly on pathways that may be implicated in the production of type 1 interferons. 2. To determine whether persistent MNV infection affects the subsequent immune responses to other enteric pathogens such as Salmonella


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION