NIHRDataInsights/HRCSData huggingface dataset:
Title: Regulation of an RNA polymerase activation pathway.
Funder: Wellcome Trust

Abstract: Mechanisms exist to make sure the information flow from DNA is tightly and appropriately regulated. We are studying a bacterial gene expression system, used to allow pathogenic bacteria to adapt to their host environments.How these genes are kept turned off is of interest, since the silencing process is an active event, and needs the action of a protein whose mechanism we plan to study. One very real possibility is that our work will reveal a new molecular strategy for stopping gene express ion, and in the longer term we would develop new intervention approaches to manage harmful pathogenic bacteria.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Development of monoclonal antibody products for post-exposure prophylaxis of rabies.
Funder: Wellcome Trust

Abstract: In this project we will study a number of different antibodies that kill common and uncommon variants of the rabies virus. These will be combined into mixtures so that we can find out which combinations are likely to be the most efficient at preventing deaths from rabies following exposure to the virus. We will clone the genes for the most suitable antibodies and will develop two new medicines. One will be a cocktail of antibodies that may be suitable to replace HRIG, the current treatment for p eople exposed to rabies (which is very expensive and in short supply). The other will be an antibody derivative that can cross the blood-brain barrier and prevent rabies encephalitis (currently there are no medicines that can treat systemic rabies infections). A key aim of the project is to produce both these medicines using plants. This is because current production methods are too expensive and limited in scale to allow the production of antibody cocktails in anywhere near the amounts required . We will test the plant-derived antibodies thoroughly to ensure they are safe and efficient and will produce them using good manufacturing practice , the regulatory system that governs the production of all drugs.


Research activity codes: 5.1 PHARMACEUTICALS;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INFECTION
Title: Investigating Trypanosoma brucei's unusual inositol metabolism.
Funder: Wellcome Trust

Abstract: The neglected disease, African sleeping sickness caused by the protozoan parasite Trypanosoma brucei, is transmitted by the bite of the Tseste fly, and affects millions across sub-Saharan Africa, which has a huge social and economic impact. Current drug treatments are woefully inadequate and new therapies are urgently required. Knowledge of how the parasite assembles and uses it s lipids and membranes will help in the understanding of which lipids are important for the parasite's survi val and multiplication within their hosts. This research will exploit and expand on differences between the parasite and man that we have already identified on the biochemistry and synthesis of an important lipid component of the parasite s membranes which forms an integral part of its defense strategy while in the mammalian host. This research uses a multi-disciplinary approach involving different techniques across chemistry, biochemistry and molecular parasitology. This work will identif y and verify new potential therapeutic targets, as well as finding ways to inhibit of these essential biosynthetic steps, in a parasite-specific manner. The ultimate goal is to form new easy to make, affordable, easy to administer, drugs in the fight against African sleeping sickness, as well as other closely related protozoan transmitted Third world diseases.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Structural and functional studies of cyclic di-GMP signalling pathways that regulate virulence in bacterial pathogens.
Funder: Wellcome Trust

Abstract: Pseudomonas aeruginosa has become a leading cause of morbidity and mortality in immunocompromised individuals. It is one of the most common pathogens isolated from short-stay hospitalized patients causing a variety of infections ranging from nosocomial pneumonia to bacteremia. It is a frequent complication in cystic fibrosis sufferers as it resists treatment due to its extensive intrinsic antibiotic tolerance and its ability to form biofilms - aggregates of bacterial cells which form on living o r inert surfaces and have been shown to resist antibiotic treatment and contribute to bacterial persistence in chronic infections. The nucleotide, cyclic di-GMP, is involved in the regulation of biofilm formation and other complex physiological processes that affect pathogenesis of many bacteria. Its concentration in the cell is regulated by proteins with characteristic amino acid motifs GGDEF motif containing proteins synthesise the nucleotide while EAL and HD-GYP motif containing proteins de grade the nucleotide. In comparison to GGDEF and EAL domain proteins, HD-GYP domain proteins are poorly characterized and little is known about their mode of action. Unravelling the atomic structure and multiple functions of HD-GYP domain proteins from P. aeruginosa, as outlined here, provides the basis for the development of new treatments for bacterial disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The immunological determinants of protective immunity and immunopathology in human Chlamydia trachomatis infection.
Funder: Wellcome Trust

Abstract: Vaccines against ocular infection with the bacterium Chlamydia trachomatis (trachoma), using bacteria that had been killed by heat or chemicals, provided protection lasting for a few months but, worryingly, there was evidence in humans and in monkeys that vaccinated individuals had a more severe disease next time they were infected than individuals who had not been vaccinated. This suggests that the body s immune response to the infection causes some or all of the damage. It is now possible to make vaccines from individual components of a bacterium, and to use chemicals called adjuvants that make the immune system respond to them in particular ways. Several Chlamydia vaccines seem promising in mice, and the type of immune response which protects mice has been identified, but the immune systems of humans and mice are significantly different. We aim to identify which immune responses are protective, and which cause damage, in humans, by studying children who are frequently exposed to oc ular Ct infection at regular intervals to look at the relationship between immune responses and the outcome of infection; and by looking for genetic differences between people with severe disease and their neighbours of the same age and sex who have normal eyes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.4 VACCINES
Health categories: INFECTION
Title: A systems-based and whole cell tomography study of Type IV pilus biogenesis in Pseudomonas aeruginosa.
Funder: Wellcome Trust

Abstract: Some disease-causing bacteria produce long thin protein fibres from their surfaces, which play important roles in the processes of infection. These fibres are called pili and they have a number of functions. They are involved in binding to specific receptors on the surfaces of the cells of the host which are infected by the bacterium; in this way, pili help the bacterium to adhere to cells before infection occurs. They are also able to propel bacteria along surfaces and are thought to help pul l the bacterium closer to a cell before infection. The aim of this proposal is to identify specific small molecules which inhibit this process at particular stages; this will allow us to construct a model for the complicated network of proteins which control the formation of pili. We also want to examine how inhibition affects the structures of the pili, using a very high power microscope to examine the bacterium which we are studying, Pseudomonas aeruginosa. Pseudomonas causes lung infections i n cystic fibrosis patients, and we know that the pili play an important role in infection and colonization.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The role of highly conserved pilins in meningococcal pathogenesis.
Funder: Wellcome Trust

Abstract: Neisseria meningitidis remains a leading cause of septicaemia and meningitis worldwide. The bacterium expresses Type four pili (Tfp), which are multi-protein, multi-functional surface organelles and essential virulence factors that promote interactions with cells and acquisition of virulence traits. Although Tfp have long been considered to be a paradigm of antigenic variation, we have recently found that the hyper-invasive lineages clonal complex-8 (cc-8, formerly A4 cluster) and cc-11 (formerl y ET-37) express pilin subunits that are remarkably conserved and predicted to have a structure distinct from previously characterised Neisseria Tfp. Our overall aim is to understand the genetic basis and biological consequences for N. meningitidis of expressing highly conserved pilins. This will be achieved through three aims: i) investigation of the basis of lack of antigenic variation in cc-11 strains, ii) examine the consequences of expressing conserved pilin on bacterial interactions with host cells, and iii) analysis of the immunogenicity of conserved pilin subunits. We will combine the applicants' expertise in pilin variation, Tfp biogenesis, cell interactions and immune responses to elucidate how the lack of pilin variation influences meningococcal virulence. Our findings may have implications for vaccine development against this important human pathogen.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Merging theory and field studies for infectious disease dynamics
Funder: Wellcome Trust

Abstract: Infectious disease dynamics is the science of understanding how and why infections spread from one person to another. It is also the science of discovering why some infections cause large outbreaks with many deaths while others affect few. The 2009 influenza pandemic was a real challenge for scientists who study infectious disease dynamics. Although there were many questions we could answer, there were many that we could not. The most obvious question we couldn t answer until very late was: how many people will get ill and how many will die. In Hong Kong, during the summer before the pandemic hit, we received funding to go out and ask people at random to give a small amount of blood. After the first wave had passed, we got blood from the same people and checked to see who had been infected: it turns out about 12% overall were infected, but 35% of school age children. In this project, I m going to try to show that for the scientists to be able to predict the severity of future pandemics , we need public health authorities to go out and take blood samples at random (either) routinely or immediately that a new pandemic starts.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: The molecular basis of female reproductive biology in the malaria mosquito Anopheles gambiae.
Funder: Wellcome Trust

Abstract: Anopheles gambiae mosquitoes are the major vectors of malaria, a disease with devastating consequences for human health. Novel methods for controlling the natural vector populations are urgently needed, given the evolution of insecticide resistance in mosquitoes and the lack of novel insecticidals. Understanding the processes at the bases of mosquito biology may help to roll back malaria. In this proposal, we will target mosquito reproduction, a major determinant of the An. gambiae capacity to t ransmit malaria. This will be achieved at two levels: (i) laboratory research, to provide a deeper knowledge of the processes regulating reproduction in this species, and (ii) field studies, to confirm and expand the data obtained in the laboratory and to validate our findings in natural populations. We will focus our analysis on two major female reproductive organs: the spermatheca, where the sperm is stored, and the atrium, where male seminal secretions are digested. This study will reveal as yet unknown molecular mechanisms underlying reproductive success in mosquitoes, considerably increasing our knowledge beyond the state-of-the-art and critically contributing with innovative tools and ideas to the fight against malaria.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION
Title: Capturing and Defining the key stages of colicin N toxicity.
Funder: Wellcome Trust

Abstract: Serious threats to human and animal health from bacteria include such diverse species as Neisseria (gonorrhoea, meningitis), Yersinia (plague), Aeromonas, Vibrio, Escherichia, Shigella, Salmonella, (food poisoning), Klebsiella/Haemophilus (pneumonia), Acinetobacter, Pseudomonas / Burkholderia , Brucella (long term / hospital infections). The outer defensive walls of all these bacteria look very similar, enabling experiments on one disease to provide cures for another. Our existing antibiotic lif esavers were the result of chance discoveries, like Alexander Fleming s discovery of penicillin, cleverly exploited to make whole families of new treatments. However, because of this family resemblance a new resistance problem can soon affect all the members. One way for us to overcome antibiotic resistance in these germs is to find completely new weapons. It is not widely known that bacteria make molecular weapons called bacteriocins to kill each other and in fact our bodies regularly play host to bacterial warfare on an epic scale without us even noticing. For many reasons we cannot use bacteriocins in the clinic but we can learn about the weaknesses in bacterial defences that they exploit. It may then be possible to design new antibiotics which use the same tactics. This project is aimed a discovering such an Achilles heel.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Do DNA double strand breaks initiate antigenic variation by homologous recombination in Trypanosoma brucei?
Funder: Wellcome Trust

Abstract: 1. Determine if lesions on, or around, the ES 70 bp repeats correspond with increased RAD51 localisation and recombination. 2. Ask if replication stalling occurs on, or around, the 70 bp repeats in the ES, leading to DNA breaks. 3. Determine if the 70 bp repeats are a focus for transcription-coupled repair, leading to DNA breaks.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Development of pyocins active against Pseudomonas aeruginosa.
Funder: Wellcome Trust

Abstract: 1. Discover novel pyocins with broad anti P. aeruginosa activity and potent anti-biofilm activity 2. Identify receptors and mechanisms of uptake for known and novel pyocins. 3. Test toxicity of purified pyocins against human epithelial cells and determination of the ability of pyocins to kill cell-associated and internalised P. aeruginosa. 4. Test efficacy of pyocins in a mouse model of chronic P. aeruginosa lung infection.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Investigation of early immune responses of trypanosome infection in mammals using intravital imaging tools
Funder: Wellcome Trust

Abstract: To establish more firmly the basics of the initiation of tsetse-transmitted infection, and to test the hypothesis above, we propose to address the following aims: (i) Spatiotemporal mapping of the key events at the bite site, including inoculation into the skin, entry into the blood or lymphatic system, and dissemination through the body. (ii) Identification of the immune cells involved in communication and migration between the site of infection and the draining lymph node. (iii) Identification of immune cells that interact with the parasite when it enters a lymph node, and the host cell-cell interactions that are initiated. (iv) Depending on the immune cell types and interactions identified in (ii) and (iii), we will use in vivo approaches to test trypanocidal activity of identified, potential immune effector cells.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Mechanistic insight and tools for disrupting calcium signalling/homeostasis in the pathogenic mould Aspergillus fumigatus.
Funder: Wellcome Trust

Abstract: Inhibition of the calcium-sensitive phosphatase calcineurin potentiates the activity of existing antifungal agents against Aspergillus and Candida pathogens. This provides the basis for our hypothesis that fungal calcium signalling and homeostatic (CSH) machineries represent novel anti-fungal targets for existing and new therapeutic agents, and that these can be used synergistically with other commonly used antifungal agents. Specific aims are: 1. To identify calcium signals associated wi th spore germination, hyphal growth, and infected-related stresses by measuring intracellular calcium using genetically encoded calcium probes. 2. To analyse the interaction and integration of calcium and calcineurin signalling networks during similar processes using a genetically encoded biosensor of calcineurin activity. 3. To systematically identify calcium-modulatory functions relevant to infection-related growth using a library of null and/or conditional mutants constructed in the calciu m and calcineurin reporter genetic background. 4. To screen the mutant library for virulence-enabling functions in murine and macrophage models of Aspergillus infection. 5. To identify interacting partners for membrane-associated CSH proteins using an A. fumigatus split-ubiquitin protein fragment complementation assay. 6. To analyse the influence of calcium/calmodulin/calcineurin modulating drugs on A. fumigatus, and identify chemical-genetic interactions using these drugs, 10,000 microbial natural product extracts and CSH mutants.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Structure and function of the cell envelope spanning YtfM-YtfN complex in E. coli.
Funder: Wellcome Trust

Abstract: Our ultimate goal is to understand how the YtfMN complex functions in autotransporter biogenesis. However, to fully understand this process will require a detailed structural model for the YtfMN complex and how this complex interacts with autotransporters. To achieve this, the following specific aims will be met. 1. Delineate the interacting regions of YtfM and YtfN 2. Determine the structure of the interacting region of the YtfMN complex 3. Determine the oligomeric state of the membrane spanning YtfMN complex 4. Determine interactions of the YtfMN complex with autotransporters during their biogenesis


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Functional analysis of Salmonella type III secretion system effector proteins.
Funder: Wellcome Trust

Abstract: The overall aim of this project is to characterize the functions of a selected SPI-2 type Ill secretion system effector protein(s) . This will be achieved by: Conducting database searches to find interesting motifs or other information that could shed light on the functions of uncharacterized effectors. Creating mutant strains of bacteria lacking effector(s) by site-directed mutagenesis of their corresponding genes. Analysing these mutants for intracellular defects and phenotypes that could help understand the functions of the genes. Identification of interacting host cell proteins using biochemical and genetic approaches. Conducting in vivo studies in mice to understand more about the physiological relevance of these genes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Function and transport of a herpesvirus encoded Ubiquitin-specific protease in virus entry and assembly.
Funder: Wellcome Trust

Abstract: This project concerns the investigation of a key structural protein, VP1-2 of herpes simplex virus (HSV) in entry and assembly. VP1-2 is essential in all members of the herpesvirus class. It plays important roles at several stages of the virus li fe cycle including early in infection where it is somehow involved in docking capsids to nuclear pores and also at later stages where it is required as the platform upon which other structural proteins are recruited to progeny capsids (1 , 3, 6, 11, 18). A novel ubiquitin specific protease (USP) is embedded within the N-terminus of VP1 -2 (1 0) and additional evidence indicates that cleavage releasing the USP domain may be required for infection (9). VP1-2 also interacts with molecular motors to transport capsid particles along microtubules into and out of the nucleus (14). While it is accepted that VP1 -2 is required at multiple distinct stages of infection, the separation of determinants involved in these multiple roles, the relationship between localisation and function and a detailed mechanistic understanding of VP1-2 involvement in entry, assembly and exit remain major points to be resolved in the field. The aims of this project are To construct recombinant fluorescent vi ruses incorporating mutations within VP1-2 with which to characterise entry and assembly pathways and the role of VP1-2. To specifically determine whether a basic motif flanking the USP domain is required as a nuclear localisation signal and the consequences of replacement by heterologous viral or cellu lar motifs in the context of transport assays of individual proteins and in the context of recombinant viruses. To identify factors which interact with the putative NLS and determine their role in VP1-2 function and virus replication To characterise interactions between VP1 -2 and other virus components that modulate its localisation and/or USP function.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Understanding the molecular basis of how African trypanosomes cross the tsetse fly peritrophic matrix.
Funder: Wellcome Trust

Abstract: African trypanosomes are the causative agents of human sleeping sickness and Nagana disease in animals. These diseases affect millions in the sub-Saharan part of Africa and are both medically and agriculturally, as infected livestock cause excessive economic losses. The parasite has a life cycle that alternates between the vertebrate host and the tsetse fly vector. Tsetse flies secrete a gut sleeve that unravels to surround an incoming bloodmeal. It is called the peritrophic matrix (PM) and it is considered to be an authentic physical barrier that prevents pathogenic organisms from infecting the delicate layers of gut cells (epithelium). For a trypanosome to migrate and develop within the fly gut, it must penetrate through this complex protective lining (PM). In this project, I intend to unravel the molecular events involved in the crossing of trypanosomes through the tsetse PM. First, we shall determine the chemical composition of the tsetse PM. Second, we shall then determine what parasite and fly molecules may be participating in the degradation of the PM. These studies are important as they could lead to the design of alternative ways to control disease transmission by blocking the interactions between trypanosomes and the tsetse vector.


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