NIHRDataInsights/HRCSData huggingface dataset:
Title: The NCEMA study: Neutrophils in Cerebral Malaria
Funder: Wellcome Trust

Abstract: Every year half of the world’s population is at risk of getting malaria, caused by the Plasmodium parasite, and almost half a million people die; mostly children in sub-Saharan Africa. Some infected children are at a higher risk of death since malaria can damage their brains as part of a severe complication called cerebral malaria (CM). Neutrophils are one of the first lines of defence against fighting infections by damaging cells, yet their involvement during CM is not entirely understood. We hypothesise that neutrophils interact with Plasmodium affecting the blood vessels of the brain and initiate or promote the progression to CM. We aim to perform a detailed analysis of the role of neutrophils in CM, using prospectively collected blood from children with CM, archival post-mortem brain tissue, blood vessel cell cultures and a mouse model. With the exception of the mouse model our project will be based in Malawi, a country endemic for malaria. Our findings will allow us to understand if neutrophils cause damage to the brain blood vessels leading to CM. This could provide the basis of a search for novel prevention and treatment strategies that can potentially decrease the high rates of death of this disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Investigating the diversity and evolution of Hepatitis B virus using Nanopore whole genome sequencing
Funder: Wellcome Trust

Abstract: BACKGROUND Chronic Hepatitis B virus (HBV) infection is a global health threat affecting 290 million people, causing 800,000 deaths a year from liver cirrhosis and liver cancer. The United Nations has set elimination targets to be achieved by 2030, however, existing strategies will not enable this goal to be met. Viral genetic sequence is linked to treatment response and clinical outcome. Studying the genetic sequence of HBV therefore provides an avenue to improve elimination strategies. Recently, we have provided proof of principle that full-genome HBV sequences can be generated using the Nanopore platform. This method is ideal for studying viral diversity due to the long reads generated. I will use this method to study the diversity of HBV within and between hosts, capitalizing on well-established cohorts in South Africa and Uganda. APPROACH 1. To optimize Nanopore methods for HBV full genome deep sequencing 2. To identify and characterise HBV strains circulating in sub-Saharan Africa 3. To characterise the kinetics of HBV evolution 4. To investigate the relationship between viral diversity and liver disease EXPECTED IMPACT This information can potentially be used to improve prognostication, understand immune control, optimise drugs and vaccines, with the potential for high impact on global health.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Computer Aided Screening for Tuberculosis in Low Resource Environments (CASTLE)
Funder: Wellcome Trust

Abstract: TB is very common among people living with HIV (PLHIV) in who are unwell and require admission to hospital. However TB can be difficult to diagnose. Digital chest X ray with computer-aided diagnosis (DCXR-CAD) and a urine test may help promptly diagnose TB. At a single hospital in Malawi, days of the week will be randomly assigned so that on some days patients with HIV coming into hospital will be offered a DCXR-CAD and urine test as well as usual care and on other days patients will be offered usual care only. We will measure how many patients in each group die in hospital, how many start TB treatment, and how many patients have their TB diagnosis missed and therefore untreated by the time they leave hospital or die. As part of this study a small number of patients will have enhanced laboratory tests for TB, monitoring of HIV severity, tests for other infectious diseases and tests of inflammatory markers. The goal is to see if DCXR-CAD and urine testing reduces deaths among people with HIV who are in hospital, and to provide insight into what diseases are causing people with HIV to become unwell and need hospital admission.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Vaccine-induced systemic and mucosal immunity to Bordetella pertussis in infancy: bringing B- and T-cell responses together
Funder: Wellcome Trust

Abstract: Whooping cough, known as pertussis, is a serious infection, especially in infants. Two types of pertussis vaccine exist: whole-cell (wP) and acellular (aP). We now think that aP vaccines may not be as long-lasting or effective in preventing infection as wP vaccines, but the cause remains unknown. It may be due to differences in specific groups of cells in the immune system called T-helper cells. The type of T-helper cells found in animals and humans who have received wP- compared to aP-vaccines is better at preventing bacteria from being passed on. We still do not know enough about all the important T-helper cells involved and there is no data in very young children. My project is set within a larger study in The Gambia that is vaccinating babies with aP or wP vaccine. I will investigate T-helper cells activated by these vaccines and see how they may help other components of the infant’s immune system. As well as taking blood samples, I will collect and analyse fluid from the infant’s nose (where pertussis bacteria initially infect), to provide further insight into how these vaccines differ in their action. My findings will help to design better pertussis vaccines in the future.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: ‘Modified Outer Membrane Vesicles as safe, effective, low cost, multivalent vaccines against typhoid and paratyphoid fever and invasive non-typhoidal Salmonella infections’
Funder: Wellcome Trust

Abstract: Salmonella are bacteria that cause life-threatening infections in adults and children. These diseases co-exist in many geographical areas, especially in Low and Middle Income Countries. Therefore, a vaccine that can protect against all the major Salmonella infections would be highly desirable. The project will exploit the remarkable features of Outer Membrane Vesicles (mOMV) to deliver antigens from many species of Salmonella that cause disease in humans. mOMV are outer membrane blebs naturally shed by Gram-negative bacteria, including Salmonella. These bacteria can be genetically manipulated to increase mOMV production, to decrease adverse reactions and to include additional antigens. mOMV are easy and cheap to produce, strongly immunogenic and protective. The innovator award will therefore allow the development of a multivalent, easy to produce, low-cost, safe, effective Salmonella vaccine to be taken towards the end of preclinical experimentation.

Lay abstract: Salmonella are bacteria that cause life-threatening diseases in adults and children. Typhoid fever, paratyphoid fever and invasive non-typhoidal Salmonella (iNTS) infections have a high incidence worldwide. These diseases co-exist in many geographical areas, especially in Low and Middle Income Countries (LMIC). Therefore, a single vaccine against all the major Salmonella infections would be highly desirable. Current vaccines against typhoid fever are safe and immunogenic, but require multiple doses and/or show moderate protective ability and some of them are expensive to produce. no vaccines against iNTS or paratyphoid fever are currently licensed. The aim of the project is to use Modified Outer Membrane Vesicles (mOMV) as multivalent and low-cost vaccines against many strains of Salmonella. mOMV are outer membrane vesicles naturally shed by Salmonella bacteria genetically manipulated to decrease adverse reactions. These vesicles are easy and cheap to produce, strongly immunogenic and protective.

Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Dissecting the molecular genetics underlying mosquito attraction to humans
Funder: Wellcome Trust

Abstract: The African malaria mosquito, Anopheles gambiae, uses an exquisitely tuned nervous system to home in on physical and chemosensory signals emanating from humans. Such host-seeking behaviour is specific to females because, unlike males, they require blood to produce eggs. Despite the epidemiological importance of this sexually dimorphic behavior, the molecular and cellular basis of how the female mosquito central and peripheral nervous system is wired to achieve this goal remains unknown. In insects, two genes called doublesex and fruitless are the master regulators of sexual differentiation and together they control the development of all sexually dimorphic tissues. To gain further insight into sex-specific differentiation of host-seeking behaviour in Anopheles gambiae, here I propose three specific aims: (i) Identify sexually dimorphic neuronal populations in the mosquito brain and sensory tissues expressing doublesex and fruitless (ii) Profile gene expression in sex-specific neuronal populations to identify candidate genes underlying female specific host-seeking behavior, and (iii) Functionally characterize the role of these sex-specific genes in mosquito attraction to human-related sensory cues. This project will provide unprecedented insights into how female mosquitoes are genetically programmed to bite humans, and provide potential novel targets for the control of malaria and other mosquito-borne diseases.

Lay abstract: Malaria is transmitted through the bite of an infected mosquito, which uses its exquisite sense of smell to specifically track down a human. This biting behaviour is strictly limited to females because a blood meal is only needed to produce eggs, whereas plant nectar can sustain both males and females. If we understood the molecular basis of mosquito attraction to humans, we could target these processes to stop the spread of malaria. I will apply the most recent advances in genome engineering and 2-photon microscopy to visualize how the female brain and sensory organs become specialized to respond to human odour. I will develop cutting edge tools to reveal potential co-factors and then modify these to assess their role in odour response using behavioural assays and live-imaging of neuron activity. Ultimately, I hope to reveal new targets for novel vector control, such as odour-baited traps or gene drives.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION
Title: Deciphering developmental commitment in African trypanosomes using single-cell transcriptomics
Funder: Wellcome Trust

Abstract: African trypanosomes, parasites spread across sub-Saharan Africa by the tsetse fly vector, cause both human and animal disease, threatening millions of people and their livestock. In the blood of such mammalian hosts, a quorum sensing (QS) process causes the asynchronous differentiation of proliferative ‘slender’ form trypanosomes into arrested ‘stumpy’ forms, which are competent for transmission to the tsetse fly. However, the hierarchy of events from QS signalling, through cell cycle exit, to molecular and morphological differentiation are not defined. I propose to decipher this process using single-cell transcriptomics. I will use single-cell RNA-sequencing to profile transcriptomes of individual Trypanosoma brucei parasites undergoing asynchronous differentiation into stumpy forms, where bulk RNA-seq is not informative. I will then generate a trajectory of differentiation by ordering cells across “pseudo-time” according to the gradual changes in their transcriptomes. By studying cohorts of genes which vary in expression across pseudo-time, I will identify the hierarchy of key events and identify putative regulatory genes. I will then validate these findings by generating null mutants of these regulatory genes, which will be assessed for their ability to differentiate. Thus, I aim to understand differentiation control mechanisms that in the future can be targeted to interrupt disease spread.

Lay abstract: African trypanosomes are unicellular parasites that infect humans and other mammals, including cattle, where they cause fatal diseases if left untreated. In order to move between mammalian hosts and spread across sub-Saharan African, the parasites must be ingested by tsetse flies during a bloodmeal. While residing in the mammalian bloodstream, trypanosomes pre-adapt for survival in the fly by altering their metabolism and molecular biology in a process termed differentiation. I will monitor gene expression changes that occur in parasites undergoing differentiation using single-cell sequencing techniques. Using computational methods to analyse these data, I will predict which genes are driving the cellular changes during differentiation and then study these further to identify their function. My work will identify key factors in trypanosome differentiation that can be targeted to perturb this process. Ultimately, this may help the development of therapies to prevent transmission of trypanosomes and associated diseases.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Fibrin films at the crossroads of haemostasis, infection control and wound healing
Funder: Wellcome Trust

Abstract: We have recently shown that fibrin forms a continuous film covering the air-blood interface of external wounds, and that these film form an almost instantaneous barrier protecting the wound against infection for at least 12 hours. This discovery is potentially paradigm-shifting in haemostasis presenting a new area of research with novel translational opportunities. I propose that fibrin films help prevent wound infection for 24-48 hours by providing a barrier across the surface of an external wound. In turn, this preclusion of infection aids the wound healing process by preventing prolonged inflammation at the site of injury. To investigate this I will assess the role of the film in preventing the proliferation and dissemination of bacteria in murine models of dermal infection over 72 hours, and explore if fibrin films can prevent infection from becoming blood-borne. I will go on to investigate how this prevention of infection influences wound healing using a murine wound healing model, and study how fibrin films influence white blood cell and fibroblast infiltration. These lines of investigation will bring together the fields of haemostasis, infection and tissue repair, uncovering new pathways to target in the treatment of dermal and blood borne infections and wound healing.

Lay abstract: When skin is injured, a repair response commences beginning with the formation of a blood clot, reducing blood loss. A main contributor of clot formation is a protein called fibrin. It forms a 3D mesh, capturing blood cells, producing a plug at the site of injury. The tissue repair process follows, but disruption by infection can lead to a painful wound that fails to heal. I recently discovered that fibrin forms continuous films along the air-blood interface at sites of external injury. Films form rapidly after injury, forming an almost instant barrier against infection. I will study how long these films prevent infection and if they can stop infection becoming systemic. I will investigate if infection prevention by films aid the wound healing process. The overall goal of my research is to better understand the role of fibrin films, uncovering new pathways to improve infection prevention and wound healing.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Artificial intelligence for rapid epidemic analysis
Funder: Wellcome Trust

Abstract: The aim of this fellowship is to accelerate detection of and response to infectious disease outbreaks, particularly where surveillance, diagnosis, and control are under-resourced. My first goal is to develop and validate machine learning methods to rapidly infer outbreak properties. I have demonstrated proof-of-concept for this approach, and I expect to be able to train machine learning models on synthetic outbreak data to infer outbreak properties almost instantaneously from data. By building on this approach, understanding its validity and weaknesses from application to historical data, and creating a database of simulations and trained models, I hope to allow outbreak data to be interpreted more quickly and simply than currently possible. My second goal is to complete and test—first against historical data and then prospectively—algorithms for aetiological identification of outbreaks. These algorithms have the potential to allow outbreaks to be detected and controlled faster, as well as to improve guidelines for syndromic surveillance. Finally, I plan to integrate these analytics for outbreak identification and analysis into lightweight software tools. After testing them in collaboration with field epidemiologists, I hope to enable public health officials to take advantage of epidemiological insights with minimal training, supporting capacity of public health systems.

Lay abstract: Early detection of infectious disease outbreaks can prevent small clusters of cases from becoming costly epidemics. However, many under-resourced health systems lack adequate capacity for rapid laboratory diagnosis, especially for rare and emerging diseases. Instead, many outbreaks are only identified based on symptoms and only fully verified after many months. Furthermore, analytical tools to track and forecast outbreaks are rarely fit for use in low-resource settings. I will develop analytical methods and tools to help identify outbreak causes and respond to outbreaks more quickly and effectively, including by combining public health and data science approaches to rapidly predict the causes and properties of infectious disease outbreaks. Over the course of this fellowship, I will develop these methods, validate them against historical outbreak data, and finally build and field test software tools to be used by public health officials, empowering them to control outbreaks locally without international outbreak responses.

Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Determining the role of inter-kingdom interactions in the evolution of antimicrobial resistance
Funder: Wellcome Trust

Abstract: Polymicrobial infections consisting of Aspergillus fumigatus and Pseudomonas aeruginosa are associated with poorer patient outcomes and are often much harder to treat. There are a very limited number of drugs available to treat fungal infections, and both bacterial and fungal resistance is rapidly spreading in environmental and clinical settings. Determining the effect of inter-kingdom interactions between these pathogens upon the evolution of antimicrobial resistance is vital for the treatment of polymicrobial infections. Multispecies biofilms caused by coinfection of these two key respiratory pathogens create a physical barrier preventing drug penetration leading to protection from antimicrobial treatment. However, we understand very little about how competitive interactions within such communities can alter the mutational drivers of resistance or how coexistence changes the pleiotropic fitness costs associated with resistance. The aim of the project is to understand how coexistence and competition between A. fumigatus and P. aeruginosa alters the rate of resistance evolution in the presence and absence of antimicrobial treatment and how interactions change the fitness landscape of resistant mutants within both species. Understanding the drivers of resistance in polymicrobial communities may increase our ability to predict resistance evolution and aid the design therapeutic of strategies that limit the emergence of resistance.

Lay abstract: Infections where multiple different types of microbe infect a patient at the same time are difficult to treat due to the rapid evolution of antimicrobial resistance. During such polymicrobial infections pathogens release a vast range of mutation causing compounds to compete with each other, potentially affecting how quickly resistance evolves and spreads. I will use a combination of detailed experiments, gene editing and DNA sequencing to examine to how competition between the most common fungal and bacterial pathogens to form polymicrobial infections in the lung, Aspergillus fumigatus and Pseudomonas aeruginosa, affects the evolution of resistance in both species. I will investigate how interactions change the rate at which resistance evolves and how they alter the spread of resistance within a microbial community. My research is critical in designing and developing new treatments for polymicrobial infections in order to mitigate the evolution and spread of resistance.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Elucidating the structure and function of the divergent and essential cytochrome bc1 complex in apicomplexan parasites
Funder: Wellcome Trust

Abstract: Apicomplexan parasites, which include Toxoplasma and Plasmodium, cause deadly human diseases, such as toxoplasmosis and malaria. Understanding their divergent cell biology could inform strategies to combat them. The apicomplexan mitochondrial electron transport chain (mETC) is essential for their survival and transmission, and highly divergent from the human mETC. Cytochrome bc1 is an mETC protein-complex that is essential, and a key target for drugs, like atovaquone. Yet its composition is unknown, and the mechanism of function and inhibition poorly understood. I propose to investigate how the cytochrome bc1 complex functions and interacts with inhibitors. Using Toxoplasma as a model, I will uncover the role of my newly discovered apicomplexan cytochrome bc1 subunits, and decipher the role of respiratory super-complex formation, in parasite energy metabolism and survival. Using cryo-EM technology I will solve this complex’s structure to elucidate its mechanism of action, highlighting key differences with the human complex, and understand the way inhibitors disrupt the electron flow essential for energy conversion. These studies will provide a mechanistic understanding of the essential apicomplexan cytochrome bc1 complex and how inhibitors stop its function. This work will fill a critical gap in our knowledge of fundamental parasite cell biology, and likely inform drug discovery.

Lay abstract: Apicomplexans parasites infect humans and cause fatal disease including malaria. To grow and transmit between people the parasite relies on its energy producing compartment, the mitochondrion, and the chain of electron-transferring protein-complexes needed for energy production. One complex, cytochrome bc1, is the target of several drugs, but their mechanism of action is poorly understood. I have recently analysed the protein composition of cytochrome bc1 in the apicomplexan parasite Toxoplasma, and found there are differences from the human complex. This provides clues about how the parasite complex is different from the human complex, but critical details need to be further investigated. I aim to use genetic manipulation and structural analysis to understand the differences in how apicomplexan versus human cytochrome bc1 complex functions, and precisely how the parasite complex binds to inhibitor drugs. My work will enhance our understanding of these divergent organisms’ biology and may help develop new anti-parasitic drugs.

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