NIHRDataInsights/HRCSData huggingface dataset:
Title: Molecular mechanisms of carbohydrate uptake in Mycobacterium tuberculosis
Funder: Wellcome Trust

Abstract: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB) and is now the leading cause of death from a single infectious agent in the world, killing more people world-wide than HIV and malaria. With the escalation of drug-resistant TB infections we urgently need to develop novel strategies and interventions to control the growing TB global epidemic. To enable this, we need a more detailed understanding of the fundamental biology of Mtb. Mtb is an unusual pathogen that has the exceptional ability to survive within the human host for decades. However the energy sources that Mtb uses within this nutrient-poor environment and the mechanisms involved in their transport are poorly understood. The overarching aim of this project is to use a multidisciplinary approach combining chemistry, biochemistry and microbiology to determine i) which carbohydrates are (re)used by Mtb, ii) how they are (re)used and iii) the molecular mechanisms involved in these processes. This project will provide key insights into carbohydrate uptake/recycling and metabolism by Mtb and assign physiological function to the proteins involved. Altogether, these results will generate important mechanistic insights into the survival of this global pathogen and validate whether these pathways represent therapeutic/diagnostic targets.

Lay abstract: Tuberculosis (TB) is one of the leading cause of death world-wide. The bacterium that causes TB - Mycobacterium tuberculosis (Mtb) – is very unusual and has the exceptional ability to survive, undetected, in the body for decades. However the nutrients that Mtb uses and the mechanisms that are involved to transport these into the cell are not known. I will use a multidisciplinary approach to determine which sugars are taken up by Mtb and the molecular details underpinning these processes. I will use biochemical and structural analyses to determine how proteins recognise and transport specific carbohydrates and visualise these interactions. I will also alter the uptake of sugars by generating genetic mutants in Mtb and explore the phenotypic changes that occur and why. Altogether, these studies will help to explain how the Mtb pathogen uses sugars with the potential to lead to new strategies and interventions for this deadly disease.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Studying hepatitis C virus to determine how viruses harness structural disorder to control entry and antibody resistance.
Funder: Wellcome Trust

Abstract: The activity of viral entry machinery is tightly regulated to ensure successful infection. We have discovered that the hepatitis C virus entry glycoproteins, E1 and E2 (E1E2), possess a hitherto unrecognised regulatory mechanism that controls virus entry and neutralising antibody (nAb) resistance. This is dependent on disorder and dynamics in the peptide tail of E2. We call this the entropic safety catch.This is important for three reasons: i) it is a significant advance in our understanding of the molecular mechanics of E1E2 ii) rational immunogen design remains hampered by a poor functional understanding of E1E2; our discovery may inform ongoing HCV vaccinology iii) it establishes that viruses can harness structural disorder to regulate virus entry, nAb resistance and protein-protein interactions.We will ask how the entropic safety catch functions during infection; examining its adaptive tuning in response to emergent nAbs, and investigating its evolutionary origins. We will use biophysical and structural analysis to determine the molecular basis that allows the safety catch to control entry. This work will uncover fundamental mechanisms by which dynamics and disorder govern protein function. This will be relevant to HCV, and likely other important pathogens, having implications throughout the viral proteome and beyond.

Lay abstract: Viruses gain access to host cells through the action of their entry proteins; these are 'spring-loaded' for dramatic, irreversible, shape changes in response to cues from the host. Premature triggering inactivates entry proteins, therefore, viruses need to carefully regulate them. We have discovered a molecular safety catch that controls the entry proteins of hepatitis C virus (HCV).Our work provides a new perspective on entry by HCV and viruses in general. We will use this knowledge to make further discoveries. The safety catch provides a means to resist immune responses; we will ask whether it permits evasion of antibodies during chronic infection. We will also determine the molecular machinery that allows the safety catch to control virus interactions with the host. This project will advance our understanding of HCV, inform future vaccine design and establish how molecular safety catches may operate in other viruses.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Evolutionary and epidemiological dynamics of multistrain bacterial respiratory pathogens
Funder: Wellcome Trust

Abstract: Population genomics demonstrates many bacterial species are subdivided into distinct strains, changes in the prevalence of which are the primary drivers of many clinically-important trends, such as the global spread of multidrug-resistance and the emergence of vaccine-evading pathogens. During my fellowship, I have developed models of the evolutionary and epidemiological dynamics of Streptococcus pneumoniae that presume they are driven by intragenomic conflict and competition between phenotypically-distinct strains. This extension will test these assumptions through experimental characterisation of clinical isolates and mutant genotypes, and panprotome-wide immunological data. The models’ applicability to two other naturally transformable respiratory pathogens, Haemophilus influenzae and Moraxella catarrhalis, will also be evaluated. Genome sequencing of isolates from systematic nasopharyngeal carriage surveys from two locations will enable comparisons with equivalent S. pneumoniae samples. Despite isolation from the same niche, these species vary in their population structure, antibiotic resistance profiles and responses to vaccination. Experiments and bioinformatic analyses will address whether this divergence is primarily driven by differences in recombination, epidemiology or ecology. These results will be used to improve models that explain the distribution of antibiotic resistance and post-vaccine changes in disease, with the aim of generating validated frameworks for aiding public health policy decisions using genomic data.

Lay abstract: Many disease-causing bacteria can be divided into strains, which often vary in traits such as virulence or antibiotic resistance. Our ability to follow trends in strains’ prevalence through surveillance is increasing, but our understanding of why these changes occur is limited. The recent availability of large collections of bacterial genome sequences has made it possible for me to construct mathematical models of what determines strains’ prevalence, and how they change over time through evolution. This project will allow me to test and improve these models through experiments and analysis of data from bacteria isolated from the nasal passages of healthy children from two locations. Despite all coming from the same habitat, these bacteria vary in their resistance to antibiotics, and their ability to evade vaccine effects. I aim to understand what underlies these differences, with the goal of helping to improve policies used to prevent bacterial infections.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Epidemiology of Tungiasis in Kenya
Funder: Wellcome Trust

Abstract: Tungiasis is an extremely Neglected Tropical Disease and has received little attention from researchers, granting bodies, and government Departments of Health. It is caused by the sand flea, Tunga penetrans, the female of which burrows into the epidermis, mostly of the feet, where it grows 2000 fold in 7 days, inducing severe inflammation, immense pain and itching. Chronic re-infection leads to severe morbidity. Although it is known to occur mostly in children under 15 years in marginalized, resource poor communities in the Caribbean, South America and Sub-Saharan Africa, not a single country knows its national prevalence, nor impact on its population. I am proposing to conduct the first ever national prevalence survey in Kenya using a cross-sectional, randomized, stratified cluster design of 10,950 students in primary schools. The survey will be repeated in the dry and wet seasons to investigate the seasonality of transmission. A sub-sample of infected and uninfected students will be selected to determine the impact tungiasis has on the quality of life, cognitive development and educational achievement. Interviews with teachers and students will investigate possible risk factors for severe disease. The goal is to provide information to mobilize resources and guide policy development for control programs.

Lay abstract: Sand flea disease has received little attention from researchers, granting bodies and government Departments of Health. It is caused by a female flea which burrows into the skin, mostly of the feet, where it grows 2000 fold in 7 days, causing immense pain and itching. Although it is known to occur mostly in children under 15 years in poor communities in the Caribbean, South America and Sub-Saharan Africa, not a single country knows how many people are infected, nor the impact on its population. I am proposing to conduct the first ever national survey of primary school students in Kenya to find out what proportion are infected. A sub-sample of infected and uninfected students will be selected to assess the impact the disease has on the quality of life and school achievement. The goal is to provide information to encourage and guide control programs.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Adaptive Molecular Diagnostics
Funder: Wellcome Trust

Abstract: Our project will use genomic data and a detailed understanding of pathogen evolution to deliver a robust, rapid, accurate and cost-effective pathogen detection kit for use in the field. Current methods are unsuitable for detection as they are slow, inaccurate and cannot be field deployed. Our work has already changed the basic understanding of how cholera spreads and identified high and low epidemic risks that are the cornerstones of disease prevention. By making robust molecular indicator kits adapted to field settings we are able to rapidly probe the likely behaviour of cholera strains and provide actionable data that can make a direct contribution to a major human health challenge.

Lay abstract: Our project will use genomic data and a detailed understanding of pathogen evolution to deliver a robust, rapid, accurate and cost-effective pathogen detection kit for use in the field. Current methods are unsuitable for detection as they are slow, inaccurate and cannot be field deployed. Our work has already changed the basic understanding of how cholera spreads and identified high and low epidemic risks that are the cornerstones of disease prevention. By making robust molecular indicator kits adapted to field settings we are able to rapidly probe the likely behaviour of cholera strains and provide actionable data that can make a direct contribution to a major human health challenge.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Investigation of pre-existing immunity to coronaviruses; implications for immunopathology and pathophysiology of COVID-19 disease
Funder: Wellcome Trust

Abstract: Background; It is unknown how prior exposure to commonly circulating human coronaviruses (HCoV) impacts immunity against highly-pathogenic species (SARS, SARS-CoV-2 & MERS). There are limited data, across Europe, Asia and Africa, on the prevalence of infection and seroconversion against widely circulating and mildly symptomatic HCoVs (229E, NL63, OC43, and HKU1). There is a current supposition that antibody-dependent-enhancement (ADE) may play a role in the pathophysiology of COVID-19. ADE occurs when non-neutralizing antiviral proteins facilitate virus entry into host cells, leading to increased infectivity in the cells. In such cases, higher viremia has been measured and the clinical course of disease can be more severe. In preclinical animal models, immunopathology was observed after challenge following vaccination with some SARS vaccines. Therefore, concerns have been raised regarding the impact of immunopathology and ADE on prophylactic vaccination against SARS and possibly SARS-CoV-2. Goals: to perform detailed systems serology of pre-existing immunity, in children and adults, from the UK and Africa, towards novel and commonly circulating coronaviruses. Impact: These studies highlight the limited knowledge in the field and a need for a systematic approach to investigate cross-reactive humoral immunity against HCoV to inform the immunopathology and pathophysiology of COVID-19.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The Impact of Pneumococcal and Malaria Vaccines on Bacterial Resistance, Febrile Illness and Antibiotic Usage in Young Children In Malawi
Funder: Wellcome Trust

Abstract: Across much of sub-Saharan Africa, pneumococcal disease (otitis media and pneumonia) and malaria are leading causes febrile illness, and therefore drivers of both appropriate and inappropriate antibiotic use. Prevention through vaccination has the potential to influence antimicrobial resistance (AMR) both directly and indirectly. We are in a unique position to leverage two large funded cluster-randomised vaccine evaluations in Malawi: 13-valent pneumococcal conjugate vaccine (PCV13) schedule change (3+0 to 2+1; extending immunity and potentially herd protection); and RTS,S malaria vaccine introduction. We will ask what are the direct and indirect selective effects of pneumococcal and malaria vaccines on antibiotic resistance, febrile illness and antibiotic usage in young children in Malawi? We will determine whether in children <3 years, a PCV13 schedule that extends protection or malaria vaccine introduction leads to a change in the AMR profile of S. pneumoniae carriage isolates; the upper respiratory tract resistome; and stool carriage of extended spectrum beta-lactamase (ESBL) E. coli or Klebsiella. We will assess whether the pneumococcal or malaria vaccines alter the frequency of febrile illness and antibiotic use in children <3 years; and then refine and test a well-established mathematical model to predict the likely impact of vaccines on AMR prevalence.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Understanding the impact of COVID-19 on bacterial sepsis, antibiotic consumption and stewardship, and antimicrobial resistance
Funder: Wellcome Trust

Abstract: This study aims to address the following questions through a global network of hospitals: 1. Is there evidence for a reduction in the total number or rates (per 1,000 inpatients) of blood cultures taken over twelve months? 2. Has there been changes in antimicrobial usage (quantitative and qualitative)? 3. Are there major changes in antibiotic resistance profiles from major pathogens? 4. Have there been changes in antimicrobial stewardship and why? 5. What is the overall change in the management of these patients? 6. What is the impact of COVID-19 on infection control practices during the pandemic? 7. Is there any evidence of reduction in nosocomial infections and bacterial outbreaks during the COVID-19 pandemic? We will collect clinical (patient-based [severe pneumonia, ARDS, sepsis patients], hospital and microbiological data from 11 countries (UK, Switzerland, Italy, Brazil, Nigeria, Malawi, Turkey, Iran, India, Bangladesh and South Korea). Our primary outcome will be to determine if there has been a reduction in blood cultures taken. Secondary outcomes include whether 1. changes in antimicrobial usage 2. major changes in antibiotic resistance profiles from major pathogens in hospitals during COVID-19 and correlate resistance profiles with antibiotic usage. 3. changes in infection control practices and other aspects of sepsis management behaviour during the COVID-19 pandemic.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: National COVID Testing Africa AAPs/Centre
Funder: Wellcome Trust

Abstract: Aims and key deliverables; 1. To provide consistent technical support to national testing programmes for SARS-CoV-2 in Kenya, Malawi and South Africa. 2. To support epidemiological research, clinical trials, immunological studies and genomics work 3. To consolidate and maintain positive relationships with national policy makers. Our respective Wellcome AAPs/Centre (i.e. MLW, KEMRI-Wellcome, AHRI and CIDRI-Africa) have responded to the COVID-19 pandemic by making resources and staff available for SARS-CoV-2 testing, accounting currently for significant proportions of the local and/or national testing capacities, especially during surges. It is ethically imperative to provide national support alongside research-driven testing, and we have found this testing provided an opportunity to develop stronger relationships with national Government, with the potential for research that is better aligned to informing policy and with a better position to communicate. The immediate need has been covered by re-allocating resources for paused activities. The proposal here will bridge the gap between our immediate response and more sustainable long-term funding. This will allow us to sustain the enhanced relationships developed through our response to the pandemic, and will avoid the reputational risks that might be associated with failing to support the obvious ongoing need while establishing more sustainable long-term projects and core provisions.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Defining the factors that determine patient outcome following Staphylococcus aureus bacteraemia.
Funder: Wellcome Trust

Abstract: Staphylococcus aureus is a major human pathogen, and of the types of infections it causes, bacteraemia is one of the most severe with mortality rates as high as 30%. With rates of bacteraemia increasing year on year, and antibiotic resistance making treatment more challenging, efforts are increasingly being focused on developing a vaccine. However, despite significant investment all attempts have failed, because we do not have a sufficiently detailed understanding of S. aureus’ pathogenicity. This proposal aims to address this deficit in understanding by applying a multi-stranded and multi-disciplinary research approach to large collections of clinical S. aureus isolates. Preliminary work modelling phenotypic, genomic and clinical data identified several novel bacterial features that significantly contribute to patient outcome following S. aureus bacteraemia. By adopting molecular, cellular, ‘omics and mathematical modelling approaches, this project will characterise these novel features and determine the contribution they make to the outcome of individual bacteraemic patients. In addition to transforming our understanding of S. aureus pathogenicity, the finding of this project has the potential to inform future S. aureus vaccine design approaches and identify bacterial targets for the development of novel therapeutic approaches.

Lay abstract: The presence of bacteria such as Staphylococcus aureus in our blood can have catastrophic effects and result in the death of up to 30% of infected patients. With worrying rates of antibiotic resistance, numerous attempts have been made to develop a S. aureus vaccine. These have unfortunately failed, because we do not fully understand how this bacterium causes severe disease. Addressing this poor understanding is the major focus of this proposal. Preliminary work has identified a number of new bacterial features that contribute to whether a patient survives their bacteraemia or not, and here I propose characterising these features to determine their activity. In addition to transforming our understanding of how this bacterium causes disease, the findings of this project can also help in both the design of future vaccines and in the development of new ways to treat infections.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Mitigating rodent impacts on health and well-being in rural Madagascar
Funder: Wellcome Trust

Abstract: In low-income countries, rodents have very significant impacts on health and well-being. Annually cereals lost to rodents could feed hundreds of millions of people, whilst rodent-borne infections (RBI) kill thousands. A major research challenge is developing holistic rodent management strategies that deliver both improved food security and reduced disease burdens, and are sustainable for communities. I will work with health and agricultural stakeholders and communities to fill key knowledge gaps and adapt and test innovative management techniques developed in the agricultural sector, primarily in Asia, to other ecological and socio-cultural contexts. Working in Madagascar, I will combine empirical and modelling studies to explore how localised control impacts on the risk from a range of RBI with contrasting transmission routes, determining in what circumstances control increases or decreases risk. I will test the cost-efficiency of different strategies, using an approach that incorporates agricultural losses, disease burdens and management costs. With communities I will explore the impacts of socio-cultural practices, identifying opportunities and constraints for community-led control. To optimise management strategies, adaptive research experiments will be co-developed and evaluated with communities and stakeholders. Active engagement with national and international stakeholders throughout the project will facilitate scaling up and policy impact.

Lay abstract: Rodents significantly impact communities in low-income countries. Each year they destroy crops that could feed hundreds of millions of people and transmit diseases which kill thousands of people. Controlling rodent populations effectively is challenging because new rodents move in from neighbouring populations, this can exacerbate disease risk in some circumstances. Innovative community-led management techniques that exploit knowledge of rodent ecology have been developed to reduce crop losses. However, the impact of these on disease risk has not been considered. Working in Madagascar, I will work with communities to develop and test control strategies that aim to reduce both agricultural losses and disease risk. I will use field experiments and computer models to determine where and when to control rodents. I will examine the cost-efficiency and feasibility of different management strategies for communities. By working with national and international organisations I will make sure that this research informs policy across Africa.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: INFECTION