NIHRDataInsights/HRCSData huggingface dataset:
Title: Remaking One Health: Decolonial approaches to street dogs and rabies prevention in India
Funder: Wellcome Trust

Abstract: This study investigates the biosocial conditions that frame the persistence of rabies as a public health concern in India to rethink One Health approaches in post-anthropocentric directions. Dog-mediated rabies in Asia and Africa is a priority in transnational public health, and One Health approaches have scientific consensus as being key to its prevention (WHO 2019). India has the highest burden of human rabies globally despite long-standing initiatives, including One Health, on rabies elimination. Our project addresses this impasse. Challenging the (post)colonial One Health conceptualisation of street dogs as out-of-place disease vectors, our analytical framework of multispecies cultures directs new inter-disciplinary attention to the lived experiences of human and nonhuman animal actors, and to multiple dimensions of people-street dog relations in urban and rural India. We will examine historical and contemporary transnational influences on dog-related public health agendas; public attitudes and knowledge; everyday interactions between people, dogs, and the biophysical environment; and institutional interventions to advance decolonial concepts and practices for healthy multispecies societies. Through this fresh approach to rabies, we will reframe how One Health is theorised and pursued, and reconfigure it to enable more equitable approaches to health in a world marked by multispecies risk and vulnerability.

Lay abstract: Dog-mediated rabies is a major concern in many parts of Asia and Africa, being almost always fatal once symptoms appear. One Health approaches have gained precedence for addressing health problems that cut across humans and animals, especially rabies. India has large street dog populations and carries 35% of the global rabies burden despite long-standing rabies prevention initiatives, including One Health-informed programmes. In this project, we investigate why rabies persists as a public health problem in India. We build on research that suggests that the answer might lie in insufficient understanding of everyday people-dog relations. We will combine human geography, history, behavioural ecology, and social psychology to study people-dog interactions, dog ecology, and rabies prevention efforts in urban and rural India. Through this, we will generate lessons on making One Health initiatives more effective and ethical, and partner with public health practitioners to develop rabies prevention interventions that are socio-culturally appropriate.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Institutional Translation Partnership Awards 'LSTM translational enabler
Funder: Wellcome Trust

Abstract: staff are expected to contribute to our translational agenda and that focus is reflected in all the strategic investments LSTM has made over the past 20 years. LSTM reviews its research portfolio regularly identifying new areas for strategic investment. Current priorities centre around antimicrobial resistance (AMR) and therapeutics (with a particular interest in biologics) and translational skills-training opportunities. A recurring theme LSTM has encountered is a lack of translational focus and understanding in Early Career Researchers (ECR) joining the School from other organisations. We propose to use the WT Translational Partnership fund to address gaps is these areas. Funding will be available to individuals who need to develop their translational skills either within LSTM or through secondment to industry. In addition funds will be used to develop a training programme (in partnership with other iPTAs in Liverpool and Malawi) in translational science relevant to LSTMs mission.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: INFECTION
Title: Mathematical Modelling and Evolutionary Analysis of Chronic Viral Infections
Funder: Wellcome Trust

Abstract: Control of HIV and hepatitis C virus (HCV) requires multi-pronged approaches, including development of curative treatment and effective vaccines, identifying drivers of epidemics, and optimal deployment of interventions. Mathematical modeling and evolutionary analysis of viral genetic data is an important component in achieving these goals, by identifying the drivers of viral spread and evolution.Chronic viruses evolve rapidly within individuals, meaning transmitted viruses are different from the strain(s) that initiate infections. HIV is arguably the most studied pathogen in history, yet key unknowns remain, including the drivers of within-host evolution, and which viruses are transmitted. Less is known about HCV, which is further complicated by its complex within-host structure. Nevertheless, methodologies developed for HIV can be immediately employed for HCV, fast-tracking the analysis of this virusA major obstacle has been the short-read nature of viral deep-sequencing, limiting the power of analyses. I will refine and use new long-read deep-sequencing approaches we have developed to sequence and analyse viral populations from an unprecedented number of longitudinally sampled individuals. I will determine the drivers of within-host evolution, with a view to characterise transmitted viruses, develop better methods to infer viral spread and predict evolution in populations, enabling better targeting of interventions.

Lay abstract: Chronic virus infections, including HIV and hepatitis C virus are major health burdens, accounting for 1.4 million deaths a year. Remarkable progress has been made treating these infections and preventing onward transmission, fueling hopes new infections could be greatly reduced within a generation. Understanding the evolutionary process is a key component of this effort, enabling us to determine the factors driving localized epidemics, and predicting how viruses will respond to different interventions such as vaccination. Until now, we have lacked power to untangle these processes because sequencing methods break up viral genomes into small fragments. Using new sequencing methods that keeps these viral fragments intact, I will sequence virus from an unprecedented number of individuals who have been followed throughout infection. Analyzing this data I will uncover factors driving evolution of these viruses. This will lead to future work, including how best to target interventions.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Tuning neutrophil activation via HIF to clear mycobacterial infection
Funder: Wellcome Trust

Abstract: TB is a global crisis and treatment requires lengthy regimens of failing antimicrobials to clear infection. I propose that strategies that target the host, alongside antibiotics, would be more efficacious and combat the increasing prevalence of bacterial resistance. I have shown that HIF (hypoxia inducible factor) manipulation can activate pro-inflammatory responses against mycobacterial infection, specifically via Hif-1alpha stabilisation and resulting neutrophil activation. In addition, I can now demonstrate that arginase, a transcriptional target of Hif-2alpha, acts as a negative neutrophil immunoregulator, that on removal can activate neutrophils via an alternative mechanism to control mycobacteria. These findings indicate that neutrophils can be differentially activated via HIF manipulation, and that their protective properties could be therapeutically tuned during disease to clear infection. Therefore, I propose to address the following aims: 1. Determine the proinflammatory properties of Hif-1alpha-activated neutrophils 2. Characterise Hif-2alpha/arginase immunoregulation and their control of neutrophil phenotypes 3. Develop therapies to fine-tune neutrophil behaviours in infection This work will extend our understanding of therapeutic targeting of HIF as a host-derived therapeutic strategy against multi-drug resistant infections. This extension will allow expansion and implementation of exciting neutrophil zebrafish models and the first steps translating these findings to human systems.

Lay abstract: Infections are becoming increasingly resistant to antibiotics, leading to a global crisis and an urgent need for new medicines. Our approach is to better understand our immune response to infections to boost white blood cells to clear our bodies of infection before drug resistance can develop. An important white blood cell is the neutrophil. Neutrophils are difficult to study outside the body as they are easily activated and die quickly in a Petri dish. We will investigate the roles of neutrophils in zebrafish larvae – a simple live setting. Using new approaches we can tune neutrophils using the cellular response to hypoxia (low oxygen levels). Immune cells are activated by hypoxia since areas of infection are often oxygen deprived. We can trick neutrophils into hypoxic behaviour to boost infection control. If we could hone this therapeutically then patients could be cleared of infection more rapidly leading to decreased drug resistance.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Covid at RHN
Funder: Royal Hospital for Neuro-disability

Abstract: This is the extension of a previous project. This project will identify the most common clinical presentation of SARS-CoV2 in patient with complex neuro-disability and highlight the lessons learnt from the different waves.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Population genomic analysis of HIV transmission fitness
Funder: Wellcome Trust

Abstract: This proposal concerns the identification of genetic polymorphisms which alter the fitness of Human Immunodeficiency Virus (HIV-1), the robust estimation of virus fitness, and the characterization of how polymorphisms influence replicative fitness within hosts versus transmission to new hosts. HIV evolves to evade the immune system, resist antiviral medications, and maximize its rate of replication within infected hosts. But at the epidemic level, natural selection promotes evolution of variants which are more transmissible. Natural selection within and between hosts can act in opposing directions, and evolutionary trends have been discerned from population based sampling of HIV such as a hypothetical transmission/virulence tradeoff. Because HIV evolves at multiple scales, the fitness of a particular polymorphism should be characterized along multiple dimensions including its impact on replication within hosts and transmission to new hosts. We will develop a framework for characterizing genetic fitness along multiple dimensions by building on theory developed for estimating state-dependent speciation rates. These methods will be applied to several large population-based samples of whole-genome deep sequencing (WGDS) of HIV. The outcome of this analysis will be an unprecedentedly detailed characterization of how particular genetic substitutions influence HIV pathogenesis and transmission at the epidemic level.

Lay abstract: HIV evolves to maximize replication within hosts and transmit to new uninfected individuals, but we currently lack a detailed understanding of how changes in the HIV genome alter the ability of HIV to reproduce and spread. To understand how beneficial mutations spread at the epidemic level requires a deeper understanding of how mutations impact transmissibility of the virus. We will develop new bioinformatic methods to estimate fitness along multiple dimensions associated with replication and transmission. We will identify new mutations which are associated with gain or loss of transmission fitness. These methods will be applied to new large population-based samples of whole HIV genomes across sub-Saharan Africa. These findings will have relevance for vaccine design and forecasting the future evolution of the HIV epidemic, and the potential for therapeutic vaccines to modify the transmissibility of HIV will be explored.

Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Functional analysis of the downstream mediators of cyclic nucleotide signalling in malaria parasites
Funder: Wellcome Trust

Abstract: Our research programme will deliver mechanistic understanding of how cyclic nucleotide signalling controls the development of two key phases of the malaria parasite lifecycle: the asexual blood stage that causes pathology, and gametogenesis that is required for transmission to the mosquito vector. We have previously shown that there is a temporal switch from cyclic GMP (cGMP) signalling to cAMP signalling as the asexual parasite progresses from egress (escape from its host erythrocyte) to invasion. Cyclic GMP signalling also controls egress of sexual stage parasites to enable fertilisation in the mosquito. In both lifecycle phases, egress requires cGMP-dependent calcium flux. We have recently identified a unique, essential membrane-bound binding partner of the cGMP-dependent protein kinase (PKG). We have also identified a set of high confidence targets of cAMP signalling required for invasion and subsequent parasite development, and have obtained exciting new insights into how cGMP production is governed. We now want to: (1) determine the mechanisms underlying the interrelationship between cGMP and calcium signalling; (2) dissect the role of cAMP-dependent phosphorylation in erythrocyte invasion; and (3) identify the parasite proteins that interact with cyclase and phosphodiesterase enzymes (which balance cellular levels of cyclic nucleotide) to understand how the pathways are regulated.

Lay abstract: Malaria parasites replicate asexually in the bloodstream of patients, causing all the symptoms of disease. Parasite proliferation also generates male and female parasites, which are taken up by a feeding mosquito and have sex in the mosquito to allow disease transmission. A parasite biochemical pathway called cyclic nucleotide signalling controls critical steps in the progression of this complex malarial life cycle. Using genetic and biochemical approaches we have discovered which malaria parasite enzymes (cyclases, phosphodiesterases and protein kinases) in this pathway are important for asexual and sexual development. We have also identified a novel protein which is key to the link between cyclic nucleotide signalling with another essential pathway driven by cellular calcium. We now want to determine the detailed mechanisms by which these proteins and pathways interact, and importantly how we can disrupt the pathways to provide targets and a rational framework for the development of next-generation antimalarial drugs.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Do agricultural insecticides utilisation in West and Central Africa select for insecticide resistance in the major malaria vector An. gambiae sl.?
Funder: Wellcome Trust

Abstract: Insecticide resistance in major malaria vectors significantly weakens control efforts and limits capacities of eliminating this disease. Agricultural use of pesticides has been suggested as a key factor contributing to resistance selection across west and central Africa. However, these preliminary findings need to be substantiated by stronger evidences from more extensive investigations. This project to be jointly conducted with the agriculture sector(One-Health) has an overall goal to thoroughly analyse the contribution of agro-insecticides in the selection of insecticide resistance in the major malaria vectors An.gambiae sl. This 5-year's proposed research will (i)help establish the resistance selection risk associated with different cropping systems, will set basis for an evidence-based dialog between public health and agricultural sectors on best ways to use existing insecticides and also anticipate on the use of new compounds,(ii)will inform on the level/intensity of selection pressure exercised by different types of insecticide residues left in breeding sites after crops treatments,(iii)will contribute to the development of molecular markers for early detection, monitoring and surveillance of insecticide resistance for improved control of malaria vectors.Information from this research will be compiled for sensitizing both agriculture extension-workers and malaria control decision makers on the need for cross-sectoral resistance management strategies (One-Health Concept).

Lay abstract: Mosquitoes, the insects transmitting the deadly malaria disease are becoming increasingly resistant to chemical insecticides used for their control.This might be due to the inappropriate use of the same chemicals in farming to kill crop pests.The resistance of malaria mosquitoes collected in and around agricultural settings has been reported from few published research.These preliminary information have to be extensively examined to really elucidate the contribution of agricultural use of insecticides in the emergence of insecticide resistance in malaria mosquitoes. In this 5-Year's research,I plan to determine the resistance status of mosquitoes breeding around different types of crops found in west and central Africa compare to those breeding where no agriculture is practiced, identify which cropping system has higher risk of contributing to resistance in malaria mosquitoes.Information from this research will be used for sensitizing both agriculture extension-workers and malaria control decision makers on the need for cross-sectoral resistance management strategies.

Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: Understanding the impact of global change on animal-borne diseases
Funder: Wellcome Trust

Abstract: We know little about how future climate change, habitat destruction, human population increases and greater globalisation processes will impact human zoonotic diseases. Here, I investigate the use of dynamic, seasonal host population models to better predict the impact of real-time environmental change on disease-carrying host species, within a general systems-dynamics, disease framework. Specifically, I will combine a mathematical compartmental disease model with a host population ecology model, within a spatial and temporal BaYESian framework. Using this approach, I will first model Lassa Fever using climate and land-use observations, collaborating with the Nigerian government. I will then augment my model to account for animal movement patterns and vector species abundances, to examine arboviral disease spread in north America. Then, I will integrate these threads into a general, dynamic modelling framework for zoonotic diseases, which will contain both the newly developed components and my previously developed model of human movement and behaviour. Working with the World Health Organisation, I will create short- and long-term disease forecasts for a set of high priority zoonoses. Once validated against human case data, these mechanistic models can be used to test interventions and create future disease management plans that are robust to upcoming global change.

Lay abstract: The natural world is expected to undergo a significant transformation over the next century, driven by climate change, habitat destruction, human population increases and greater globalisation. Diseases, such as Ebola, Plague and Anthrax, are caught when people come into contact with wild animals and these diseases, called 'zoonoses', are likely to be strongly impacted by global change processes. To better understand this, I will create a dynamic model of seasonal changes to disease-carrying, wild-animal populations and the pathogens they host, to help predict the long- and short-term future risk for a set of high priority zoonoses, including Lassa Fever and West Nile Virus. Then, working alongside the World Health Organisation and Nigeria Centre for Disease Control, I will create a set of practical tools to allow decision-makers to better understand how to prepare disease management frameworks that are robust to upcoming future global change, to help prevent future disease.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The translational potential of mass spectrometry and next-generation sequencing in patients with central nervous system infections in Vietnam
Funder: Wellcome Trust

Abstract: Central nervous system (CNS) infections are devastating conditions worldwide, especially in low- and middle-income counties (LMIC). Clinical outcomes are dependent upon the rapid identification of the causative agent and instituting effective antimicrobial therapy, although the causative agent is only identified in <50% of patients. Furthermore, Southeast Asia is highly susceptible to the emergence of novel and drug resistant pathogens. New diagnostic techniques are urgently required for rapid response to future outbreaks, and to improve patient outcomes. This Fellowship will focus on the translational potential of mass spectrometry and next-generation sequencing (NGS) in clinical diagnostics of CNS infections in Vietnam, and has three key goals: 1. To determine whether Mass spectrometry of cerebrospinal fluid (CSF) will identify protein/peptide signatures associated with different infectious aetiologies. 2. To determine whether NGS-based metagenomic analysis will identify a broad range of known/unknown pathogens in the CSF and improve upon current standard laboratory assays. 3. To determine whether NGS can provide rapid, whole genome sequence-based prediction of antimicrobial susceptibility for Mycobacterium tuberculosis and Streptococcus pneumoniae. I aim to provide proof-of-principle that CSF proteomics- and NGS-based methods can improve upon the diagnostic assays currently available in hospital settings, especially in LMIC, and thereby potentially improve patient outcomes.

Lay abstract: Brain infections are common in low- and middle-income countries and are often fatal. Doctors are currently hamstrung by inadequate laboratory tests, especially in poorer parts of the world, and often don’t know what caused the infection and can’t give effective treatment. The situation is exacerbated by the emergence of new, previously unrecognized infections and infections resistant to antibiotics. I aim to show that new diagnostic tests, targeted at proteins found in brain fluid of patients and the genetic material of infectious agents, can improve upon tests commonly used in Vietnamese hospitals. Better tests, which quickly tell doctors the cause of the infection and which antibiotics will kill it, will help patients with brain infections worldwide. I will recruit 750 patients with brain infections over 3 years at the Hospital for Tropical Diseases, in Ho Chi Minh City, Vietnam. I will analyze brain fluid from these patients to: 1. discover whether the proteins in the fluid can tell us what is causing the infection 2. determine if finding the complete genetic code of the bug causing the infection is better than current conventional tests 3. determine if the genetic code can rapidly predict antibiotic resistance and guide effective treatment

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