NIHRDataInsights/HRCSData huggingface dataset:
Title: Cellular immunity and resistance to schistosomiasis in the Philippines
Funder: Medical Research Council

Abstract: Schistosomiasis remains a major health risk in the Philippines, with 12 million people at risk of infection. The aim of this proposal is to assess the role of immune cells in resistance or susceptibility to reinfection. Previous studies have shown that anti-schistosome IgE responses are associated with resistance to reinfection, while IgG4 responses are associated with susceptibility, but the mechanisms controlling IgE and IgG4 antibody generation in schistosomiasis remain poorly understood. The current proposal aim to address this gap by analysing correlates of protection in a prospective, longitudinal cohort study of individuals living in a schistosome-endemic area of the Philippines. Cellular and antibody responses will be analysed at baseline and at follow up intervals after treatment to correlate immune phenotype with reinfection status. We hypothesise that the frequency and phenotype of follicular T helper cells (Tfh) and follicular T regulatory cells (Tfr) determine the antibody classes produced and hence, a resistant or susceptible phenotype in infected individuals. No previous studies have investigated the role of Tfh and Tfr cells in schistosomiasis and the new information gained from this study will be of importance to combat this debilitating disease in the Philippines, as it remain a major barrier to social and economic development. Our study will provide a better understanding of the immune response and will inform the future development of vaccines. Thus, our project will promote advancement in biotechnology and health sciences that will impact public health in the Philippines and globally. Our proposal will benefit the international mobility of Filipino researchers and the establishment of sustainable global scientific partnerships. These advances in scientific understanding and in capacity building will provide a framework for tackling barriers to development and for nurturing progress, allowing Filipino investigators to be key drivers in change.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: INFECTION
Title: Using host-responses and pathogen genomics to improve diagnostics for tuberculosis in the Philippines
Funder: Medical Research Council

Abstract: Tuberculosis disease (TB), caused by M. tuberculosis (Mtb), is an important global public health issue. The Philippines remains one of the 22 high-TB burden countries in the world. Improving diagnostic tools for TB could assist the identification of active disease and evaluation of the response of anti-tuberculosis treatments, ultimately leading to disease control. Our study aims to use next-generation sequencing and bioinformatic techniques to characterise the human response to Mtb infection, which has previously been shown to offer an accurate and sensitive diagnostic for active TB. However, previous work has not assessed the impact of Mtb strain on diagnostic ability, or converted these signatures into useable in-house assays, such as PCR. In this project, we will seek to generate a human blood transcriptome based risk score, measured by a PCR assay that can be used in the Philippines across their strain diversity and local environments. Insights from this work could lead new diagnostics and control policy. This project will also capacity build in the Philippines for genomic technologies and analysis.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: ZooTRIP. Zoonotic transmission of intestinal parasites: implications for control and elimination
Funder: Medical Research Council

Abstract: This interdisciplinary project will assess the contribution of zoonotic transmission and environmental reservoirs to the burden of human intestinal helminth infection in the Philippines, and determine the most effective strategies for intestinal helminth control and elimination. Objective 1 will investigate the epidemiology of intestinal helminths circulating in humans, animals and the environment through a cross-sectional community-based field study, involving parasitological and molecular diagnosis of intestinal helminths in participants and their animals, detection of helminth eggs in soil and crop samples and a questionnaire to gather demographic, socio-economic and environmental data. Objective 2 will use genome sequencing to characterise Filipino helminth isolates, identify markers for molecular epidemiology and establish a multi-locus sequence typing scheme. Genotyping assays will be used to detect zoonotic transmission and anthelmintic resistance markers in samples collected during the field survey. Objective 3 will develop mathematical models to quantify the contribution of zoonotic transmission and environmental reservoirs to human infection risk and predict the effects of intervention strategies. Epidemiological and genetic data gathered under Objectives 1 and 2 will be used for model parameterisation. Objective 4 will formulate policy recommendations based on model outcomes and an evaluation of the socio-economic and health impacts of intestinal helminth infections in the Philippines. This will involve quantitative risks assessment, impact quantification and economic valuation of impacts. Overall the project will shed new light on the epidemiology of intestinal helminths in the Philippines and quantify the contribution of zoonotic transmission to human infection. Project findings will lead to increased effectiveness and sustainability of intestinal helminth control in the Philippines and worldwide, and ultimately to health improvements in endemic areas.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: SPEEDIER - Surveillance integrating Phylogenetics and Epidemiology for Elimination of Disease: Evaluation of Rabies Control in the Philippines
Funder: Medical Research Council

Abstract: SPEEDIER's aim is to deliver a cost-effective, epidemiologically robust, enhanced surveillance and response package to guide and sustain the elimination of rabies from the Philippines. The package includes integration of surveillance and response activities by the human and animal health sectors ('One Health') through a program of Integrated Bite Case Management to improve patient care and trigger early detection of animal rabies cases. As part of the package we will develop a genomic surveillance platform as a decision support tool to inform control activities and assess incursions risks, and undertake epidemiological modeling to inform contingency planning for managing re-emergence and maintaining disease freedom. We will specifically develop protocols, integrated training and surveillance tools with comprising: 1) risk assessments of bite victims as part of Integrated Bite Case Management; 2) the latest WHO recommended PEP protocols; 2) Epidemiological investigations including animal observation, sample collection and rapid diagnostic testing and 3) use of a mobile phone application for reporting by human and animal health workers and 4) real-time whole genome sequencing of viruses using a multiplex/MinION approach incorporated into genomic surveillance platform for communicating risks of rabies spread and progress towards elimination. This enhanced surveillance will be implemented over across 3 provinces: Romblon, Mindoro Occidental and Mindoro Oriental to generate comprehensive data on dog bite incidence, associated rabies risk, PEP use and circulating viruses. Within this implementation study, a pragmatic stepped-wedge cluster-randomised trial of rationalized use of PEP will assess potential for cost savings and improved patient care. The tools and best practice produced by SPEEDIER will enable sustainable national roll out and provide a model for the global target to achieve zero human rabies deaths by 2030.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.3 INFLUENCES AND IMPACT
Health categories: INFECTION
Title: Understanding human cytomegalovirus latency as a means to target the latent reservoir
Funder: Medical Research Council

Abstract: HCMV primary infection of the immunocompetent is asymptomatic. However, infection of individuals with compromised or immature immune systems can be life threatening. Furthermore, HCMV persists for the lifetime of the host which, due to its ability to avoid immunesurveillance and, ultimately, establish a latent infection. Cellular latency is defined maintenance of viral genomes in the absence of infectious virus production. Consequently, current therapies targeting HCMV replication will not target the latent virus; yet reactivation from latency is a major cause of disease in immune suppressed transplant patients. Work from our laboratory has been instrumental in identifying some of the viral genes expressed during latency, the host immune responses to these antigens and how these genes modify the latently infected cell. However, the viral transcriptome is likely far more complex than initially thought and how latent virus modifies the latently infected cell will be a result of a complex array of interactions between multiple latency-associated viral gene products and a multitude of host cell functions. On this basis, we have now made considerable efforts to try to analyse changes in the total cell proteome resulting from latent infection by unbiased approaches which has helped identify important phenotypic changes resulting from latent infection. We also have developed unbiased screening technologies to identify viral and cellular factors necessary for the establishment and maintenance of latency, as well as reactivation, in the myeloid lineage. Such analyses will allow a more comprehensive understanding of how this human pathogen persists for the lifetime of the host and will also help us to exploit the phenotypic changes in the latently infected cell for chemotherapeutic and immunological targets to lead to credible strategies aimed at eliminating latent virus in vivo and in solid organ donor tissue.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Effectors of tissue invasion in Aspergillus fumigatus, the major fungal pathogen of human lungs
Funder: Medical Research Council

Abstract: To identify A. fumigatus effectors of tissue invasion (eTINs) we used a HTP fusion PCR approach to construct null A. fumigatus mutants for all 253 of the SignalP proteins whose expression, relative to laboratory culture, is significantly upregulated during mouse colonisation. We then screened the mutant collection in a 384 well format, epithelial lysis assay to identify mutants having lytic defects in host co-culture. The starting point for this proposal is a collection of n = 42 signalP protein-encoding genes which are specifically upregulated in response to the mammalian host environment and whose encoded gene products are required for lysis of human respiratory epithelia. This collection is a first-in-field collection of A. fumigatus effectors of tissue invasion (eTINs). The aims of this study are to: 1. Screen the collection of eTIN null mutants in neutropenic mice to identify dominant effectors of tissue invasion 2. Sort eTINs according to modes of host activation using established in vitro infection models 3. Define spatiotemporal localisation profiles of eTINs during A. fumigatus co-culture with human respiratory epithelia 4. Combine high throughput gene deletion and classical genetics to define the minimal invasive secretome of A. fumigatus 5. Define eTIN modes of translocation and identify host binding partners


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Evaluation of a Mask Aerosol Sampling System (MASS) as an Active Case Finding Approach Focused on Infectious TB in Low-Resource Settings.
Funder: Medical Research Council

Abstract: We aim to evaluate use of our mask aerosol sampling system (MASS) to detect individuals with pulmonary TB (pTB) in a community oriented primary care programme in Tshwane district (RSA). We will test the capacity of MASS combined with Xpert MTB/RIF analysis to detect pTB at similar or greater rates than conventional symptom and sputum review. Mask samples are obtained in 15 min from all who take part. Because many individuals with pTB either do not produce sputum or attend clinic when requested, we believe MASS may increase detection rates. Recent evidence clearly indicates that analysis of patient aerosols for Mtb provides a more accurate assessment of infectivity than sputum. Our unpublished MASS studies show that up to 20% of individuals may be discrepant for aerosol and sputum positivity at any one sampling time. Thus, in addition to its potential to increase community-based pick up rates, we suggest that MASS will preferentially detect people who are actively spreading TB. If diagnostic rates in this study are favourable and if the results of our ongoing transmission related studies support the capacity of MASS to detect infectious pTB then we will use these results to develop an intervention study. This will test, in a defined target community, whether active case finding by MASS compared to conventional screening can a) increase the number of individuals diagnosed and treated; b) allow focusing of limited resources on individuals and contacts most likely to be involved in transmission and c) reduce the prevalence of TB within 4-5 years. Following optimisation of MASS sampling for implementation in Tshwane, CHWs will sample entire HHs triggered by detection of symptomatic members. They will then sample an equal number of HHs matched for key indicators without symptom assessment. Screening of 240 HHS and ~1,200 individuals in this way will allow feasibility and design of the follow on intervention trial to be determined.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: MRC-FAPESP: New approaches to the treatment of Paracoccidioidomycosis
Funder: Medical Research Council

Abstract: The innate immune system of vertebrates plays a central role in the detection and clearance of infections. Pathogen associated molecules such as bacterial lipids and non-self nucleic acids are recognised by a family of pattern recognition receptors the TLRs. The TLRs activate an inflammatory response and also provide the second signal required for the development of adaptive immunity. Over the last few years the Brazilian lab has identified and characterised a novel class of pathogen associated activators of the TLRs. These molecules are lectins that bind specifically to N-linked glycans present on the receptor ectodomain and activate TLR signalling. In this project the Brazilian and UK labs will collaborate to define the mechanism by which artin M from the jack fruit, and paracoccin from the pathogenic yeast Paracoccinoides brasiliensis activate TLR signalling. We will use biochemical, biophysical and structural methods to elucidate and quantify the molecular interactions of these molecules with TLR2/1, 2/6 and 4. We will use this information to develop an early stage screen to identify small molecule agonists and antagonists that can inhibit lectin mediated innate signalling. Molecules identified in the screen will be developed further as potential therapeutics for paracoccidioidomycosis, a common disease in Brazil which has a significant economic impact.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: CARRIAGE: Understanding the biological basis of persistent carriage of Staphylococcus aureus in humans
Funder: Medical Research Council

Abstract: The human nasal microbiota is a nutrient-limited environment inhabited by a variable range of bacterial species, including the important pathogen Staphylococcus aureus. Approximately 20% of humans persistently carry S. aureus in their nose. The human nose is the primary ecological niche of S. aureus, and understanding the basis for persistence is fundamental to our understanding of its biology. Nasal carriage is also important because carriers are at much greater risk of S. aureus infection, and can act as the source of transmission on to others. The biological basis for composition of the nasal microbiota, and why some people carry the S. aureus is not understood, but variation in human genes and lifestyle may both have a role to play. I propose to identify the contribution of host genetics and phenotypes to the composition nasal microbiota and how this effects S. aureus carriage by carrying out a multidisciplinary study combining microbiome analysis and conventional microbiology with genome-wide and phenotypic association studies. I will screen healthy adults who have been extensively characterised both genetically and biologically for S. aureus carriage and will assess nasal microbiota composition by microbiome sequencing. I will identify the genetic and biological factors that influence the nasal microbiota and specifically S. aureus carrier status by carrying out a genome-wide and phenotypic association studies. The proposed research will shed new light on the interaction between host genetics, lifestyle and microbiome composition, and the biology of S. aureus carriage. Improved understanding of this fundamental aspect of the biology of S. aureus will help human health by identifying new ways to prevent S. aureus infections.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Complications of herpes zoster: quantifying their burden to inform clinical and public health guidance, using electronic health records from the UK
Funder: Medical Research Council

Abstract: Herpes zoster is a painful rash, arising from the reactivation of latent varicella-zoster virus (VZV) following reduced cell-mediated immunity. Risk factors for zoster and its most common complication, postherpetic neuralgia (PHN), include older age and poor immunity. Although uncomplicated zoster is a mild, self-limiting condition, serious cutaneous, visceral, neurological and ocular complications can occur; some lead to severe illness, high healthcare costs and mortality, such as stroke, encephalitis and pneumonia. However, our knowledge on the frequency of, and risk factors for, complications (besides PHN) is limited. A single-dose, live vaccine against zoster (Zostavax) was licensed in 2006 by the FDA; vaccine effectiveness is around 50% for zoster and 60% for PHN. It is approved for use in over 60 countries including the UK. In 2017, a non-live and more efficacious two-dose vaccine (Shingrix) was recommended for immunocompetent adults over 50 years old by the US CDC and initial analyses suggest it would be good value. Its use is under consideration elsewhere, including the UK. With countries facing the decision of which vaccine to use, and which patients to vaccinate, understanding the epidemiology of zoster complications and accounting for them in cost-effectiveness analyses will help inform vaccine policy. This research project therefore aims to quantify the relative and absolute risks of complications following zoster, assess the effectiveness of zoster vaccines and antivirals against these complications, and utilise these findings to inform public health assessment of the cost-effectiveness of zoster vaccines. This project will use routinely collected electronic healthcare data from the United Kingdom and the United States of America. Understanding the epidemiology of zoster complications will inform zoster vaccine decisions in the UK and elsewhere.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFECTION
Title: Minimum Models for Optimal Epidemic Monitoring and Control
Funder: Medical Research Council

Abstract: Complex modelling can translate into unreliable policy. As outbreak surveillance has improved, epidemic models have become increasingly complex or "realistic". While such realism promises sharper insight and smarter interventions, it can actually conceal parametric assumptions and obscure the relationship between monitoring and control. Policy informed by overly complex models, is unreliable, overconfident and could cause economic liability, resource mismanagement and even mortality. Ebola and seasonal influenza are two priority diseases where existing model complexity has been questioned. I will develop justifiably complex and demonstrably reliable (minimal) models for these epidemics; through a novel combination of minimum description length (MDL) and event-triggered control (ETC) theory. MDL theory, by treating modelling as a data compression problem, quantifies the complexity of parametric assumptions by the hidden information they introduce. ETC laws clarify monitoring-control dependencies by prescribing interventions as responses to observed events (triggers). Standard epidemiological tools rarely assess parametric complexity, and ETC laws are known to be more reliable and resource-efficient than conventional strategies. I will liaise with public health officials to pinpoint specialised and decisive triggers for Ebola and influenza. Evaluating these triggers within MDL frameworks should generate minimal models that inspire low-risk policies that can confidently relieve the burden of disease.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: INFECTION
Title: Use of dynamic network models to explore the role of social media use in HIV transmission and health promotion among gay men and other MSM
Funder: Medical Research Council

Abstract: This project aims to explore the feasibility and value of data-driven dynamic sexual partnership network models of HIV transmission applied to intervention design, particularly to investigate the role of social media in partnership formation and health promotion among gay men and other men who have sex with men (MSM) in sub-Saharan Africa. This project will use population-based data on sexual partnerships and HIV epidemiology collected in 2017 from MSM in Nairobi (n=618) and Johannesburg (n=301). Sampled network data from a population representative sample can be used to infer whole network characteristics. For dynamic networks, models of tie formation and dissolution over a series of time steps can be built using separable-temporal exponential random graph models (STERGM). Target parameter values for network statistics can be set using the sampled partnership data, and Markov Chain Monte Carlo used to simulate networks whose characteristics reflect, though vary stochastically around, these target network statistics. An individual stochastic model for HIV transmission can then be run alongside the dynamic simulated networks using current HIV epidemiological and behavioural characteristics estimated in from the data, supplemented by a literature review of HIV transmission among MSM. The model will be calibrated using Bayesian methods such that I will be able to generate a field of potential models that fit the data, including all the uncertainty in the inferred models. By varying the parameter values of the STERGM, the effect of different network characteristics on HIV transmission can be modelled. The first 18 months of the project will be dedicated to developing the modelling framework, at which point I will discuss and confirm the specific health promotion questions to apply the model to informing in each setting, alongside local researchers, service providers and MSM community based organisations.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION