NIHRDataInsights/HRCSData huggingface dataset:
Title: The mechanistic basis for the ZAP antiviral system targeting viral and cellular RNAs
Funder: Medical Research Council

Abstract: ZAP is an antiviral protein that inhibits a broad range of viruses. It binds viral RNAs to inhibit their translation and target them for degradation. One application of the ZAP antiviral system is to introduce ZAP-response elements through synonymous genome recoding into viral RNA. This has at least two potential applications. First, it could be used to develop live attenuated virus vaccines by introducing ZAP-response elements into viruses that have evolved to supress these sequences in the viral RNA, which is common in many human RNA viruses. Second, several types of cancer have decreased ZAP expression and ZAP-sensitive oncolytic viruses could be a novel treatment for these cancers since they would preferentially replicate in the cancer cells compared to the healthy adjacent tissue. However, there are several knowledge gaps for how ZAP inhibits viral replication and these need to be overcome to fulfil the therapeutic potential of this antiviral system. While ZAP directly binds a CpG dinucleotide, other unclear sequence characteristics are also required for ZAP to target a specific RNA. We will use a combination of in vitro and in vivo binding experiments to define optimal ZAP-response elements and test them using synonymous genome recoding with a focus on influenza A virus. While ZAP interacts with a large number of proteins, only a few have been functionally validated to promote or inhibit ZAP antiviral activity. We will identify and characterise novel ZAP cofactors or regulatory proteins. Finally, how ZAP localises to specific cytoplasmic membranes or compartments to mediate antiviral activity is unclear and we will use live cell imaging technologies to characterise how ZAP traffics and localises in the context of a viral infection. Overall, we will analyse how ZAP selects specific target RNA, which proteins it interacts with to inhibit viral replication and how subcellular localisation controls ZAP antiviral activity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: INFECTION
Title: Molecular basis for Rift Valley fever phlebovirus NSs protein function
Funder: Medical Research Council

Abstract: Rift Valley fever phlebovirus (RVFV) is one of the 8 priority pathogens identified by the WHO that urgently require strategies for the prevention of epidemics and treatment of the disease caused. RVFV relies on its non-structural NSs protein for pathogenicity. NSs is imported into the cell nucleus where it forms characteristic filaments and suppresses the interferon response by interfering with the TFIIH complex, shutting down global transcription, and by specifically inhibiting IFN expression. The modes of action of NSs are poorly understood. The first structure for NSs provided a molecular basis for filament formation and will now inform dissection of NSs functions and interactions. We will use cryo-EM and X-ray microscopy to resolve NSs filament structures. We will use correlative fluorescence and EM to home in on filaments, and various sectioning approaches to obtain medium to near-atomic resolution structures. Crystallography and NMR will be used to obtain the missing structure of the N-terminal domain of NSs, which has been shown to be functionally important. Comparative structural analyses of NSs proteins of two other human-pathogenic phleboviruses will provide insights into the molecular determinants of NSs localisation and polymerisation. Structural work will be complemented by functional analyses using a recombinant viruses, and transient expression systems. We will use a variant of NSs that lacks the ability to form filaments to assess their role in interferon suppression. Using a covalent tagging system for pull-downs we will identify NSs binding partners in cytosol and nuclei that might be required for filament formation and import into the nucleus. Our data show a direct interaction of a soluble NSs variant with the TFIIH complex, which we will characterise using structural biology and functional assays. This project will generate fundamental insights into molecular mechanisms underpinning pathogenesis of RVFV and other phleboviruses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Immune:microbiota cross-talk in regulation and repair of intestinal inflammation
Funder: Medical Research Council

Abstract: Intestinal inflammation is carefully regulated to enable clearance of pathogens while avoiding excessive responses against harmless challenges such as resident microbes and food. Although immune cells lie at the heart of this process, the specific cell types involved and the core mechanisms they employ are not completely understood. It is clear that commensal microbes and their products can influence almost every aspect of host health, including immune cell and cytokine networks, and promotion or regulation of mucosal inflammation. However, the mechanistic basis for this impact of the microbiota on intestinal health has not yet been defined. Our work will address the fundamental question of how barrier immunity is regulated by the microbiota from a novel perspective, using tissue-damaging helminth infection in mice to establish an inflamed yet 'regulated' intestinal environment. Using cutting edge approaches including multiparameter flow cytometry, imaging mass cytometry, shotgun metagenomics and metabolomics, we will define the immune, microbial and tissue repair features that are hallmarks of controlled intestinal inflammation. Guided by these results, we will use culturomics, faecal transplants, germ-free and transgenic mice to identify the role and importance of candidate bacteria, immune cells and mediators in regulation of intestinal inflammation and repair. This innovative project will tackle the fundamental question of how barrier immunity is regulated from a novel perspective, linking together immune cell function and the microbiota to reveal core mechanisms that promote or regulate colonic inflammation and disease in the context of a relevant murine model of intestinal damage and repair. In addition to discovery in this important area, the information gained from this work will provide a platform for future research addressing mechanisms that regulate human inflammatory disease in the intestines, as well as in other mucosal sites such as the lung.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The role of host-derived lipids in Mycobacterium tuberculosis infection
Funder: Medical Research Council

Abstract: Metabolic adaptation in bacterial populations is thought to be a strong determinant of pathogenesis. Therefore, the overarching aim of this study is to elucidate the role of host-derived lipids in the adaptation of M. tuberculosis to acidic pH, a major environmental condition encountered during infection and pathogenesis. Our preliminary data suggest that the cAMP-dependant lysine acetyltransferase (Rv0998, KATmt) is a key player in Mtb adaption to acidic pH via the degradation of lipids. We hypothesise that KATmt plays a critical role in resistance to acidic stress via the regulation of host derived lipids metabolism at acidic pH, and by fine tuning the activity of Mtb metabolic pathways. We will use complementary approaches to address this problem combining omics data with infection models and validating our results using M. tuberculosis H37Rv genetic mutants. In aim 1, we will use mass spectrometry tools genetic mutants to determine the impact of KATmt on the remodelling of mycobacterial physiology. We will identify and validate the key metabolic pathways involved by performing metabolomics and 13C flux analysis. Characterization of the protein acetylome will be performed in order to decipher how lysine acetylation by KATmt controls mycobacterial physiology and metabolic plasticity. In aim 2, we will determine the role of KATmt in M. tuberculosis pathogenesis in cellulo using the macrophage model. We will use a combination of both bioenergetics and metabolomics to investigate how KATmt manipulates host metabolism. Finally, in aim 3, we will test the role of KATmt in M. tuberculosis infection and pathogenesis in vivo using the mouse model of infection. This work will provide an unprecedented understanding of the interplay between host-derived lipids, acidic pH and M. tuberculosis metabolic flexibility


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: MRC FAPESP: Defining the role of the hematopoietic parasite reservoir in Plasmodium vivax infection and pathology
Funder: Medical Research Council

Abstract: Plasmodium vivax (P. vivax) places a heavy disease burden across endemic regions worldwide and presents a major challenge for malaria eradication. Recent studies from our laboratories and others have demonstrated that the extravascular bone marrow niche and potentially the spleen represent a major tissue reservoir for parasite proliferation and transmission stage maturation across Plasmodium spp. lineages, with significant implications for malaria diagnosis and treatment success. P. vivax is restricted to invasion of the youngest red blood cells, known as immature reticulocytes, which originate in the bone marrow. This restriction results in a distinct and poorly understood biology that we believe has precluded previous efforts to establish in vitro parasite culture and systematic study of P. vivax. Importantly, P. vivax elicits a potent host response and causes severe and fatal manifestations at much lower parasitaemia than P. falciparum, suggesting that P. vivax restriction to host cells enriched in the hematopoietic niche of BM and spleen could induce alterations in host homeostasis such as anaemia, lymphopenia, thrombocytopenia and splenomegaly. This collaborative proposal will employ for the first time a systematic investigation of the biology of the P. vivax reservoir in BM and spleen and its role in disease pathogenesis, infection and transmission in a series of cohorts of patients in Brazil. We will characterize parasite and host biology in infected tissues and investigate their behaviour ex vivo using a series of cutting edge technologies and in collaboration with world leading experts. The proposed work will thus close a major knowledge gap in our understanding of P. vivax biology and pathogenesis and provide critical tools for the development of new P. vivax control measures to support the ongoing malaria elimination agenda.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: SARS COV2 vaccine ResPonse In Obesity - SCORPIO study
Funder: Medical Research Council

Abstract: Over 20% of the UK population are obese; people with obesity have substantially higher morbidity and mortality from COVID-19 infection. As obese people have reduced immune responses to other vaccines (influenza, hepatitis), we hypothesise that obesity may similarly reduce the protection offered by SARS-CoV-2 vaccines by impairing cellular immunity, reducing initial antibody titres and/or by causing an acceleration of the natural decline in antibody titres. We will address this question by recruiting a cohort of 200 patients with severe obesity (Body Mass Index (BMI)>40 kg/m2) - the population we suspect is at highest risk - from clinics in Cambridge University Hospital and Kings College Hospital, London (SCORPIO study). We will compare their vaccine responses (T and B cell-mediated immunity, neutralisation assay, anti-Spike and Nucleocapsid antibodies, inflammatory cytokines) to 1500 normal weight people studied using the same assays. To comprehensively investigate the impact on vaccine responses of BMI across the full range from overweight, to obese and severely obese, we will collaborate with a network of investigators leading existing UK studies to perform a meta-analysis of 50,000 people. We will seek to identify predictive nutritional and metabolomic biomarkers (obese responders vs non-responders) and test whether weight loss (shown to improve response to the influenza vaccine in mice) can improve vaccine responses in obese people. This ambitious programme of research will deliver new insights into the relationship between BMI, metabolic health and the response to SARS-CoV-2 vaccines and inform public health policy in this area, within 12 months.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: The Durability of immune Responses to vaccination against SARS-CoV-2 and its Variants.
Funder: Medical Research Council

Abstract: This proposal comes from a team who have been at the forefront of decoding immune parameters in COVID-19 throughout the pandemic, giving us a sharp focus on the current questions. The concern is to understand, at a qualitative and quantitative level, the details of immune response durability in 'real-life settings' of different vaccination regimens, with or without prior infection. We will study large, longitudinal, cohorts (totalling 12097 individuals) with different exposures to SARS-CoV-2 and its variants, in the UK, South Africa and Brazil, enabling us to study vaccination using diverse platforms, with or without infection by SARS-CoV-2 and the alpha, beta, gamma and delta variants of concern (VoC). These are cohorts with a high-granularity history, encompassing infection and symptom history as well as immune data. Moving forward, we wish to understand the durability and nature of immune protection, including susceptibility to reinfection and breakthrough infections. To achieve this, we will track longitudinal immunity, analysing serum antibody durability, live virus neutralisation, antibody affinity, B cell receptor repertoire and B cell memory frequency, both to wild-type and variant targets. In terms of T cell immunity, we will track durability of response frequency to wild-type and variant epitopes using a wide range of approaches. The CLARITY and CML-Co-vax Cohorts will enable us to probe vaccine response impairment and its mitigation in immunosuppressed cohorts (IBD and chronic myelogenous leukemia) after Infliximab or tyrosine kinase inhibitor (TKI) therapy respectively. Data will be modeled in relation to CoP values to extrapolate and provide guidance regarding the need / timing of boosts for different vaccine platforms in healthy adults and immunosuppressed patients to achieve protective immunity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFECTION
Title: An immunogenetic approach to guide the need for booster shots and combat immune failure in SARS-CoV-2 vaccine response
Funder: Medical Research Council

Abstract: Vaccination has been hugely impactful in control of the current COVID-19 pandemic. However, in a significant proportion of individuals, the immune response to vaccination is insufficient to control SARS-CoV-2 and this may be exacerbated with viral variants of concern. To establish the optimal strategy for booster vaccination, we propose a programme of work that will advance our ability to identify individuals who have, or are at risk of mounting, a low response to COVID-19 vaccination; to understand the underlying heritable, molecular and immunological mechanisms for this response; and whether booster dose vaccination can mitigate a dampened immune response. To deliver this, we propose a collaborative, multi-disciplinary and multi-centre approach. We will work with the National COVID-19 Infection Survey to contact individuals in the general UK population with extremes of antibody responsiveness to vaccination and map genetic associations with response. This will deliver specific predictive genetic biomarkers that can help identify at risk individuals and populations and reveal novel insights into mechanism of poor vaccine response. Complementing this genetic analysis, we will investigate the role of clonal hematopoiesis of indeterminate potential and of epigenetics. We will determine the effect of booster vaccination in poor responders to facilitate multivariate analysis of the immune response and help identify associated immune correlates. The project deliverables will directly impact and inform vaccine policy and rollout.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFECTION
Title: Investigation of proven vaccine breakthrough by SARS-CoV-2 variants in established UK healthcare worker cohorts: SIREN consortium & PITCH Plus Pathway
Funder: Medical Research Council

Abstract: The SIREN Consortium aims to investigate the correlates of immunity against SARS-CoV-2 post-vaccination, including the durability of the immune response in healthcare workers (HCW). The study uses the strengths of the largest global cohort study (N~45,000) with regular serological and alternate weekly SARS-CoV-2 PCR testing. This additional funding enables detailed immunological nested case-control studies where cases are infections post-vaccination and compared to appropriately matched controls. 75 proven vaccine breakthrough cases have already been identified and daily alerts for new infections are in place. It will assess host and pathogen factors related to infections post-vaccination with the PITCH Plus pathway 1. Anti-S and anti-N neutralising antibodies against the current SARS-CoV-2 variants of concern, using validated pseudovirus microneutralisation (pMN) assay and live virus MN & Tcell memory responses, by IFNG Elispot and T cell proliferation assay 2. The durability of binding and quantification S and N antibody, neutralising antibody and T-cell responses in recipients of different vaccines and vaccination schedules 3. Genotype to phenotype mapping including centralised genomic surveillance for all cases, analysis and exploratory assessment to better define the correlates of humoral and cellular immunity for novel mutations/ emerging variants. 4. Clinical immunology consultation: individuals with post-vaccine infections will be invited to a telephone consultation to review their medical history, have bloods undertaken to assess underlying health conditions, associated immunodeficiency and the humoral and cellular immune system. 5. Human genotyping with consent we will obtain and store genetic material from vaccine breakthrough cases to enable future assessment of known single nucleotide polymorphisms and where necessary whole genome sequencing for associations with suboptimal vaccine response and immunodeficiency.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFECTION
Title: MICA: Developing a rectal formulation of ceftriaxone for community-based management of neonatal sepsis in low- and middle-income countries
Funder: Medical Research Council

Abstract: Neonatal sepsis is the single greatest cause of preventable death in children living in tropical countries, being responsible for more than half a million of the estimated 2.4 million deaths that occur each year. Most deaths occur at or near home. Prompt administration of effective antibiotics by injection is life saving, but is usually not possible in the rural tropics where health centres are frequently several hours' journey away. Alternative strategies are needed to deliver effective treatment at the community level. Since 2012 we have worked on the pharmaceutical development of a rectal formulation of ceftriaxone, a broad spectrum, slowly eliminated, and widely-used antibiotic. The objective is to make effective community-based neonatal sepsis treatment feasible at low cost, and therefore used early and widely enough to prevent a substantial proportion of neonatal deaths from sepsis in high-burden low- and middle-income countries (LMICs). Roche gave us access to data from prior studies of intra-rectal ceftriaxone in animals and man showing bioavailability sufficient for treatment of serious infections. We developed several prototypes, and tested pre-clinical bioavailability, confirming earlier results. Our industrial partner (Orofino), has evaluated our candidate formulations for feasibility for industrial production and has lowered the cost of producing the absorption enhancer. The next steps are to i) manufacture GMP clinical batches, ii) evaluate bioavailability and tolerability of two formulations in healthy adults and iii) assess absorption and tolerability of the leading formulation in sick neonates. If rectal ceftriaxone is absorbed adequately and is well-tolerated, we will assess this formulation in field trials to measure impact on mortality, with the goal of including rectal formulations of ceftriaxone in World Health Organization Treatment Guidelines. This would pave the way for widespread uptake in high burden LMICs.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Africa CDC - LSHTM MRC International Statistics & Epidemiology Group Partnership to Support Robust Analysis of COVID-19 Seroprevalence Data in Africa
Funder: Medical Research Council

Abstract: Africa CDC is coordinating a unique, multi-national research initiative, supporting African Union Member States to carry out robust nationally-representative COVID-19 seroprevalence surveys, in order to inform rapid response prevention planning, policy, and practice at country and continental level. Seventeen countries joined the first wave of surveys, of which six have completed data collection, and seven are expected to do so by October 2021. Participating countries will analyse their survey findings with support from Africa CDC as needed, and have agreed to share their data for aggregate analysis and interpretation under precedent-setting data-sharing agreements. However, there is currently insufficient statistical and epidemiological capacity to undertake these critical activities. The aim of this proposal is to employ a medical statistician, initially on a six-month basis, to rapidly undertake time-critical analysis of the COVID-19 seroprevalence data, facilitated by Africa CDC, in order to inform policy decisions for pandemic response including vaccine scale-up. The statistician will manage and analyse this complex multi-country survey data, advise country-level teams on survey design and analysis issues, and establish the database for future research. They will provide on-the-job training and mentoring to the Africa CDC epidemiology analytics team and will support strategic interpretation and use of COVID-19 seroprevalence and vaccine coverage data and findings to inform Africa CDC and the Member States in their ongoing COVID-19 response including vaccine roll-out strategies. Following the six-month period, further funding will be identified to extend the duration of the post and to enable sustainable strengthening of biostatistical capacity at Africa CDC.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION