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Results

Characterising metabolic mechanisms conferring deltamethrin resistance in Anopheles albimanus, major malaria vector in Guatemala 22 Nov 2016

Malaria is still a publich health in Guatemala, reportin a total of 4,931 confirmed malaria cases for 2014. The main malaria vector is An. albimanus because is the most abundant and widely distributed species. Insecticide-based vector control strategies are maily used in Guatemala, which includes pyrethroid LLIN's. Unfortunately, the emergence of resistance to insecticides is threatening the continued success of the insecticide-based vector control interventions. Bioassays, molecular and biochemical assays indicated development of pyrethroids resistance in An. albimanus from Guatemala with early evidences suggesting a predominant role of metabolic resistance mechanisms. Therefore, this project aims at elucidatin the metabolic resistance mechanisms involved in the deltamethrin resistance in Guatemalan An. albimanus. So, insecticide resistance profile will be assessed in field populations of An. albimanus throughout Guatemala using CDC bottle bioassays and synergist assays. Resistant mosquitoes will be used to detect key genes conferring metabolic resistance using RNA-seq transcriptomic approach with Illumina and quantitative PCR. In addition, deltamethrin resistance markers will be detected by sequencing of candidate genes between resistant and susceptible mosquitoes. This will allow us to design DNA-based diagnostic tools which will to enhance the sentinel surveillance to detect insecticide resistance at early stage.

Amount: £140,950
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Raising awareness and interest in biomedical science research in Malawian schools 27 Nov 2016

The host antiviral immune response is relatively effective at recognising and eliminating most HIV-infected cells. However, HIV manipulates resting memory CD4 T cells and persistently resides in them in a latent state, resulting in formation of viral reservoirs. These reservoirs are poorly recognised by antiviral cytotoxic cells and are less susceptible to the effects of the current antiretroviral therapy (ART), leading to incomplete clearance of the infection. In the lung, alveolar macrophages (AM) have a long life span, can harbour HIV and are relatively resistant to the cytopathic effects of HIV, making them an important potential viral reservoir. Recently, we have shown that HIV persists in AM in HIV-infected individuals on long term ART despite undetectable plasma viraemia. This fellowship proposes using bronchoalveolar lavage (BAL) and peripheral blood obtained from HIV-infected and uninfected Malawian adults to address the hypothesis that HIVs ability to hinder immune recognitio n and block the induction of apoptosis leads to its persistence in AM. Specifically, the following questions will be addressed a) How does HIV hinder immune recognition of HIV-infected AM by cytotoxic cells? b) How does HIV block progression to apoptosis in HIV-infected AM? c) Which viral proteins are responsible for modulation of macrophages?

Amount: £30,800
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £40,930
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Vacation Scholarships 2017 - Liverpool School of Tropical Medicine 16 Jun 2017

Vacation Scholarships 2017 - Liverpool School of Tropical Medicine

Developing a universal antivenom to treat snake venom-induced consumption coagulopathy 24 Feb 2016

Snakebite is a neglected tropical disease that causes ~100,000 deaths each year. Venom-induced consumption coagulopathy (VICC) is the most common, clinically important, pathology associated with snakebite. Existing antivenom treatments exhibit limited paraspecific efficacy, poor levels of antibody specificity and high incidences of adverse reactions. The aim of this project is to develop a single, pathology-specific, antivenom to be used throughout the world for treating venom-induced consumption coagulopathy caused by snakebite. The specific goals are: To identify the venom constituents that cause procoagulant bioactivities induced by different snake venoms To determine whether a panel of murine monoclonal antibodies can neutralise procoagulation irrespective of snake species To demonstrate proof of concept for humanising murine monoclonal antibodies specific to venom toxins To do so, I will first characterise the specific venom toxins found in different snake species that cause VICC using small-scale proteomics and biochemical assays. Next, I will design epitope-string immunogens to stimulate the production of antibodies specific to those toxins. I will then use a monoclonal antibody approach to generate a first of its kind, pathology specific, antivenom that will be validated pre-clinically for future worldwide use for treating VICC. Key words: snakebite, antivenom, protein, toxins, pathology, antibody

Amount: £817,821
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Development of a model to image Plasmodium falciparum cytoadherence in vivo 08 Apr 2015

The outcome of this work will be to have tested the primary hypothesis that the efficiency of recruitment to endothelium at the vessel wall is a major component of disease in P. falciparum malaria. In addition we will understand how different endothelial receptors contribute to this recruitment and retention of IE. This research will also provide information on the impact of cytoadherence on the circulation, the local endothelial response (inflammation and signalling) and effects at the level of the tissue. Our intention is to use this data to identify specific adhesion-based therapies that target recruitment and retention of IE in the brain and develop them into products that will reduce the mortality of cerebral malaria.

Amount: £122,177
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Institutional Strategic Support Fund Phase2 FY2014/16 27 Oct 2014

Supported by ISSF funding, LSTM has offered a number of competitive challenge grants to LSTM based research projects in the general area of resistance (with a focus on drugs and insecticides – RDI). These projects will need to be completed within two years (Oct 2016).The research will focus on an area relevant to RDI, will involve PIs from more than one discipline (including external partnerships with NHS Trusts, other academic groups and industry partners), and will have the potential to generate data that can leverage further competitive research funding on completion. Funding: Renewal of Gates-funded IVCC and AWOL programmes, the latter with a major component using a novel mouse model for basic and translational research Reachout consortium. funded by EU to look at strengthening health systems through close-to-community services Cookstove project in Malawi funded by MRC MRC New Investigator Award – "Is targeting vascular remodelling by filarial parasites a viable anti-morbidity solution" CouNTDown programme for NTD implementation research funded by DFID (Adams, Reimer) Health Impact: Development of innovative ‘tiny target’ control systems for tsetse flies (Torr) Discovery of a previously unidentified reservoir of Schistosoma infection in pre-school children (Adams). Introduction of intermittent preventive therapy during pregnancy as a WHO policy recommendation (Terlouw). Development and validation of a human challenge model for Streptococcus pneumonia (Glennie). Development of new monitoring and evaluation systems for malaria surveillance (Terlouw) LSTM’s improving and rapidly growing media visibility and social media presence are beneficial in creating attention for our various PE initiatives

Amount: £1,050,000
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Wellcome Trust Clinical PhD Programme, University of Liverpool 'Health Priorities in the Developing World' 20 Jul 2015

Despite the high incidence of chronic respiratory damage following treatment for pulmonary TB disease (PTB), including residual changes to lung physiology and structure, little is known about the associated medium or long-­-term morbidity, or the risk of empirical TB-­-retreatment due to chronic respiratory symptoms. There is a paucity of data from sub-­-Saharan Africa and HIV co-­-infected populations. In this prospective cohort study 400 adult patients will be recruited on completion of PTB treatment in urban Blantyre. The presence / absence of post-­-TB lung disease (PTLD) at baseline will be defined using computerised tomography imaging and spirometry. Patients will be followed for 1-­-year, during which morbidity (patient costs, health related quality of life, functional capacity, incidence rate of acute exacerbations) will be measured. Morbidity will be compared in patients with and without PTLD at baseline. A nested case-­-control will be conducted to investigate the relationship between chronic respiratory symptoms present 1-­-year after PTB treatment, which place patients at risk of empirical TB-­-retreatment, and PTLD at baseline. A predictive tool will be designed to identify those patients at risk of ongoing morbidity or chronic respiratory symptoms after PTB treatment, using clinical variables that can be easily measured on treatment completion in resource-­-limited settings.

Amount: £386,814
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Wellcome Trust Clinical PhD Programme, University of Liverpool 'Health Priorities in the Developing World.' 20 Jul 2015

Tuberculosis is responsible for the death of nearly 1,500,000 people annually. TB treatment takes a minimum of 6 months, and even with excellent adherence, is complicated by the risk of treatment failure and acquired drug resistance. Outcomes are worse in those with HIV-TB co-infection, with higher mortality and greater risk of TB relapse or re-infection after completion of treatment. We hypothesise that the intrapulmonary and intracellular site of Mycobacterium tuberculosis infection represents a sanctuary from drug- and immune-mediated eradication, and is an obstacle to effective and shorter therapy. In the context of a longitudinal cohort study, I will conduct an intrapulmonary study to explore the compartmental pharmacology of anti-TB drugs, and local immunology in the infected lungs, of patients receiving treatment for pulmonary TB. Bronchoalveolar lavage will be performed to collect samples for pharmacokinetic analysis and functional immunologic assays. I will develop population pharmacokinetic models of TB drug exposure in plasma, epithelial lining fluid, and alveolar macrophages, and assess alveolar macrophage function in the presence or absence of HIV early and late in treatment. The relationship between these predictor variables and the endpoints of sputum culture conversion, bacillary elimination rates, and clinical outcomes will be explored in mathematical models.

Amount: £364,589
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Identification of genes for insecticide resistance in the lymphatic filariasis vector Culex quinquefasciatus. 25 Nov 2013

Culex quinquefasciatus (Diptera: Culicidae) is a pantropical pest and urban vector of Bancroftian filariasis. Studies to detect incipient resistance and the underlying mechanisms in field populations of Culex to public health insecticides is very important to design effective strategies to control both lymphatic filariasis and malaria occurred. In the present project we will exploit the Culex quinquefasciatus whole genome microarray already available to investigate range of resistance mechanis ms and type of cross resistance are involved in the resistance of Cx. quinquefasciatus against insecticidal classes licensed for public health. Here, we will: (i) Describe the distribution of insecticide resistance in the Cx. quinquefasciatus from selected sites throughout Benin, ii) Apply a whole transcriptome microarray to identify genes associated with resistance to deltamethrin (used for ITN) and bendiocarb (used for IRS), iii) To use in vitro expression systems to confirm that the candidate genes identified from interact and/or metabolize the insecticide used.

Amount: £100,336
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Investigating impact of insecticide resistance and immune system on Plasmodium falciparum development in the major malaria vector Anopheles funestus in Cameroon 25 Nov 2013

Resistances to anti-malarial drugs and to insecticides are presently disrupting malaria control in Africa. Therefore, novel control strategies are needed. One of these is the replacement of vector populations by non-vector ones to disrupt parasite transmission by taking advantage of observed natural refractoriness to infection in mosquitoes. This requires a good understanding of the factors impacting vectorial competence in natural populations of Anopheles and of the complex interactions between the mosquito vector and the Plasmodium parasite. If progress has been made to elucidate these interactions in An. gambiae, nothing is still known for the other major vector An. funestus. Besides, the impact of insecticide resistance on Plasmodium development in Anopheles vectors has not yet been thoroughly assessed. The present project aims to fill these important gaps in our knowledge taking advantage of progress recently achievedin the genetics, genomics and rearing of An. funestus. I plan in this project to: - Aim 1. Assess the impact of insecticide resistance on the development of P. falciparum in An. funestus, - Aim 2. Assess the molecular basis of immune response to P. falciparum infection in An. funestus - Aim 3. Study the population genetic of P. falciparum resistance genes in An.funestus.

Amount: £237,834
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Biomedical Vacation Scholarship 23 Jun 2014

Not available

Malawi-Liverpool-Wellcome Trust Clinical Research Programme. 17 Apr 2013

MLW is strategically placed to conduct high quality laboratory, clinical and epidemiological science relevant to health in sub-Saharan Africa. The programme is embedded within a rapidly growing medical school, co-located within the largest teaching hospital in Malawi with direct access to urban and rural populations. In the next 5 years, MLW research will increase fundamental understanding of disease mechanisms and burden, test novel interventions and ensure translation into health care. The cor e programme will ensure MLW delivers the following aims: (1) Pursuit of cutting-edge research focused on health problems with a high disease burden. Research management, mentorship, development of bioinformatics expertise, and clinical and diagnostic laboratory competencies, ensuring the highest quality. (2) Provision of a research training environment for clinicians, epidemiologists and laboratory scientists. Local research infrastructure, operational and financial systems, data manageme nt and research governance support. (3) Development of globally competitive research leaders. Moving towards local leadership, embedded within the University of Malawi College of Medicine, attracting further intermediate and senior Fellows, and encouraging re-entry of trained Malawian scientists. (4) Translation of scientific advances into human health improvements. Defining national and international research agendas through policy relevant evidence; policy committee membership; research synthesis workshops; and public engagement.

Amount: £13,200,000
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Spatial and temporal distribution of the N1575Y allele and his impact on the malaria vector control activities. 26 Feb 2013

The primary goal of the proposed project is to understand the driving forces selecting for an emerging insecticide resistance mutation in the malaria mosquito, Anopheles gambiae. Pyrethroid resistance threatens to compromise the gains made in reducing malaria from large-scale distribution of long-lasting insecticide treated nets (LLINs) and indoor residual spraying (IRS) [8]. The pyrethroid resistance mutations, commonly referred to as knockdown resistance or kdr (L1014F/L1014S) are extending th eir range, and in the case of L1014F, approach fixation over much of West Africa. A secondary mutation, N1575Y, was recently detected at low but rising frequencies in Burkina Faso suggesting an ongoing selective sweep [5]. The resistant haplotype provided added benefit to mosquitoes exposed to pyrethroids/DDT (odds ratios = 1.93 2.60). The discovery of a new resistance mechanism while at a relatively low frequency is a unique opportunity to address some of the key questions in our understanding of resistance management strategies while providing important information for vector control operations within the local setting. The project will tackle these questions by estimating the selection of N1575Y over the past 20 years; investigating potential sources of selection pressures and exploring the fitness costs associated with kdr haplotypes.

Amount: £111,220
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Insecticide Quantification Kits (IQK) for Vector Control Programmes in India 24 Jan 2012

Visceral leishmaniasis (Kala Azar) and malaria are deadly diseases that are widespread in the Indian subcontinent. Since they are transmitted by sandfly and mosquito vectors respectively, insecticides are the most effective way to control these diseases, but only if the correct amount of insecticide is deposited on the sprayed surfaces. Too little and the sand flies and mosquitoes will survive and become resistant to the insecticide, too much and human health and the environment can suffer. Unfortunately, monitoring insecticides is an expensive process involving sophisticated equipment or complex biological assays. Therefore, it is not routinely done, putting populations at increased risk of disease. Dr Pradeep Das and his team at the Rajendra Memorial Research Institute of Medical Sciences in Patna (RMRI) are involved with the eradication of Kala Azar in northern India and bordering countries. Simple visual assays (quantification tests) for the rapid and reliable monitoring of DDT, carbamate and organophosphate, the classes of insecticide commonly used against sand flies and mosquitoes, have been developed by Dr Paine and colleagues at the Liverpool School of Tropical Medicine (LSTM),using funding obtained through the Innovative Vector Control Consortium (IVCC). RMRI and LSTM have been awarded Affordable Healthcare Funding to join forces in developing these assays further and establishing them as convenient tools (Insecticide Quantification Kits) for monitoring the quality of indoor residual spray programmes against insect borne diseases in India and elsewhere. This will involve assay refinement, kit development and field trials to demonstrate kit effectiveness, practicality and reliability. The goal is to provide field operatives with simple visual rapid tests for the precise monitoring of insecticides to maximise the benefits from vector control and minimise the risks to public health and the environment.

Amount: £955,627
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

An initiative for research in non-communicable diseases at MLW: The risk of chronic disease following severe acute malnutrition 02 Aug 2012

MLW is strategically placed to conduct high quality laboratory, clinical and epidemiological science relevant to health in sub-Saharan Africa. The programme is embedded within a rapidly growing medical school, co-located within the largest teaching hospital in Malawi with direct access to urban and rural populations. In the next 5 years, MLW research will increase fundamental understanding of disease mechanisms and burden, test novel interventions and ensure translation into health care. The cor e programme will ensure MLW delivers the following aims: (1) Pursuit of cutting-edge research focused on health problems with a high disease burden. Research management, mentorship, development of bioinformatics expertise, and clinical and diagnostic laboratory competencies, ensuring the highest quality. (2) Provision of a research training environment for clinicians, epidemiologists and laboratory scientists. Local research infrastructure, operational and financial systems, data manageme nt and research governance support. (3) Development of globally competitive research leaders. Moving towards local leadership, embedded within the University of Malawi College of Medicine, attracting further intermediate and senior Fellows, and encouraging re-entry of trained Malawian scientists. (4) Translation of scientific advances into human health improvements. Defining national and international research agendas through policy relevant evidence; policy committee membership; research synthesis workshops; and public engagement.

Amount: £197,170
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Surveillance for influenza in the context of pandemic H1N1 in an African population with a high burden of HIV, malaria and malnutrition. 16 Apr 2012

Sub-Saharan countries such as Malawi have a very high infectious disease burden. Although influenza is likely to be prevalent, there is little or no infrastructure to capture the contribution of influenza to morbidity and mortality or define the potential for pandemic influenza to be more severe in these frequently more immunocompromised populations. In this project we will: 1) Assess the burden of Influenza-like Illness (ILI) and Severe Acute Respiratory Infection (SARI) amongst adults and c hildren presenting to a large Central Hospital in Malawi and to determine the contribution of seasonal (including H3N2 and H1N1) and pandemic H1N1 influenza virus to this disease. 2) Describe the severity and outcome of laboratory proven seasonal and pandemic H1N1 influenza in a population with a high prevalence of HIV, malnutrition and malaria. 3) Determine the influence of HIV on the duration of shedding of seasonal and pandemic H1N1 influenza virus. 4) Document the frequency of secon dary invasive bacterial infections in adults and children with influenza-associated SARI. The findings that arise from this study will provide the detailed understanding of the epidemiology, clinical presentation and outcome of influenza urgently required by public health planners and policy makers in Africa.

Amount: £64,917
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Investigation of putative causal factors for low rate of parasitological cure of standard dose praziquantel for intestinal schistosomiasis in Ugandan infants and pre-school children 05 Apr 2012

The project will build upon excellent established collaborations between Natural History Museum and Vector Control Division researchers. We will investigate the occurrence of intestinal schistosomiasis in infants and preschool children to develop best treatment options for this ageclass and assess their role in local disease transmission. These two complementary objectives will combine field-based and laboratory-based epidemiological investigations namely, 1. field-based: monitoring biannually a n enrolled study cohort of mother and child pairs over a 3-year period collecting epidemiologically and clinically relevant information pertaining to treatment with praziquantel and reinfection dynamics, as well as, recording monthly environmentally relevant data describing local S. mansoni infection dynamics in intermediate snail hosts. 2. laboratory-based: molecular DNA typing of genetic diversity within S. mansoni larval forms shed from snails (cercariae) and selected mother and child pairs ( eggs); conducting multivariate statistical modelling comparing parasite burdens and putative risk factors to identify best praziquantel treatment regime. The project will better elucidate parasite transmission biology in young children. The main goal will be to further develop the Ugandan national policy for control of intestinal schistosomiasis in infants and preschool children and, through realignment of ongoing integrated preventive chemotherapy campaigns, more broadly improve maternal and ch ild health in sub-Saharan Africa.

Amount: £92,700
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine