Research team

Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Expertise

- In vitro and in vivo pre-clinical models of (viral) infectious diseases. - pre-clinical evaluation of vaccines - Development of vaccines: inactivated, attenuated, DNA and RNA based, vector vaccines - Generation of recombinant viruses using BAC based virus plasmids - reverse vaccinology - virus detection in and isolation from patient samples - Analysis of immune responses to viral infections (serology, antibodies, cellular immunity) - Antibody and nanobody (single domain antibody) development, production and modification. - Ultracentrifugation - PCR-based detection and quentification of viruses

Virus infections of man and animal 01/01/2021 - 31/12/2025

Abstract

The FWO Scientific Research Network brings together Flemish experts and their international connections in a consortium that is able to study different crucial aspects of viral diseases of man and animal and to identify novel targets for the generation of vaccines and antiviral drugs. The consortium consists of members who are active in virus characterization, virus-host interactions and pathogenesis, virus evolution and spread and development of vaccines and antivirals.

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Immunological control of Varicella zoster virus (VZV)-infected iPSC-derived brain models by steady-state and immune-compromised astrocytes and microglia. 01/01/2021 - 31/12/2024

Abstract

Varicella zoster virus (VZV) is a member of the herpesvirus family and is a highly successful and ubiquitous human pathogen. Both in children and in adults, varicella-related complications may lead to hospitalisation. While in children direct neurological complications may occur following primary infection (varicella), in adults vasculitis and neurological complications are not uncommon following reactivation of latent VZV (herpes zoster). With a clear link between VZV and neuropathology, it is inevitable that the immune system of the central nervous system (CNS) will be challenged by VZV. However, to date little is known about how astrocytes and microglia behave upon encounter of VZV in the CNS. In this project, we will address this question using an established human in vitro model of axonal infection of human induced pluripotent stem cell (hiPSC)-derived CNS neurons with fluorescent reporter VZV stains. Using this model, we will first longitudinal monitor how hiPSC-derived astrocytes and microglia influence the processes of VZV infection, latency and reactivation. Next, using iPSC models derived from VZV patients with mutations in POLRIII, we will investigate whether immune compromised astrocytes and/or microglia can control neuronal VZV infection. Altogether, these studies will help us understanding innate immune control of VZV in the CNS, and will allow - beyond the scope of this project – to develop novel strategies to prevent VZV spreading in the CNS.

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COVID-19 National surveillance in wastewater. 09/12/2020 - 14/09/2022

Abstract

Tracking the presence of SARS-CoV-2 in wastewater allows to monitor the spread of the virus in the population at regional and subregional level, several days earlier compared to data obtained from screening of patient samples. This wastewater monitoring is no replacement for current clinical testing, yet it is pivotal in early detection of future changes in the epidemic and the tracking of novel outbreaks in specific regions. As such this testing will contribute to a proactive management and containment of the epidemic.

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V-CALSA – Visual Computer-Aided Lung Sound Analysis. 01/10/2020 - 30/09/2024

Abstract

Lung auscultation, which is the process of listening to breath sounds, is one of the most commonly used examinations to evaluate respiratory health. Over the last decades computational methods have been developed for the analysis of recorded lung sounds. Computer Aided Lung Sound Analysis (CALSA) aims to overcome limitations associated with standard lung auscultation by removing the subjective component of the process and allowing quantification of lung sound characteristics. To date, no accepted standard for data acquisition and analysis has been set and none of the proposed approaches have been successfully implemented in clinical practice. During this project we will develop a simple but robust visual representation for CALSA, which can be easily interpreted by health care professionals. Several clinical studies described in this project aim to validate this analysis and to study the ability of CALSA to measure the severity of RSV-bronchiolitis and the effects of respiratory therapy. Digital auscultation has the potential to be a sensitive, objective and non-invasive tool by providing regional information associated with local changes in the airways.

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SARS-CoV-2 RNA quantification in wastewater as complementary epidemiological indicator to monitor the epidemic. 01/06/2020 - 31/05/2021

Abstract

This project aims to detect SARS-CoV-2 RNA in wastewater sampled throughout Belgium as a complementary epidemiological indicator for the rapid and constant follow-up of the current epidemic at high spatial and temporal resolutions. This translational data-driven epidemiological research will provide direct added value to support and evaluate policy initiatives and to detect novel outbreaks. This project fills current knowledge gaps in monitoring the epidemic by providing prevalence estimates in the general population without the need for individual testing. Furthermore, through triangulation of our data with data from diagnostic testing and clinical surveillance, this project will make a more comprehensive prediction and control of the COVID-19 epidemic possible. The idea to measure SARS-CoV-2 RNA in wastewater as a proxy for its infection in the general population is innovative and epidemiologically highly informative as community-wide data can be obtained at high temporal (daily) and spatial (city or town) resolutions. This proposed wastewater surveillance strategy can be regarded as a sensitive early-warning tool and can substantially improve models/predictions of the ongoing epidemic. Specialists in wastewater-based epidemiology and virology are brought together in this consortium to make this project feasible within the proposed timeframe.

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Characterization of a contemporary Respiratory Syncytial Virus isolate for use in pre-clinical and clinical research (ReSVistrain). 01/06/2020 - 31/05/2021

Abstract

Recently, we have obtained a Respiratory Syncytial Virus (RSV) isolate with unique characteristics for applications in pre-clinical and clinical research. With this project we aim to gather additional knowledge on this primary isolate and to identify genomic changes responsible for the observed phenotype.

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A platform to functionally assess clinically relevant respiratory parameters in small animal models for infectious and non-infectious pulmonary research. 01/01/2020 - 31/12/2021

Abstract

This application relates to the purchase of new basic infrastructure, more specific a FlexiVent system from Emka Technologies. FlexiVent is a platform for standard respiratory research that can be used across many pulmonary applications and which has major advantages compared to the classical, non-invasive, unrestrained plethysmography because it is accurate, reproducible and proven. FlexiVent is much more capable of detecting pulmonary abnormalities via changes in functional residual capacity, total lung capacity, vital capacity, and compliance of the respiratory system. Furthermore, analysis of pulmonary functions via FlexiVent allows distinction between respiratory diseases in mice by clinically relevant variables and is therefore generally accepted as the standard in the functional evaluation of infectious and non-infectious pathological, respiratory disease models.

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Identification of host-virus interactions contributing to immunopathology and disease severity in respiratory syncytial virus infections in children. 01/11/2019 - 09/02/2022

Abstract

Respiratory Syncytial Virus (RSV) is worldwide the leading cause of serious airway infections. It's so common that most children will be infected by age 2. In adults and older children, RSV symptoms are mostly mild and typically mimic a common cold, but younger children can develop very severe disease. Preventive and therapeutic options are limited and currently it is not clear why some children develop severe disease while others do not. We therefore aim to investigate host- and virus-related factors that influence disease severity. To reach this objective, we will isolate RSV from children with respiratory disease, characterize the isolates and objectify differences between them. Next, we will investigate the effect of different virus isolates on the immunological response induced by a human respiratory epithelial cell line, since epithelial cells are the primary target cells and are implicated in the pathogenic reaction upon RSV infection. Lastly we want to evaluate whether the same clinical isolate induces a different immunological response in respiratory epithelial cells isolated from different patients. We will thus not only gain fundamental insights in the causes of RSV induced disease, but we will finally also correlate the virus- and host-related risk factors identified in the lab with clinical symptoms observed in patients. With this project we aim to identify patients prone to severe disease in an early stage, thus improving therapeutic options and disease outcome.

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Elucidating the mechanism of action of small molecule replication inhibitors of RSV and hMPV. 01/09/2019 - 31/08/2023

Abstract

The objective of this project is to elucidate the exact molecular MOA of small-molecule polymerase inhibitors of RSV and hMPV. This research will significantly increase the field's understanding of how these small-molecule replication inhibitors work and ultimately contribute to providing a new and highly effective treatment strategy for RSV and hMPV. More precisely, this projects aims to: (i) elucidate the precise molecular effects of small-molecule polymerase inhibitors of RSV and hMPV, (ii) study the mechanisms by which potential resistance may emerge against these inhibitors and (iii) contribute to the elucidation of the structures of the full-length RSV and hMPV polymerases by discovering conformation-stabilizing antibodies, that can be used in crystallization or cryo-EM approaches; and by measuring the extent of the stabilizing effects of these antibodies and small-molecule inhibitors, enabling optimized design of drug candidates. To do so, we will use, develop and exploit challenging and innovative techniques to find an effective treatment for RSV and hMPV infections.

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Progress new assets (one pre-new molecular entity and one first-time-in-human start) for tuberculosis that act synergistically with bedaquiline, cytochrome bc or cytochrome bd inhibitors (RespiriTB). 01/05/2019 - 30/04/2025

Abstract

Despite recent progress in biomedical research, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is still the world's leading infectious disease killer worldwide. Treatment options are limited, and expensive, recommended medicines are not always available in many countries, and patients experience many adverse effects from the drugs. Thus, there is an acute need for the development of a novel combination regimen with an indication for effective, shorter, and safer treatment of all forms of TB. The overall objective of RESPIRI-TB is to find new drug candidates as potential components of a new, more efficient combination drug regimen against TB that is less prone to resistance and allows shortening of treatment duration for TB, and multidrug-resistant TB. Such a drug combination will synergistically target the energy metabolism of Mtb or complementary targets. To achieve this, we will advance recently discovered inhibitors of the Mtb respiratory pathway. In addition, we will target the Mtb specific molecular mechanism that reduces reactive oxygen species in the cell.

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Identification of host-virus interactions contributing to immunopathology and disease severity in respiratory syncytial virus infections in children. 01/10/2018 - 30/09/2022

Abstract

Respiratory Syncytial Virus (RSV) is worldwide the leading cause of serious infections of the lower airways, and nearly all children are infected with RSV by the age of two. RSV is responsible for different clinical presentations, ranging from mild to very severe disease. Limited preventive and therapeutic options are available, and furthermore, it is not clear why some infected individuals develop severe disease while others do not. We therefore aim to investigate host- and virus-related factors that may influence disease severity. To reach this objective, we will divide our research project in four different goals. Firstly, we will isolate RSV from patients and investigate which of two commonly used virus collection methods is best to obtain viable RSV isolates. Secondly, we will investigate the effect of different virus isolates on human respiratory epithelial cells, since these are not only the primary target cells, but also implicated in the pathogenic immune response upon RSV infection. Thirdly, we want to evaluate whether respiratory epithelial cells from different patients, react differently upon infection with the same virus, which may explain differences in disease severity observed in patients. We will thus not only gain fundamental insights in the causes of RSV induced diseases, but we will finally also correlate risk factors identified in the laboratory with clinical symptoms in patients, supporting the translational character of this research project.

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The Biomolecular Interaction Platform (BIP) at UAntwerp. 01/05/2018 - 30/04/2021

Abstract

Physical and functional interactions between biomolecules play pivotal roles in all aspects of human health and disease. Gaining a greater understanding of these biomolecular interactions will further expand our understanding of diseases such as cancer, metabolic diseases and neurodegeneration. At UAntwerp, 7 research groups have joined forces to obtain the absolutely necessary equipment to measure these interactions with a Biomolecular Interactions Platform (BIP). This will allow to detect interactions and precisely determine binding affinities between any kind of molecule, from ions and small molecules to high-molecular weight and multi-protein complexes. The BIP will also allow to identify collateral off- targets, crucial in the drug discovery field. Access to a BIP will strongly support ongoing research projects and bring research within the BIP-consortium to a higher level. Since biomolecular interactions are highly influenced by the methodology, it is recommended to measure the interaction by several, independent techniques and continue with the most appropriate one. For this reason, the consortium aims at installing a BIP, consisting of several complementary instruments that each measure biomolecular interactions based on different physical principles. They wish to expand the existing Isothermal Titration Calorimetry with two complementary state-of-the- art techniques: MicroScale Thermophoresis and Grating- Coupled waveguide Interferometry.

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An interdisciplinary study on the role of the HLA genes and T-cell diversity as risk factors for herpes zoster. 01/01/2018 - 31/12/2021

Abstract

Chickenpox is a consequence of primary infection of varicella-zoster virus (VZV). Afterwards, VZV remains latent in neural ganglia until symptomatic reactivation called herpes zoster (HZ, shingles). In this project, we will first develop a novel computational framework that will allow us to estimate the probability that a pathogen-derived antigen is adequately recognised by the major histocompatibility complexes (MHC) encoded by HLA genes. Antigen bounding by MHC molecules is a necessary step prior to recognition (and further management) of infected cells. Next, we will obtain HLA data from 150 HZ patients and 150 matched controls. This will allow us to estimate whether and which HLA A/B/C genes are enriched or depleted in HZ patients. Our computational framework will allow us to estimate which VZV proteins are most likely of importance in controlling VZV. We will assess whether the HLA data is readily translated into the diversity of the T-cell receptor (TCR) against VZV, and against which of the most important VZV proteins. Finally, we will differentiate blood-derived inducible pluripotent stem cells (iPSC) into neuronal cells, infect these neuronal cells with VZV and study whether depletion of VZV-specific T-cells affects VZV proliferation, thereby confirming our earlier obtained HLA-TCR predictions.

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Labo protocol. 14/09/2020 - 09/12/2020

Abstract

Tracking the presence of SARS-CoV-2 in wastewater allows to monitor the spread of the virus in the population at regional and subregional level, several days earlier compared to data obtained from screening of patient samples. This wastewater monitoring is no replacement for current clinical testing, yet it is pivotal in early detection of future changes in the epidemic and the tracking of novel outbreaks in specific regions. As such this testing will contribute to a proactive management and containment of the epidemic.

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Wastewater as early warning system for COVID-19 surveillance 13/07/2020 - 15/11/2020

Abstract

This project aims at optimising an analytical protocol for the detection of SARS-CoV-2 RNA in wastewater. This will then applied to wastewater samples collected across Belgium to investigate the early warning character of the methodology. Triangulation of the wastewater data with other datasets (e.g. hospital data, infections) will be performed to investigate the complementarity of the data.

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ReLACT: Intranasal probiotics against respiratory viral infections. 01/10/2019 - 31/12/2020

Abstract

Respiratory Syncytial Virus (RSV) is the leading cause of severe lower respiratory disease in young children worldwide. Nearly all children are exposed to RSV by the age of 2, approximately 40 % will develop a lower respiratory tract infection such as bronchiolitis and up to 10 % of these children require hospitalization. Severe inflammation is a typical hallmark of the hospitalized children. Despite the discovery of the virus in 1956, prevention and treatment options for RSV are limited. In this project, an innovative approach based on the intranasal application of specific probiotic strains is explored to prevent the severe lung inflammation that follows the acute infection. We will investigate whether delivery of intranasal probiotics prior to RSV infection can prevent the development of severe RSV disease by functioning as immunomodulatory agents that can reduce RSV-associated inflammation. Furthermore, we will test if delivery of an RSV vaccine together with intranasal probiotics enhances both safety and efficacy of this vaccine.

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Improved respiratory syncytial virus (rsv) vaccines based on glycan modification of the viral fusion (f) protein. 01/04/2018 - 30/03/2019

Abstract

This project aims to improve current RSV vaccines, using glycan modifications of the RSV F protein to augment the capacity of the RSV F protein to induce neutralizing antibodies. This approach will be applicable in different types of vaccines, such as DNA vaccines, live attenuated vaccines, vector vaccines… Besides efficacy, evaluating of safety, and especially RSV vaccine-enhanced disease and mucus induction will be evaluated.

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Nanobody-assisted targeting of sialoadhesin-positive macrophages to improve the treatment of tuberculosis. 01/10/2017 - 30/09/2020

Abstract

Treatment of tuberculosis is severely complicated by the adaptations of its etiological agent, Mycobacterium tuberculosis, allowing survival and replication within the host phagocytes. A better understanding of the host-pathogen interaction and the development of novel treatment strategies are thus critical. We strongly believe in a promising strategy involving the receptor-mediated delivery of therapeutics via the endocytic Sialoadhesin (Sn) receptor present on the surface of phagocytes.

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Pathogenic processes of viral infections of mammals. 01/01/2016 - 31/12/2020

Abstract

For many viruses, efficient vaccines and/or antivirals are in use. Yet, for some viruses, vacccines/antivirals only provide limited protection, or fail because of induction of resistance, or are simply lacking because of a lack of fundamental knowledge. Since these products are crucial to control virus replication and virus-induced disease, we propose a programme of fundamental research to gather new insights in some crucial aspects of the pathogenesis of viral diseases, which should allow development of future vaccines and antivirals.

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Lactobacillus exopolysaccharides as antipathogenic and immunomodulatory adjuvantia 01/01/2016 - 31/12/2019

Abstract

In this project the potential antipathogenic and immunomodulatory activity of exopolysaccharides of model Lactobacillus strains is investigated by in vitro and in vivo models. Methods for extraction, characterization and formulation of the exopolysaccharides are also optimized.

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Characterisation of a novel Respiratory Syncytial Virus (RSV) immune evasion mechanism and evaluation of the impact for development of novel vaccines and prophylactic and/or therapeutic antibodies 01/10/2015 - 30/09/2019

Abstract

Respiratory Syncytial Virus (RSV) is the leading cause of severe lower respiratory disease in young children and is the second most important viral cause of respiratory disease in adulthood, after influenza virus. Currently, no vaccines and no antivirals are available to control RSV infections. Recent advances in RSV research have shown that the F protein is a major target for development of novel therapy and prophylaxis. F-specific antibodies, such as Palivizumab, are available, but were shown not to be fully effective, since hospitalization rates are reduced only by 55%. In addition, vaccines may also not fully protect against infection. This is exemplified by the fact that even after natural infection(s) and induction of F-specific neutralizing antibodies, RSV is able to reinfect. Since re-infection occurs without considerable antigenic change, there must be a different immune evasive mechanism than that influenza A virus reinfections, which is dependent on antigenic drift/shift. Our understanding of RSV F protein functionality, besides its role in fusion, is however insufficient to explain the immune evasive mechanisms involved. Currently there is a great risk that newly developed monoclonal antibodies and vaccines will suffer from constrained effectiveness. Very recently, preliminary studies in our research group have shown that upon binding of RSV-specific antibodies to RSV F protein expressed on the surface of infected cells, internalization occurs of RSV protein-antibody complexes. As a result, infected cells will most likely no longer be efficiently detected and eliminated by antibody-based immunity. In addition, a reduction in the expression of RSV proteins on the surface of infected cells may interfere with the immunogenicity and hamper the induction of strong immune responses. This novel finding may have profound effects on (1) our understanding of RSV pathogenesis and the occurrence of frequent RSV reinfections and (2) the development of new RSV vaccines and monoclonal antibodies. It is therefore the aim of this project to fully characterize this endocytosis process up to the molecular level, both in vitro and in vivo. We will (A) characterize the endocytic process and the consequences for RSV immune evasion, (B) identify amino acids of the F protein involved and create F proteins that show no internalization, (C) generate recombinant viruses with mutant F proteins lacking endocytic properties and (D) evaluate the recombinant viruses in vivo.

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Medicinal Chemistry-Drug Discovery (ADDN). 01/01/2015 - 31/12/2020

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

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Study of the role of immune cells in RSV infections. 01/01/2015 - 31/12/2018

Abstract

RSV is worldwide an important cause of medical relevant lung infections, which can lead to life-threatening bronchiolitis in children and elderly. Besides the acute pathology, there is a link between severe bronchiolitis and chronic respiratory problems. The pathology is induced by both the cytopathic effect of the infection as well as the RSV induced immunomodulation. Since immune cells are an important component, we will study the interaction of RSV with these cells and try to modulate their activities.

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The potential of Lactobacillus exopolysaccharides and glycoproteins as safe vaccine adjuvants. 01/01/2015 - 31/12/2015

Abstract

Ligands of the innate immune system form an important new class of adjuvants, but the desired immunostimulation is often linked with toxicity and serious side-effects. These ligands or 'microbe-associated molecular patterns' (MAMPs) can also be found on the surface of lactobacilli with a 'generally regarded as safe' status. Various studies have demonstrated the specific effects of certain lactobacilli and their surface molecules, but the potential of MAMPs such as exopolysaccharides and glycoproteins of lactobacilli still requires further investigation. Hereto, the project is divided in three parts. First, the molecular interactions between the glycoconjugates and receptors such as Toll-like receptors and C-type lectins will be mapped. Next the in vitro immune response of these molecules in immunological important cells will be investigated. Finally, the potential of selected molecules will be validated in a mouse model.

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Equipment for high-speed refrigerated, preparative ultracentrifugation, automated gradient formation and fraction collection and analysis. 19/05/2014 - 31/12/2018

Abstract

This project represents a formal research agreement between UA and on the other hand the Hercules Foundation. UA provides the Hercules Foundation research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Mechanism of infection of sialoadhesin (Sn)-positive macrophages with respiratory syncytial virus (RSV) and its implications for inflammation and immune pathology during bronchiolitis. 01/01/2014 - 31/12/2017

Abstract

Respiratory syncytial virus (RSV) is the major cause of bronchiolitis, itself the commonest single cause of hospitalization during infancy. In older children and in adults, RSV is associated with acute exacerbations of both asthma and chronic obstructive pulmonary disease (COPD). Following the infection of ciliated epithelial cells, the manifestations of bronchiolitis are caused by a combination of viral cytotoxicity and the uncontrolled immune response to infection.

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Study of the role of membrane receptor signalisation in immune cell infection and regulation. 01/01/2013 - 31/12/2016

Abstract

This project aims to identify new mechanisms for the modulation of macrophages during activation of the immune system and during pathogen infections, using sialoadhesin, a macrophage-specific surface protein.

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A drug discovery with a particular focus on tropical protozoa (leishmaniasis, malaria, sleeping sickness and Chagas disease) and mycotic infections (yeasts, dermatophytes and fungi). 01/09/2011 - 31/12/2016

Abstract

This project represents a formal research agreement between UA and on the other hand DNDI. UA provides DNDI research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Integrated evaluation of test compounds against Leishmania and Trypanosoma parasite species. 01/09/2006 - 31/10/2015

Abstract

For most infectious diseases, chemotherapeutics are still required for disease control as vaccines are generally lacking. In addition, drug resistance has become a critical issue, which endorses the need for continuous drug research. LMPH is actively involved in the identification of new synthetic and natural lead compounds, with a particular focus on the tropical protozoal diseases Leishmaniasis, sleeping sickness, Chagas disease and malaria. Validated in vitro and in vivo test systems and drug screening technologies have been developed. The Drugs for Neglected Diseases Initiative (DNDi) has access to compound libraries which have never been tested for the listed diseases. In this project, both groups have joined expertise and know-how to achieve a more productive drug discovery platform.

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