Projects - Ali Mirazimi group
Ongoing projects for the Ali Mirazimi Research group.
Molecular pathogenesis for viral hemorrhagic fevers
The major aim of my project is to study the molecular mechanisms behind the pathogenesis of CCHFV. The main objective will be to characterise the pro-inflammatory response induced by CCHFV infection in vitro. We will investigate the effect of these molecules secreted from CCHFV-permissive human target cells in tight junctions between cells and also define the mechanism of leakage of erythrocytes and plasma through the vascular endothelium caused by CCHFV in an in vitro model system. There is evidence that certain haemorrhagic fever viruses are capable of infecting dendritic cells and impairing their innate antiviral activity by limiting their ability to initiate the adaptive immune response. It has also been demonstrated that a molecular trigger for disseminated intravascular coagulation through the (over)expression of tissue factor (TF) on the surface of virus-infected monocytes and macrophages can cause the disease. The effects on haemostasis are probably triggered by the VHF infecting and activating the macrophages, which are then stimulated to secrete cytokines. Interestingly, we and others have recently demonstrated that CCHFV can infect mDC and macrophages in vitro. However, to date, there is a huge gap in knowledge on CCHFV-host cell interaction. Programmed cell death and regulation of apoptosis in response to a viral infection is an important factor for host or virus survival. We have very recently demonstrated that CCHFV induces apoptosis in late post infection in vitro, but we do NOT know the mechanism behind this regulation. Taken together, we hypothesise that the systemic spread of CCHFV could be the result of early infection of monocytes, followed by their extravasation into parenchymal tissue, enabling the virus to interact with basolateral receptors (we have previously demonstrated that CCHFV primarily infects and is released from the basolateral compartment in polarised cells). Secondary replication in these organs followed by basolateral release would further systemic spread of the virus. In the late stage of the disease, erythrocytes and plasma leak through the vascular system into tissues connected with bleeding. This vascular leakage is most probably caused by disruption of the tight junctions which constitute the endothelial barrier between cells. The reasons for the interruption of tightness between these cells are not clearly understood. This is a Collaboration between us and Prof. Friedemann Weber (Germany) and Prof. Yee-Joo Tan (Singapore)
Virus-Host cell interaction
Biomedical research has facilitated the identification and characterisation of gene products in host cells that have a role in microbial diseases. The identification and characterisation of cellular genes and pathways exploited by pathogens is essential to elucidate the process by which the microbes cause disease. Recently, colleagues developed haploid embryonic stem (ES) cells, which give the possibility of combining the power of a haploid genome with the pluripotency of embryonic stem cells to study fundamental biological processes at genomic scale. ES cells can be efficiently mutated and used as a novel genome-wide screening system for different purposes. This system has many advantages over RNAi screening such as complete knockout, stable silencing, etc. In this project we will focus to determine the role of genes responsible for resistance against CCHFV, Marburg/Ebola and Zika Virus. We are also investigating how the CCHFV interact with the natural host cells, tick cells, as CCHFV is a tick-borne disease. This is a collaboration between us and Prof. Friedemann Weber (Germany) and Prof. Josef Penninger (Austria), Prof. Johan Neyts (Belgium), Dr. Lesley Sakyi (Pirbright Institute, UK)
Vaccine development (CCHFV)
To date, there is NO FDA approved vaccine against CCHF available. Due to the lack of Vaccine for this important disease has European Commission, H2020, dedicated a big project (CCHFVaccine) for developing a vaccine against CCHF. The CCHFVaccine project, has been built on the success of the CCH Fever project (FP7), which had focused on improving the knowledge of CCHFV, in general. The specific aim of the CCHFVaccine project is to develop and deliver a vaccine, which can significantly increase our capacity to control the situation of Crimean Congo Haemorrhagic fever (CCHF) disease on a global basis.
The vaccine candidates developed within this project will not only be developed for human use but also for domestic animals in endemic and non-endemic areas.
To achieve this overall aim, an intensive work plan (based on the previous CCH Fever and EDENext project results) will be put in place with the following specific objectives:
- Objective 1: to produce already available and promising vaccine candidates and also further establish new vaccine candidates for CCHFV for animal experimentation.
- Objective 2: to bring several unique animal models into front line vaccine research and to implement a roadmap for animal model evaluation.
- Objective 3: to validate and bring the most promising vaccine candidates to clinical trials .
- Objective 4: to ensure that an immune mediated protection is adequately understood and that the candidate vaccine(s) can elicit an appropriate and protective immune response.
- Objective 5: to establish a clinical trial road map and perform clinical trials at Phase I for the most promising platform. In addition ensure a strategy for the effective deployment, utilisation in resource-poor settings, field-deployment logistics and an evaluation of the predicted cost and affordability of the final vaccine products.
- Objective 6: to widely publicise the project and its results to public health bodies, NGOs,outbreak management teams and develop an exploitation plan.
This is a Collaboration between us and 14 other institutes, including NIH/USA.
Antivirals against RNA viruses
RNA viruses are highly dependent on host cell machinery to fulfill their replication cycle and produce new progeny virus. To date, most of the drugs against viruses act as direct-antivirals, meaning that compounds are designed to directly target viral proteins. Direct antivirals are believed to act as highly selective towards specific viruses, however these treatments are often accompanied with severe side effects and viral resistance. In this project we will developing antivirals by targeting host cell proteins/enzymes needed in the viral life. The overall objective of this project is to provide basic knowledge on molecular events of RNA virus infections and to develop novel antiviral strategies to battle against several highly pathogenic RNA viruses such as Zika, CCHF, and Ebola virus. This is a Collaboration between us and Prof. Thomas Helleday’s laboratory.
Developing new diagnostic tools
The overall aim of this project is to develop and deliver rapid and bedside diagnostic tool(s) that will significantly increase our capacity to handle outbreaks of highly pathogenic viral diseases at endemic area. To achieve this overall aim an intensive work plan has been put in place with the following specific objectives...
- Objective 1: to develop a biosafe detection method (diagnostic tool) for use at points of care;
- Objective 2: to implement a strong capacity building programme in Africa and other endemic area with focus to rapid diagnostic, biosafety measure and outbreak management;
- Objective 3: to disseminate widely the project and its results to public health bodies, NGOs, outbreak management teams and local hospitals in West Africa via WP5.