Neutrophils are abundant immune cells that are essential for defence against pathogens. They combat microbes by phagocytosis, degranulation and release of neutrophil extracellular traps (NETs). Neutrophils can detect and eliminate a variety of bacteria, fungi and parasites but their role in viral infections is less clear.
This project will compare interactions of neutrophils with two medically relevant viruses. Influenza A virus (IAV) affects millions every year by causing acute respiratory disease and is associated with significant mortality. Neutrophils were shown to have both protective and pathogenic roles in progression of influenza. Cytomegalovirus (CMV) causes morbidity and mortality in immune compromised and immunologically immature individuals. The Humphreys lab demonstrated a role for neutrophils in defence against CMV. In both cases, little is known about mechanisms at the molecular level.
The student will investigate the following questions:
1) Which cell surface receptors and signalling molecules are utilised by neutrophils to respond to IAV and CMV? We will perform CRISPR/Cas-mediated knockout of candidate neutrophil genes implicated in viral sensing.
2) Which viral components are sensed by neutrophils? We will screen a panel of clinical and laboratory virus strains of different properties to identify the viral molecules involved in neutrophil activation.
3) How do individual neutrophils react to viruses? We will use fluorescence microscopy and electron microscopy (EM) to image viral internalisation and to analyse neutrophil behaviour upon exposure to IAV and CMV.
4) How do neutrophil responses contribute to the outcome of infectious disease in mouse models? We will target specific neutrophil responses and/or receptors (identified in aims 1 and 3 above) via pharmacological inhibitors and knockouts in established mouse infection models of IAV and CMV.
The project is expected to lead to new insights into pathways involved in the neutrophil response to viruses. We also expect to unravel the role of neutrophils in the immune response to IAV and CMV.
Dr. Amulic (Bristol) will supervise all aspects of neutrophil manipulation and functional analysis. Dr. Yamauchi (Bristol) will supervise virus assays and manipulations involving IAV. Prof. Humphreys (Cardiff) will oversee all CMV experiments and in vivo work in mouse disease models. EM will be carried out under the direction of Dr. Vicki Gold (Exeter). The student will have access to state-of-the-art flow cytometry and imaging platforms (Bristol, Wolfson Bioimaging Facility). The student will be based in Bristol but is expected to spend substantial amounts of time at all three institutions to receive training and perform experiments.
How to apply:
This project is being advertised as part of a competition for GW4 BioMed Medical Research Council (MRC) funded projects (https://www.gw4biomed.ac.uk
), where 18 studentships are available. Studentships will be allocated to the highest quality candidates. You are strongly encouraged to contact the primary supervisor Dr. Borko Amulic ([email protected]
) before making an application. Applications can be submitted, and further information found by following the link below: https://www.gw4biomed.ac.uk/doctoral-students/