Novel role for neutrophils in CMV dissemination and reactivation

MRC PhD Studentship x 5
The Department of Medicine is seeking applications from eligible students who wish to undertake an MRC-funded 3 year PhD studentship starting October 2012. The five research projects available, together with supervisor details, can be found on the Departments website at: http://www.med.cam.ac.uk/mrc-phd-studentship-2012-project-outlines/.

Andrew Cowburn, Matthew Reeves, Edwin Chilvers

Divisions of Respiratory Medicine and 2Infectious Diseases, Department of Medicine, University of Cambridge School of Clinical Medicine

Human cytomegalovirus (hCMV) remains a major cause of viral disease in transplant recipients, patients who are critically ill and those with late stage HIV infection. To date, the interaction between neutrophils and hCMV remains contentious and, as such, no precise role for neutrophil function in hCMV infection has been defined. Our recent studies however have shown clear evidence for hCMV binding to, and activation of, human neutrophils, which triggers a profound survival response in these cells and also the production of a soluble factor(s) that results in monocyte chemotaxis, differentiation, and strikingly, hCMV reactivation in latently infected cells. Furthermore, the observation that these events occur in the absence of any lytic viral gene expression suggests that the interaction at the point of virus entry is an important mediator of this response. This establishes the hypothesis that during primary infection, binding of hCMV to neutrophils (which are themselves recruited via hCMV-induced epithelial CXCL-1) triggers a cytokine response that promotes monocyte recruitment and differentiation, which in turn supports more efficient virus dissemination. In the context of latent infection, hCMV reactivation and disease is common in patients who are exposed to other primary infections and thus we hypothesise that neutrophil activation by an alternative viral or bacterial infection, could also result in the production of a cytokine milieu that promotes hCMV reactivation in recruited myeloid cells harbouring latent hCMV genomes.

This project, which represents a new collaboration between the ID (Reeves/Sinclair) and Respiratory (Cowburn/Chilvers) labs, will: (1) define the precise neutrophil-derived factor(s) responsible for hCMV reactivation in human monocytes, (2) address if other viral, bacterial or pathogen-derived molecules including inflammatory cytokines can initiate a similar neutrophil response, (3) examine patients with sepsis to see if this causes a generic expansion of the circulating myeloid-derived suppressor cells (MDSC) subset and determine the extent of hCMV carriage in these cells, and (4) explore whether the neutrophil-derived factor(s) identified can, ultimately, reactivate naturally latent hCMV from blood and tissue (BALF) monocytes/dendritic cells. This project will give broad based and specific training in several aspects of neutrophil cell and molecular biology, hCMV infection and cellular immunology.

This project is supported by a collaboration with Professor JH Sinclair, Professor of Molecular Virology, Department of Medicine.

Post short-list enquiries can be made to Professor Edwin Chilvers ([Email Address Removed]).

Fixed-term: The funds for this studentship are available for 3 years in the first instance.
The University values diversity and is committed to equality of opportunity. The University has a responsibility to ensure that all employees are eligible to live and work in the UK.

Applicants should submit a full CV, including details of two referees, and a covering letter clearly indicating which of the projects they are interested in to Mrs Linda Whyles via email: [Email Address Removed].
Applications must be received by 5pm on the closing date.

Quote reference: RC00092, Closing date: 19 February 2012.