Defining the reciprocal interaction between neutrophils and human cytomegalovirus

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Human Cytomegalovirus (hCMV) is a highly prevalent opportunistic virus that infects up to 90% of the adult population and persists dormant in the body for life. The initial "primary" infection usually causes a mild glandular fever-like illness, but in certain at-risk populations the virus can cause substantial disease, or reactivate to cause "secondary" infection at a later date. Infection during pregnancy can result in congenital CMV infection in the newborn, leading to birth defects, and in immunosuppressed patients such as organ transplant recipients or HIV-infected individuals CMV is a major cause of disease, leading to increased hospitalisation, reduced survival of transplanted organs, and higher mortality.The virus is believed to lie dormant in the bone marrow, and spreads by hijacking the hosts own cellular mechanisms to replicate, leading ultimately to rupture or lysis of the host cell and escape of large numbers of infectious virus particles. This "lytic" infection has been seen in certain white blood cell types such as the macrophage but not in the more common white blood cell, the neutrophil. This cell type protects the body from most bacteria and certain viruses, engulfing and killing the organisms then undergoing a process of self-destruction known as apoptosis, which triggers resolution of the inflammatory response. Recent research however has shown that certain viruses and bacteria can evade the neutrophil's defence mechanisms and survive its normally inhospitable internal environment, using it as a "Trojan horse" to replicate and spread. In this context, neutrophil apoptosis may even promote infection, allowing the transfer of live organisms to macrophages and other cell types, which remove apoptotic neutrophils from the inflamed site.My preliminary work has shown that contact between hCMV and purified healthy neutrophils causes a profound increase in neutrophil survival by inhibiting apoptotic cell death. The surviving neutrophil does not produce new virus, but does release substances that quite profoundly affect its neighbouring cells, increasing the lifespan of other neutrophils and causing macrophages to alter their surface signals, making them potentially more susceptible to hCMV infection.I will be investigating exactly how the virus produces this effect in the neutrophil, by defining its point of contact with the neutrophil surface and how this triggers a downstream effect to inhibit the cell death process. Additionally, I will determine the precise nature of the active substances that neutrophils produce following treatment with hCMV by analysing the material released by these cells and exploring exactly how these substances act to prolong their lifespan. Finally, I plan to explore how the increased immune cell survival may be used by the virus for its own advantage, investigating whether the neutrophil can transfer intact virus to other cell types - the "Trojan Horse" model - or make surrounding macrophages more susceptible, producing more virus upon infection.As an Infectious Diseases specialist trainee caring for HIV-infected patients I see first-hand the effects of this devastating opportunistic infection, and seek to find ways to better understand and treat CMV. This project has the potential to reveal new insights into the way hCMV spreads around the body, which in the future may enable us to combat its spread in those most at risk.