Viral subversion of host cell apoptosis
The programmed death of cells (apoptosis) is a critically important mechanism that enables multicellular organisms to eliminate damaged, infected or unwanted cells during development, growth and tissue homeostasis. Failure to regulate apoptosis leads to a number of diseases including arthritis, autoimmune diseases and cancer. Viruses have evolved a powerful ability to inhibit host cell apoptosis in response to viral invasion to ensure their own survival and proliferation.
We are interested in understanding the molecular mechanism underlying virus-mediated inhibition of apoptosis using X-ray crystallography, a technique that allows us to visualise the molecules responsible for apoptosis inhibition at the atomic level.
Tumour viruses: The ability of pathogenic viruses to disable the cell death machinery of invaded host cells is of critical importance for viral infectivity, persistence and replication. Viral infections, such as those by gamma-herpesviruses including Kaposi's sarcoma-associated herpesvirus (KSHV) or Epstein-Barr virus (EBV), have been shown to be intimately linked to malignancies including Kaposi's sarcoma or Burkitt's lymphoma. A key group of virulence factors that allows gamma herpesviruses to overcome the apoptotic machinery of host cells and persist in the host are viral Bcl-2 proteins.
We are currently investigating how viral Bcl-2 proteins contribute to the development and maintenance of virus-associated tumours such as Burkitt's lymphoma and Kaposi's sarcoma.
Poxviruses: Viruses have a powerful ability to inhibit host cell apoptosis in response to viral invasion. The importance of Bcl-2 proteins for controlling apoptosis is highlighted by the number of viruses that express identifiable homologs of Bcl-2. However, a number of poxviruses do not contain obvious Bcl-2 homologs, despite repressing host cell apoptosis after infection.
Using X-ray crystallography, we showed that the two poxviral proteins M11L (myxoma virus) and F1L (vaccinia virus) adopt a Bcl-2 fold, despite lacking sequence similarity to any other cell-death inhibitor. More importantly, they inhibit apoptosis using a mechanism similar to mammalian Bcl-2 proteins. This suggests that many other anti-apoptotic viral proteins exist that are not readily identifiable on a primary amino acid sequence level.