Role of granzymes in innate immunity [ 2006 - 2008 ]

Research Grant

Researchers: Arno Mullbacher (Principal investigator) ,  Dr Matthias Regner ,  The Australian National University (Managed by)

Brief description The immune system employs a variety of strategies to combat parasites including viruses. One of them is cytolytic lymphocytes, cells that can recognize and destroy virus-infected target cells. These cells use, besides other molecules, enzymes called granzymes to kill target cells by inducing suicide in them. We intend to investigate if those granzymes can protect cytolytic lymphocytes themselves from being infected by viruses and turned into viral factories. We are going to use a model of a natural infection, ectromelia, mouse pox. Mouse pox is fatal in resistant strains of mice if the genes for the two dominant granzymes are deleted. This indicates that granzymes are essential for fighting this viral disease. We will explore in which cells of the immune system granzymes are expressed and whether virus entry into a cell can actually trigger their expression. Furthermore, we will investigate how the granzymes inhibit virus infection within the infected cell to determine whether the mechanisms involved resemble those used by cytolytic lymphocytes in killing of target cells (i.e. degradation of DNA and mitochondrial damage), or whether they represent entirely new facets of granzyme function. Finally, using viruses from a number of different families, we will establish whether these functions of granzymes also contribute to protection from other viral infections. An understanding of the role of these granzymes in the innate immune response, i.e. before antigen specific T cell and antibody responses are fully activated, is of great significance as it may allow us to manipulate this particular anti-viral response and thus enhance survival and reduce morbidity in viral infections.

Funding Amount $AUD 500,008.80

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant