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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
Irwin M. Arias, MD Postdoctoral Research Fellowship
Project Title: The Role of Unconventional Secretion in the Cell-Cell Spread of Hepatitis A Virus
An estimated 25,000 people in the US and 1.4 million people world-wide are infected with hepatitis A virus (HAV) annually. HAV is spread by the fecal-oral route, mainly from person to person or through contaminated foods, though the primary site of replication and pathogenesis is the liver. While it causes pathogenesis, HAV does not induce lysis of infected liver cells and the mechanism of this non-lytic cell-cell spread of HAV in liver tissue remains to be elucidated. HAV is a small, positive-strand RNA virus that is very closely related to poliovirus, for which a mechanism of non-lytic spread involving the autophagy pathway has recently been proposed. Autophagy (“self-eating”) is a cellular process stimulated by starvation and other stresses. Components within the cell, including invading pathogens such as viruses are broken down and removed. Autophagy is therefore considered part of the non-specific “innate” immune response. In apparent opposition to this idea, autophagy appears to benefit, rather than hinder, the growth and spread of certain viruses including poliovirus. Dr. Clancy proposes that HAV also subverts the autophagy pathway to spread non-lytically among neighboring cells. The growth of HAV and release of mature virions will be monitored by qRT-PCR in the presence of stimulators or inhibitors of the autophagy pathway to determine if autophagy is indeed involved in non-lytic release. Through the aid of cells expressing GFP-conjugated LC3 protein, the trafficking of virions to the cell surface will also be monitored using total internal reflection fluorescence (TIRF) microscopy. Finally, the role of component of the newly discovered unconventional secretion pathway in non-lytic release of HAV will also be determined using targeted siRNA knock downs. Dr. Clancy will determine; 1) whether HAV, like poliovirus, also exploits the autophagy machinery and 2) whether autophagic exit without lysis (AWOL) involves a newly appreciated mechanism of unconventional secretion.