Infectious diseases of children
CVI Program Unit(s):
Cardiovascular Development / Congenital Heart Disease
Myocyte Biology / Heart Failure
CVI Research Description:
We study the coxsackieiviruses, a major cause of viral myocarditis, with a focus on the role of receptors in pathogenesis. The major coxsackievirus receptor,CAR is a component of specialized intercellular junctions, including the intercalated disc of mature cardiomyocytes. CAR mediates homophilic and heterophilic cell adhesion, and work with some tumor cell lines suggests that CAR may transmit growth-inhibitory signals. We recently found that cardiomyocyte-specific deletion of the murine CAR gene results in embryonic death, with hyperplasia of the left wall of the embryonic heart, and malformation of sinuatrial valves. The CAR-deficient myocardial cells express N-myc, a compact layer marker, but do not express trabecular markers, such as BMP10 and ANF. We would like to define how CAR functions during cardiac development; specifically, the mechanism by which CAR influences the
formation of the normal ventricular wall.
We are interested in the structure and function of virus receptors, with a particular interest in the receptors for coxsackieviruses and adenoviruses.
Key Words: Virus entry, adenovirus, coxsackievirus, viral pathogenesis, virus receptor.
Description of Research
Coxsackieviruses? non-enveloped viruses that cause neurologic and cardiac disease in humans)? interact with at least two receptors during virus infection? CAR (the coxsackievirus and adenovirus receptor), and DAF (CD55, a complement regulatory molecule). On polarized epithelial cells, which are likely the first targets of natural infection, CAR is sequestered in intercellular junctions, and is inaccessible to virus; in contrast, DAF is expressed on the cell surface. We have found that DAF-mediated signals are important for virus infection of polarized cells. We are interested in defining the signaling molecules and other cellular factors required for coxsackievirus infection of polarized cells, and the mechanisms by which other viruses infect these cells. We are studying the cell biology of virus entry, with a focus on understanding the separate roles of the two receptors during the entry process. We have also developed transgenic and conditional knockout systems with which to examine the function of the two receptors during infection in vivo.
We have found that DAF-mediated signals are important for virus infection of polarized cells. We are interested in defining the signaling molecules and other cellular factors required for coxsackievirus infection of polarized cells. We are also interested in the routes by which other DAF-binding viruses enter these cells. In further work, we want to define the structural features of virus-DAF interaction.
1. Cell biology of picornavirus entry
2. Mutational analysis of virus-receptor interactions
3. CAR interactions with intracellular proteins
4. CAR purification for structural studies
Jieyan Pan, Postdoctoral fellow
Chonsaeng Kim, Postdoctoral fellow
Lili Zhang, Research Technician
Bhargavi Naraynan, Research Technician
- Assistant Professor of Microbiology at University of Pennsylvania School of Medicine (2003– present)
- Professor of Pediatrics at University of Pennsylvania School of Medicine (2010– present)
- Assistant Professor of Pediatrics at University of Pennsylvania School of Medicine (1997 – 2004)
- Associate Professor of Pediatrics at University of Pennsylvania School of Medicine (2004 – 2010)
- M.D., University of Pennsylvania (1981)
- A.B., Harvard College (1972)
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- Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krikthivas A, Hong JS, Horwitz MS, Crowell RL, Finberg RW. Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science. Vol 275. 1997:1320-1323.
- Cohen CJ, Shieh JT-C, Pickles RJ, T Okegawa T, Hsieh J-T, Bergelson JM. The coxsackievirus and adenovirus receptor (CAR) is a transmembrane component of the tight junction. Proc. Natl. Acad. Sci. USA. Vol 98. 2001:15192-15196.
- Chen, Jin-Wen. Zhou, Bin. Yu, Qian-Chun. Shin, Sangyoon J. Jiao, Kai. Schneider, Michael D. Baldwin, H Scott. Bergelson, Jeffrey M.. Cardiomyocyte-specific deletion of the coxsackievirus and adenovirus receptor results in hyperplasia of the embryonic left ventricle and abnormalities of sinuatrial valves.. Circulation Research. Vol 98. 2006:923-30.
- Coyne CB, Bergelson JM. Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions. Cell. Vol 124. 2006:119-131.
- Coyne CB, Kim KS, Bergelson JM.. Poliovirus entry into human brain microvascular endothelial cells requires receptor-induced activation of the tyrosine phosphatase SHP-2.. EMBO Journal. Vol 26. 2007:4016?4028.
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- Kallewaard Nicole L, Zhang Lili, Chen Jin-Wen, Guttenberg Marta, Sanchez Melissa D, Bergelson Jeffrey M. Tissue-specific deletion of the coxsackievirus and adenovirus receptor protects mice from virus-induced pancreatitis and myocarditis.. Cell host & microbe. Vol 6(1) . 2009 Jul:91-8.
- Bergelson Jeffrey M. Intercellular junctional proteins as receptors and barriers to virus infection and spread.. Cell host & microbe. Vol 5(6) . 2009 Jun:517-21.
- Patel KP, Coyne CB, Bergelson JM. Dynamin- and lipid raft-dependent entry of DAF-binding and non-DAF-binding Coxsackieviruses into non-polarized cells.. Journal of virology. 2009 Aug.