Michael N. Teng Assistant Professor of Biochemistry and Molecular Biology 406 South Frear Laboratory, University Park, PA 16802 Phone: (814) 867-2299 Fax: (814) 863-7024 Email: mnt2@psu.edu S.B. in Life Sciences, Massachusetts Institute of Technology Ph.D. in Immunology, University of Chicago Postdoctoral Fellow, The Scripps Research Institute Research Fellow, National Institute of Allergy and Infectious Diseases Teng Lab Web Site

Virus-host interactions in the pathogenesis of viral infection

In order to infect a host successfully, a virus must meet two requirements. First, the virus must be able to attach and enter host cells in order to replicate itself and produce progeny virions. Second, the virus needs to avoid host defense mechanisms. To complete these two missions, viruses interact with cellular proteins. Viral infection can then result in the development of disease. Some pathogenic mechanisms are shared among different viruses while others are unique to particular viruses and virus families. The understanding of which viral factors affect pathogenesis as well as their modes of action will allow intervention in particular viral diseases, either by eliminating the virus or by preventing its harmful effects. Furthermore, understanding the interaction of viral proteins with the host can provide greater insight into basic aspects of the cellular machinery.

As a model system, I am investigating the interactions of human respiratory syncytial virus (RSV) with the host in order to define how RSV replicates, spreads, and modulates the host immune response to cause disease. RSV is one of the most important etiologic agents of pediatric respiratory disease, leading to 100,000 hospitalizations and 5,000 deaths per year in the US. RSV is a member of the Family Paramyxoviridae which includes such members as measles and mumps viruses. The RSV genome encodes 10 genes, from which 11 proteins are translated. I am interested in how these proteins interact with host cell proteins to achieve RSV pathogenesis. In particular, my laboratory is focused on two areas of viral pathogenesis: viral attachment and modulation of the antiviral immune response. To study these questions, we are using a reverse genetics system to produce mutant viruses for evaluating virus-host interactions in the context of an active infection.

Of the 11 RSV-encoded proteins, three are present on the virion surface. The F protein is responsible for viral membrane fusion. The function of the SH protein is unknown, though it is dispensable for viral infection in vitro and in vivo. The G protein is thought to be the viral attachment protein. However, the cellular receptor(s) for RSV G is currently not known. The RSV G protein is produced in both a membrane-bound as well as a secreted form. Using mutant RSVs, we have found that either form of G is sufficient to allow viral infection both in vitro and in vivo. Deletion of the G protein results in altered tropism of RSV in vitro and markedly decreased growth in vivo. In addition, RSV infection can be inhibited by soluble heparin, due in large part to binding to G. However, deletion of a putative heparin-binding domain in G had no effect on the heparin sensitivity of RSV suggesting that this region is not important for viral infection. We are currently examining the functional domains and requirements for G function as well as determining its receptor.

RSV also encodes two small nonstructural proteins, NS1 and NS2, which have no defined function. We have found that deletion of either protein results in attenuation of RSV both in vitro and in vivo. However, both proteins appear to be dispensable for viral replication in vitro. Other researchers have found that the corresponding proteins in bovine RSV appear to counteract the antiviral effects of type I interferon. We are presently determining how these proteins affect the antiviral activity of interferons and how they function in the viral life cycle.

Representative Publications:

• Teng MN, Collins PL. Identification of the respiratory syncytial virus proteins required for formation and passage of helper-dependent infectious particles. J Virol 1998;72:5707-5716.
• Teng MN, Collins PL. Altered growth characteristics of recombinant respiratory syncytial viruses which do not produce the NS2 protein. J Virol 1999;73:466-473.
• Teng MN, Whitehead SS, Bermingham A, St Claire M, Elkins WR, Murphy BR, Collins PL. Recombinant respiratory syncytial virus that does not express the NS1 or M2-2 protein is highly attenuated and immunogenic in chimpanzees. J Virol 2000;74:9317-9321.
• Teng MN, Whitehead SS, Collins PL. Contribution of the respiratory syncytial virus G glycoprotein and its secreted and membrane-bound forms to virus replication in vitro and in vivo. Virology 2001;289:283-296.

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