Luis J. Sigal, D.V.M., Ph.D.
Member, Fox Chase Cancer Center
Adjunct Assistant Professor, Department of Microbiology

Microbiology , Virology and Parasitology Program

Address

Fox Chase Cancer Center
333 Cottman Avenue
Philadelphia, PA 19111-2497
Office tel. 215-728-7061
Lab tel. 215-728-7065

Fax: 413-487-5406; 215-728-2412
E-mail: Luis.Sigal@fccc.edu

Link(s)

Dr. Sigal's FCCC web page

Education

University of Nebraska Ph.D. (Immunology), 1994

University of Buenos Aires, Argentina, D.V.M., 1984

Research Interests

• We are interested in viral immunology in particular the mechanisms whereby antigens are presented to T cells to initiate anti-viral T cell responses, and also in understanding the mechanisms of protective immunity following primary and secondary infections with highly pathogenic viruses.

Key words: Antigen presentation; viral immunology; vaccinia virus; ectromelia virus.

Search PubMed for articles

Description of Research

Mechanisms of cross presentation during viral infections

Cytotoxic T lymphocytes (CTL) are a major arm of the immune system responsible for eliminating virus-infected cells. Fully differentiated CTL (effector cells) can recognize infected cells and kill them, thereby eliminating sites of production and/or persistence of virus. CTL are able to recognize these cells, because they display antigens on the cell surface as fragments of viral proteins (peptides) bound to Major Histocompatibility Complex class I molecules. While CTL have probably evolved to fight viral infections, it has been found that they can also eliminate tumor cells displaying tumor-specific peptides.

Because of their aggressive nature and the risk of inflicting severe autoimmune diseases, the activation of CTL must be tightly controlled. Before recognizing antigen for the first time, CTL are said to be naive and are in a resting state. While activated CTL can recognize and kill any type of cell expressing the appropriate antigen, the activation of naive CTL requires the antigen to be initially presented by a specialized subset of cells known as professional antigen presenting cells (pAPC). These cells are very mobile and can carry antigen from the peripheral tissues into the secondary lymphoid organs where naive CTL reside. Importantly, pAPC do not necessarily need to be infected because they have a unique capacity to acquire antigen from other infected cells. A major interest of our laboratory is to understand the process whereby pAPC acquire antigens from virus-infected cells and display them on the cell surface to initiate CTL responses. The understanding of this process might be important for the development of antiviral vaccines. Moreover, because tumor cells cannot initiate CTL responses by themselves, this knowledge might be essential in the development of anti-tumor vaccines and immunotherapies relying on CTL immunity.

Immunity to ectromelia virus infection

Smallpox was an epidemic viral disease characterized by severe skin rashes and high mortality that was caused by the highly pathogenic Orthopoxvirus variola. Through the efforts of a World Health Organization vaccination campaign, smallpox was eradicated as a natural disease in 1977. Following eradication, most stocks of variola were destroyed and vaccination was discontinued. However, there is great fear that concealed stocks of variola could be expanded and used as a bioweapon. The effect of such an attack would be devastating in an unvaccinated population. The vaccine used for the eradication used live vaccinia virus, another Orthopoxvirus that induces an immune response that is cross protective against variola. Although this vaccine is effective in preventing smallpox, it is not safe by current standards, especially for immunodeficient individuals. Therefore, there is a need to develop a safe anti-smallpox vaccine that ideally will not use live viruses and will be effective for immunodeficient people. In addition, it will be necessary to develop effective anti viral treatments for individuals already infected with variola. For this purpose it is necessary to use animal models where we can learn about the pathogenesis of highly pathogenic orthopoxviruses, and the mechanisms involved in immune protection to secondary challenge in normal and immunodeficient individuals. An excellent model for this purpose is ectromelia, an Orthopoxvirus that is highly pathogenic for the mouse where it produces a disease known as mousepox. Similar to smallpox, the mouse disease is characterized by its high transmission rate, severe rash, and lethality. Moreover, it can be prevented by vaccinia inoculation. In addition, ectromelia and variola are genetically very similar. An interest of our laboratory is to determine the immune mechanisms whereby resistant strains of mice control primary ectromelia infection and how the vaccinia-based vaccine induces protection from mousepox. Furthermore, we are testing whether non-viral model vaccines targeted to induce cytotoxic T or B lymphocyte responses can induce long-term protection against ectromelia replication and/or mousepox in immunocompetent and immunodeficient animals. These studies will be valuable towards the development of new and safe smallpox vaccines. In addition, our results should provide important insights into the pathogenesis and immunity of generalized and lethal cytolytic viral infections.

Recent Publications

Shen, L., Sigal, L.J., Boes, M., Rock, K.L. Important role of cathepsin S in generating peptides for TAP-independent MHC class I cross presentation in vivo. Immunity 21:155-165, 2004.

Fang, M., Sigal, L.J Antibodies and CD8+ T cells are complementary and essential for natural resistance to a highly lethal cytopathic virus.? J. Immunol. 175:6829-6836, 2005.

Fang, M., Cheng, H., Dai, Z., Bu, Z., Sigal, L.J. Immunization with a single extracellular enveloped virus protein produced in bacteria provides partial protection from a lethal Orthopoxvirus infection in a natural host.Virology 345:231-243, 2006.

Fang, M., Sigal, L.J. Direct CD28 costimulation is required for CD8? T cell-mediated resistance to an acute viral disease in a natural host. J. Immunol. 177:8027-8036, 2006.

Xu, R.H., Fang, M., Klein-Szanto, A., Sigal, L.J. Memory CD8? cells are gatekeepers of the lymph node draining the site of viral infection. Proc. Natl. Acad. Sci. USA 104:10992-10997, 2007.

Lab

Rotation Projects

Projects are available in antigen presentation and also in immune response to ectromelia virus according to the interests of the rotating student.

Lab personnel:

Min Fang, Ph.D., Postdoctoral Associate
Ricardo Lopez, Ph.D., Postdoctoral Associate
Dominic Salerno, Ph.D., Postdoctoral Associate
Ren-Huan Xu, Ph.D., Postdoctoral Associate
Sanda Chhann, B.S., Graduate Student
Xueying Ma, M.S., Scientific Technician