Sigal Research


Name: Luis Sigal, DMV, PhD
Position: Professor

233 South Tenth Street
Bluemle Life Sciences Building, Room 709
Philadelphia, PA 19107

Contact Number(s):

Research in my laboratory revolves around viral immunology and pathogenesis. While during my career I have worked and published papers using multiple viruses (foot-and-mouth disease virus, influenza virus, poliovirus, Lymphocytic choriomeningitis, vaccinia virus), during the last decade, one of our major interests has been to study the immunobiology and pathogenesis of ectromelia virus (ECTV), which causes mousepox, the mouse homolog of human smallpox. ECTV is an outstanding model to study acute viral infections as they spread in their biological host following infection through a natural route. Many of our ECTV papers have been published in high impact journals such as Immunity, Cell Host & Microbe, J. Exp Med, PNAS, PLoS Pathogens, and others. These papers identified some of the mechanisms whereby various components of the immune response protect from mousepox including Type I and II interferons, NFkB­­ signaling, natural killer cells, CD8 T-cells, helper and cytolytic CD4 T-cells, and B lymphocytes. Some of these papers also addressed the role of viral immune evasion proteins that counteract various immune mechanisms of resistance to viral disease. Another interest of my laboratory is to use viruses as tools to combat cancer, at this time we are focusing on ovarian cancer.

Research Projects

Anti-viral Protection by Type I Interferon (Type I IFN) & NFκB

The mechanism whereby Type I IFNs and NFκB protect from viral infections and how viruses evade their function in vivo remain incompletely understood. ECTV encodes a Type I IFN decoy receptor (EVM166) but its role in pathogenesis was unknown. Using a deletion mutant virus, we showed that EVM166 is essential for ECTV virulence and that mice can be protected from mousepox by vaccinating with recombinant EVM166. We also demonstrated that Type I IFN act local in tissues and not systemically and that Type I IFN signaling can be restored in the liver and mice cured from mousepox if treated with a mAb that neutralizes EVM166 (Figure 1). Moreover, we showed that the transcription factor NFκB is essential for resistance to mousepox and that an ECTV mutant lacking an NFκB inhibitor activates NFκB more effectively in vivo. Notably, NFκB activation compensates for defects in the Type I IFN pathway, such as a deficiency in the transcription factor IRF7. Thus, the overlap between the Type I IFN and NFκB pathways allows the host to overcome genetic or pathogen-induced deficiencies in Type I IFN. These findings may also explain why some pathogens target both pathways to cause disease.

More recently, we have found that the main producers of Type I in the draining lymph node are inflammatory monocytes which sense infection via a mechanism that involves the detection of intracellular virus, the signaling adapter STING, and the transcription factors IRF7 and NFκB. The inflammatory monocytes are recruited to the lymph node by chemokines produced by dendritic cells, which recognize infection via the pathogen recognition receptor TLR9, the adapter MyD88 and IRF7.

Anti-viral Protection by Memory CD8 T-Cells

Work in my laboratory has shown that memory CD8 T-cells maintained in the absence of antigen protect mice from mousepox. Moreover, we showed that a major mechanism of memory CD8 T-cell protection is to restrict virus spread from the draining lymph node (Figure 2). Further, we demonstrated that both dominant and subdominant epitopes can be protective and that protection by memory CD8 T cells required IFNγ and perforin. However, while the CD8 T cells must express perforin autonomously, IFNγ can be outsourced to other cells.

Anti-viral Protection by Natural Killer Cells

Until recently, most of our knowledge about NK cells in ant-viral protection had been learned from studies that used mouse cytomegalovirus. While it had been known for some time that NK cells also played a role in the natural resistance of C57BL/6 (B6) mice to mousepox, the mechanisms remained elusive. We showed that B6 mice resistance to mousepox requires the direct cytolytic function of NK cells. Furthermore, we showed that the activating receptor NKG2D is required for optimal NK cell-mediated resistance to lethal mouse pox. Moreover, we showed that similar to memory CD8 T-cells, NK cells protect, at least in part, by restricting virus spread from the draining lymph node (Figures 3 and 4). We also demonstrated that natural resistance of B6 mice to mousepox requires CD94 on NK cells, and that B6 mice deficient in Qa1b, the ligand for CD94, are also susceptible. In addition, we found that B6 mice lose their resistance to mousepox as they age, and that this is due to NK cell defects in maturation and migration to the draining lymph node. This established a new mechanism that can explain the increased susceptibility of the aged to viral diseases.

Anti-viral Protection by cytolytic CD4 T-cells (CD4 CTL)

CD4 T-cells are generally regarded as helpers and regulators of the immune response. Although cytolytic CD4 T-cells have been described, whether those generated during the course of a viral infection play a role in virus control remained unknown. We showed that during acute infection with ectromelia virus, the mouse homolog of the human virus of smallpox, large numbers of CD4 T-cells in the draining lymph node and liver of resistant mice have a CTL phenotype. We also show that these cells kill targets in vivo in a perforin-dependent manner and that mice with specific deficiency of perforin in CD4 T-cells have impaired virus control. Thus, our work demonstrated for the first time that CD4 CTL killing of infected cells is an important mechanism of antiviral defense.