We study viral pathogenesis in two animal viruses, mouse adenovirus type 1 (MAV 1), and Punta Toro virus (PTV), a bunyavirus. We are currently investigating how attachment and entry of MAV-1 affect and effect the host response, how MAV-1 breaks down the blood-brain barrier, and which components of innate and adaptive hose response are important for pathogenesis. We are developing PTV as a model for disease caused by the related highly pathogenic Rift Valley fever virus in humans. For both MAV-1 and PTV we are using positional cloning to identify host susceptibility genes.

A.R Welton, E.J. Chesler, C. Sturkie, A.U. Jackson, G.N. Hirsch, and K.R. Spindler. Identification of quantitative trait loci for susceptibility to mouse adenovirus type 1. Journal of Virology 79:11517-11522 (2005).

Pigmentation is an excellent model system for studying gene action and interaction, cell signaling and cell biology. Mouse pigmentation mutants often have pleiotropic effects, providing an entry point to studying diverse biologic systems. Mice lacking the ubiquitin ligase Mahogunin Ring Finger-1 (MGRN1) have dark fur and defects in patterning the left-right body axis, and develop adult-onset spongiform neurodegeneration similar to that observed in prion diseases or caused by infection with certain viruses, including HIV. The Gunn lab uses genetic, proteomic, biochemical and cell biology approaches to identify MGRN1 tagets and understand its biological functions. We are also interested in other pigmentation mutants with similar phenotypes as they will provide insight into the biological pathways that regulate pigmentation and neurodegeneration.

Studies in mice have shown that natural killer cells deploy multiple mechanisms to deal with mouse cytomegalovirus infection, which involve receptors of the C-lectin type superfamily. In particular, activating Ly49receptors seem to recognize host and/or virus MHC class I related structures. While reviewing genetic and molecular data supporting these receptor-ligand interactions, we will highlight the central role that specific recognition of the cytomegalovirus infected cell by NK cells plays in host resistance to infection.

S.G. Adam, A. Caraux, N. Fodil-Cornu, J.C. Loredo-Osti, S. Lesjean-Pottier, J. Jaubert, I. Bubic, S. Jonjic, J.L. Guenet, S.M. Vidal, F. Colucci. Cmv4, a new locus linked to the NK cell gene complex, controls innate resistance to cytomegalovirus in wild-derived mice. Journal of Immunology,176:5478-85 (2006).

M.P. Desrosiers, A. Kielczewska, J.C. Loredo-Osti, S.G. Adam, A.P. Makrigiannis, S. Lemieux, T. Pham, M.B. Lodoen, K. Morgan, L.L. Lanier, S.M. Vidal. Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection. Nature Genetics, 37:593-9 (2005).

S.H. Lee, A. Zafer, Y. de Repentigny, R. Kothary, M.L. Tremblay, P. Gros, P. Duplay, J.R. Webb, S.M. Vidal. Transgenic expression of the activating natural killer receptor Ly49H confers resistance to cytomegalovirus in genetically susceptible mice. The Journal of Experimental Medicine, 197:515-26 (2003).

Using genomic and proteomic approaches to identify new pathways and genes in immunity. Innate immunity - mechanisms of action and function of the NLR genes. Adaptive immunity - mechanisms of action and function of plexins and semaphorins in the immune system.

B.P. O'Connor, S-Y. Eun, Y. Zhengmao, A.L. Zozulya, J.D. Lich, C.B. Moore, H.A. Iocca, K.E. Roney, E.K. Holl, Q.P. Wu, H.W. van Deventer, Z. Fabry and J.P. Ting. Semaphorin 6D regulates the late phase of CD4+ T cell primary immune responses. (PNAS, in press).

Our primary interests are in understanding how the various receptor molecules used by natural killer (NK) cells and T cells are employed in the recognition of pathogens and cancer cells, and how these receptors regulate lymphocyte development.

S. Gasser and D.H. Raulet. The DNA Damage Response Arouses the Immune System.Cancer Research, 66:3959-62 (2006).

N.C. Fernandez, E. Treiner, R.E. Vance, A.M. Jamieson, S.Lemieux, and D.H. Raulet. A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules. Blood, 105:4416-23. Epub 2005 Feb 22.

S. Gasser, S. Orsulic, E.J. Brown and D.H. Raulet. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature, 436:1186-90 (2005).

Steven Wasserman , Ph.D.
Professor of Cell and Developmental Biology; Director, Center for Molecular Genetics
University of California,
San Diego

We are interested in how information regulating gene expression is encoded, transmitted, and interpreted. In addressing this question, we have focused on the conserved Toll signaling pathway, which has evolved a rich array of variations adaptive to diverse functions in development and defense. We have carried out our investigations of mechanism and adaptations primarily in the fruit fly, where we can readily generate mutations that disrupt pathway function, monitor and manipulate gene activity, and map out regulatory circuitry using molecular, biochemical, and bioinformatic techniques. Our recent studies provide insights into Toll signal transduction and transcriptional output in organisms ranging from insects to humans.

M.S. Busse, C.P. Arnold, P. Towb, J. Katrivesis and S.A. Wasserman. A kB sequence code for pathway-specific innate immune responses. EMBO Journal 26:3826–3835(2007).

H. Sun, P. Towb, D.N. Chiem, B.A. Foster and S.A. Wasserman. Regulated assembly of the Toll signaling complex drives Drosophila dorsoventral patterning. EMBO Journal 23: 100–110 (2004).

Our laboratory has two main interests: 1) to understand the innate and adaptive mechanisms involved in natural and acquired resistance to mousepox. 2) To understand the molecular, cellular and organismal mechanisms of antigen presentation that induce effective anti-viral CD8+ T cell responses.

R.H. Xu, M. Fang, A. Klein-Szanto and L.J. Sigal. Memory CD8+ T cells are gatekeepers of the lymph node draining the site of viral infection. Proceedings of the National Academy of Sciences of the United States of America 104:10992-7 (2007).

R-H. Xu, M. Cohen, Y. Tang, E. Lazear, J. C. Whitbeck, R. J. Eisenberg, G. H. Cohen and L.J. Sigal. The Orthopoxvirus Type I IFN binding protein is essential for virulence and an effective target for vaccination. Journal of Experimental Medicine (In Press).

M. Fang, L.L. Lanier, L.J. Sigal. A Role for NKG2D in NK cell-mediated resistance to poxvirus disease. PLoS Pathogens 4:e30, 2008.

We have been examining the role of dendritic cells and memory T cells in control of infection confined to non-lymphoid tissues. In particular, we have focused on infection by herpes simplex virus of skin and neuronal tissues. We have found that distinct dendritic cell subsets are called into play during the different phases of infection and that memory T cells located at peripheral sites of infection are critical to the protection against subsequent virus exposure.

R.S. Allan, J. Waithman, S. Bedoui, C.M. Jones, J.A. Villadangos, Y. Zhan, A.M. Lew, W.R. Heath, and F.R. Carbone. Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming.  Immunity, 25:153-162 (2006).

Waithman, R.S. Allan, H. Kosaka, H. Azukizawa, K. Shortman, M.B. Lutz, W.R. Heath, F.R. Carbone and G.T. Belz. Skin-derived dendritic cells can mediate deletional tolerance of class I-restricted self-reactive T cells.  Journal of Immunology,179:4535- 4541 (2007).

L.M. Wakim, J. Waithman, N. van Rooijen, W.R. Heath and F.R.Carbone. Dendritic cell-induced memory T cell activation in non-lymphoid tissues. Science, 319:198-202 (2008).

Plasmodium development within Anopheles mosquitoes represents a vulnerable step in the parasite transmission cycle and is a promising target for malaria control. The development of Plasmodium in the mosquito is considerably hindered by a powerful immune response. Parasite lysis in the mosquito midgut is mediated by TEP1 binding to the ookinete surface. It appears that a hetero-dimer composed of two LRR proteins, LRIM1 and APL1, prevents uncontrolled attachment of TEP1 to mosquito tissues. Our results reveal an unexpected interplay between LRR proteins and a homolog of mammalian complement factors.

S.A. Blandin, E.A. Levashina. Phagocytosis in mosquito immune responses. Immunological Reviews, 219:8-16 (2007).

S.H. Shiao, M.M. Whitten, D. Zachary, J.A. Hoffmann, E.A. Levashina. Fz2 and cdc42 mediate melanization and actin polymerization but are dispensable for Plasmodium killing in the mosquito midgut. PLoS Pathogens, 2:e133(2006).

C. Frolet, M. Thoma, S. Blandin, J.A. Hoffmann, E.A.Levashina. Boosting NF-kappaB-dependent basal immunity of Anopheles gambiae aborts development of Plasmodium berghei. Immunity, 25:677-85(2006).

Research in my group focuses on the innate immune system and defense mechanisms in metazoan. Currently, we have three research projects, two of which extend and complete the work on Drosophila that we followed over the past. In Drosophila, recognition of microbes activates two pathways in the fly immune system, namely the Toll and IMD pathways. The first two projects aim at understanding how these two pathways are activated. The third project concerns the study of the immune system of the snail Biomphalaria glabrata, intermediary host of the parasite that causes schistosomiases.

T. Michel, J.M. Reichhart, J.A. Hoffmannand J. Royet. Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein. Nature, 414:756-759 (2001).

P. Ligoxygakis, N. Pelte, J.A. Hoffmann and J.M Reichhart. Activation of Drosophila Toll during fungal infection by a blood serine protease. Science, 297:114-116 (2002).

M. Gottar, V. Gobert, A.A. Matskevich, J.M. Reichhart, C. Wang, T.M. Butt, M. Belvin, J.A. Hoffmann, D. Ferrandon. Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors. Cell, 127:1425-1437 (2006).

A. Goto, K. Matsushita, V. Gesellchen, L. El Chamy, D. Kuttenkeuler, O. Takeuchi, J. Hoffmann, S. Akira, M. Boutros and J.M. Reichhart. Akirins are highly conserved nuclear proteins required for NF-κB-dependent gene expression in drosophila and mice. Nature Immunology, 9:97-104 (2008).

We use mouse model of infection with virulent Mycobacterium tuberculosis for systematic forward genetic analysis of host susceptibility to this pathogen and positional cloning of key host resistance genes. Elucidation of mechanisms important for control of tuberculosis infection in the lung is our top priority, because lung is the organ that the pathogen destroys to ensure transmission in human populations, and which is especially difficult to protect with existing anti-tuberculosis drugs and vaccines. Better understanding why mechanisms of host resistance fail in the lungs of immunocompetent individuals is necessary to reduce transmission of MTB and the overall burden of the disease.

H. Pan, B. S. Yan, M. Rojas, Y. V. Shebzukhov, H. Zhou, L. Kobzik, D. E. Higgins, M. J. Daly, B. R. Bloom, and I. Kramnik. Ipr1 gene mediates innate immunity to tuberculosis. Nature, 434:767-72(2005).

B.S Yan, A. Pichugin, O. Jobe, L. Helming, E. Eruslanov, J. Gutierrez-Pabello, M.Rojas-Lopez, Y.V. Shebzukhov, L. Kobzik, and I. Kramnik. Progression of Pulmonary Tuberculosis and Efficiency of Bacillus Calmette-Guerin Vaccination Are Genetically Controlled via a Common sst1-Mediated Mechanism of Innate Immunity. Journal of Immunology, 179:6919 -6932(2007).

H. Pan, G. Mostoslavsky, E. Eruslanov, D.N. Kotton, and I. Kramnik. Dual-promoter lentiviral system allows inducible expression of noxious proteins in macrophages. Journal of Immunological Methods, Epub(2007).