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Immunology and Microbial Science

Chairman's Overview

Argyrios N. Theofilopoulos, M.D.

Argyrios N. Theofilopoulos, M.D.
Chairman and Professor

The Department of Immunology and Microbial Science has seen a great many changes this past year. First was the retirement of Richard Ulevitch from the chairmanship after 14 years of exceptional service. His steady leadership and clear focus allowed the department to thrive even during challenging times. His many seminal scientific contributions in the field of innate immunity have been, and continue to be, widely recognized. In consideration of Dr. Ulevitch's exceptional service, the president of Scripps Research, Richard Lerner, conferred upon him the title of chairman emeritus, and we are happy that he will maintain a presence among us as a professor of immunology. The faculty, as a whole, wishes him all the best in his new endeavors.

I am indeed honored to have been entrusted by the president with the stewardship of the department, and I thank my colleagues for their advice and assistance.

Dr. Lerner's confidence in the department is clear in the recent initiative to encompass in our faculty several illustrious virologists previously affiliated with various other departments. This merging of highly complementary investigators, technologies, and methods broadens the mission of the department in exciting ways and provides new opportunities to break uncharted scientific ground and to enhance the reputation of Scripps Research as a whole. The Department of Immunology and Microbial Science now has 25 professors, 4 emeritus professors, 15 associate professors, 9 assistant professors, and 132 research associates, staff scientists, and adjuncts.

The caliber of research in the department has long been our strength, as recently exemplified by the election of Michael Oldstone to the National Academy of Sciences, the latest of many well-deserved honors he has received throughout his career. Frank Chisari is also a member of the academy, and we are proud to include 2 members of this highly distinguished group of scientists in our department. We also congratulate Bruce Beutler, a former member of this department and currently chairman of the Department of Genetics, and Peter Wright, chairman of the Department of Molecular Biology, on their election to the National Academy of Sciences.

On a more somber note, we mourn the passing and celebrate the life and memories of Frank Dixon, a world-renowned immunopathologist, founder of Scripps Research, and first chairman of this department. Dr. Dixon led the way in the study of mechanisms by which viruses and immune complexes result in a broad array of autoimmune and other diseases. Although his highly distinguished achievements and honors are well recognized, it is his role as a mentor, colleague, and friend that resonates most deeply with many of us who were privileged to work with him.

Members of the department continue to publish seminal findings in virology, autoimmunity, cancer, cell biology, and other areas. Although we take great pride in the depth and breadth of the entire body of work of our staff, which is detailed in the ensuing individual reports, a few highlights deserve mention.

Dennis Burton and colleagues published 2 important articles that may have considerable impact on the treatment of AIDS and hepatitis C. In research reported in Nature, they found that broadly neutralizing human monoclonal antibodies against HIV require interactions with Fc receptors on effector cells to exert their full protective effects. In other research reported in Nature Medicine, they identified human monoclonal antibodies that neutralize genetically diverse isolates of hepatitis C virus (HCV) and protect against challenge with heterologous quasi species of HCV in a human liver-chimeric mouse model. These results raise the hope of using such antibodies to HCV to protect against heterologous viral infections and suggest that a broadly active vaccine against this virus may be possible.

Michael Oldstone and members of his laboratory reported in the Journal of Experimental Medicine and earlier in Nature Medicine that IL-10 is a major immunosuppressive factor that compromises T-cell antiviral responses; conversely, blockade of IL-10 promotes T-cell responses and enhances clearance of persistent viral infections. These findings have important implications for restoring T-cell activity and creating more efficacious vaccination protocols in many viral diseases, including HIV and hepatitis B and C, in which immunosuppression and vaccine inefficiency are common occurrences.

Philipe Gallay and Frank Chisari published the results of 2 studies in the Proceedings of the National Academy of Science in which they identified an amphipathic α-helical peptide, C5A, that has marked virocidal effects on both HIV and HCV. C5A corresponds to the N terminus of the membrane-associated nonstructural protein 5A of HCV, an essential component of the viral replication complex. Because of its unique mechanism of action, the development of C5A is an important addition to protease inhibitors currently in use to treat HIV disease and is under development for the treatment of hepatitis C.

Jason Whitmire and Lindsay Whitton published results in the Journal of Immunology that challenge current dogma that early inflammation, particularly production of IFN-γ, programs contraction of the T-cell population. They clearly showed that instead, IFN-γ exerts a pronounced positive effect throughout the T-cell response and that CD4+ and CD8+ T cells that cannot respond to this cytokine are 100-fold less likely to enter the memory pool than are CD4+ and CD8+ T cells that can respond. Moreover, in research described in PLoS Pathology, they showed that both memory and naive T cells have an extended and indistinguishable delay in the onset of proliferation in response to antigen, a finding contrary to the generally held belief that memory T cells initiate division much more rapidly than do their naive counterparts. This delay in the proliferation of memory T cells appears to provide an evolutionary safeguard that balances the risk of infection against the consequence of severe immunopathologic changes.

Erica Ollmann Saphire and colleagues, in a prominent full article in Nature, described their success in obtaining the crystal structure of Ebola virus glycoprotein in a trimeric conformation and in complex with a neutralizing antibody fragment derived from a human survivor of a 1995 outbreak of the virus. This major achievement has important implications for understanding the immunopathology of Ebola virus and in advancing efforts to develop vaccines and other therapeutic agents in the event of a natural, accidental, or intentional release of this life-threatening virus. The unique crystal structure obtained was featured on the cover of Nature, a signal honor.

Glen Nemerow and colleagues reported in Cell Host and Microbe that human α-defensins inhibit adenovirus infection and that this inhibition requires direct association of the defensin with the virus. Moreover, defensins inhibit virus disassembly at the vertex region, thereby restricting the release of an internal capsid protein required for penetration of the endosomal membrane during cell entry. Thus, defensins have remarkably distinct modes of activity against bacteria and viruses, and their function may provide insights for the development of new antiviral strategies.

Dwight Kono and colleagues, in research described in Immunity, showed that a spontaneous function-impairing mutation of the gene for coronin-1A (an F-actin inhibitor) suppresses lupuslike autoimmunity by reducing T-cell activation and migration. This finding provides a strong rationale for investigating the role of actin-regulatory proteins in autoimmunity and their potential as therapeutic targets.

In an article in Nature, Wolfram Ruf, Hugh Rosen, and colleagues described a novel mechanism by which hyperactivation of the immune system can lead to bacterial sepsis. They found that thrombin induces signaling by the protease-activated receptor 1 on dendritic cells, thereby amplifying inflammatory responses that, surprisingly, take place not in the vascular bed but rather in the lymphatic system. They further showed that blocking interactions between this receptor and sphingosine 1-phosphatase receptor 3 can interrupt systemic inflammation and death due to bacterial sepsis in experimental animals, thereby providing a potential new approach for the treatment of this condition in humans.

In research reported in the Journal of Experimental Medicine, Linda Curtiss and Peter Tobias made an important connection between atherosclerosis and inflammation by showing that endothelial cells in regions of disturbed blood flow on arterial walls express Toll-like receptor 2 and by providing evidence in experimental animals that interactions of either oxidized lipoproteins or bacteria with this receptor can provoke inflammation and subsequent atherosclerosis. Dianne Mackay also obtained evidence, presented in the Journal of Immunology, that Toll-like receptors expressed in kidney allografts play a role in rejection and in ischemia-perfusion injury, suggesting that blockade of these receptors and other molecules associated with innate immunity may be a new approach for the treatment of atherosclerosis and allograft rejection.

Michael G. McHeyzer-Williams and colleagues published an article in Nature Immunology on research in which they found that high-affinity follicular B helper T cells are important participants in the induction of humoral responses against protein vaccines. In another article, in Immunity, they reported that the nature of the adjuvant used in vaccination greatly influences the clonal composition of the responding T cells. These findings have important implications for the design of effective protein subunit vaccines.

In research described in Immunity, David Nemazee found that receptor editing, necessary for B-cell self-tolerance and formation of light chains, is highly dependent on intact recombination sequences. Mice with mutations of the kappa-deleting element are the first mouse strain with a defect solely in autoreactive B-cell editing. Another study by Ann Feeney, published in the Journal of Experimental Medicine, indicated that some lupus-prone mice have partial defects in the control of B-cell tolerance mediated by receptor editing.

Gary Bokoch and his group continue to advance our understanding of the Rho GTPase signaling mechanisms that underlie cell division and motility. In articles published in Developmental Cell and Molecular and Cellular Biology, they reported the crucial role of the Rho regulator guanine nucleotide exchange factor H1 in coupling the polymerization state of microtubules to cell contractility. An example is the key role of the factor in regulating formation of cleavage furrows during cell division. Dr. Bokoch and his coworkers have also shown that Rac GTPase acts through its downstream mediator, cofilin, to regulate the coupling of dynamic actin networks at a cell's leading edge that control motility. These results establish new insights into how cell signals couple to the molecular machinery that regulates actin dynamics and motility, findings particularly relevant to chemotaxis of phagocytic leukocytes.

Reviewing these contributions has deepened my appreciation of the quality of the scientists in the department and has instilled in me a sense of pride and confidence that we will continue to push the cutting edge of biomedical research. As Dr. Lerner recently said, the fact that we continue to list such achievements despite the current economic difficulties speaks volumes about the talents, skills, and innovation of our faculty.

Finally, it is important to acknowledge the integral and crucial functions of our support staff, who are a great credit to Scripps Research. We are fortunate to be able to depend on laboratory, office, and administrative staff who ensure our success in myriad indispensable ways. From the smooth work flow in our laboratories, offices, and technologic service facilities to the administrative departments that keep us abreast of opportunities and ever-changing regulations, the professionalism and dedication of these individuals are valuable for the performance and public dissemination of our science.

In offering my congratulations to my colleagues and coworkers for their achievements, it is my strong belief that this department will continue to be recognized worldwide as a leader in the study of immunology and microbial biology and that the pioneering contributions of our staff will continue to advance the sciences of medicine and health.