Chairman’s Overview
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.
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