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ESI Special
Topics: August 2007
Citing URL: http://esi-topics.com/tlr/interviews/Alexopoulou_Flavell.html |
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An INTERVIEW with Dr. Lena Alexopoulou and Dr. Richard Flavell |
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 his
month, Special Topics talks with Dr. Lena Alexopoulou and
Dr. Richard Flavell about their highly cited paper,
"Recognition of double-stranded RNA and activation of
NF-kappa B by Toll-like receptor 3," (Alexopoulou L, Holt
AC, Medzhitov, and Flavell RA, Nature 413[6857]:
732-8, 18 October 2001). This paper ranks at #6 on our list
of the top 20 papers on Toll-like receptors published in the
past decade. According to
Essential
Science IndicatorsSM,
the paper currently has 1,166 citations to its credit. Dr.
Alexopoulou’s work can be found in the field of Immunology,
and Dr. Flavell’s work can be found in the fields of
Immunology, Molecular Biology & Genetics, Clinical Medicine,
and Neuroscience & Behavior. Dr. Alexopoulou is the Group
Leader for the Laboratory of Toll-like Receptors and Innate
Immunity at the Centre d’Immunologie de Marseille-Luminy.
Dr. Flavell is Professor and Chairman of Immunobiology and
Professor of Molecular, Cellular & Developmental Biology at
the Yale University School of Medicine, as well as an
Investigator for the Howard Hughes Medical Institute. |
 Would
you please give our readers a brief summary of your October 2001
Nature paper?
Through a series of in vitro and in vivo
experiments we showed for the first time that TLRs are implicated in
viral recognition. When we started our studies, the ligand and
function of Toll-like receptor 3 (TLR3) was unknown, and we decided
to generate TLR3-deficient mice by gene targeting, with the idea
that the analysis of these mice would let us uncover the biological
function of TLR3.
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“As our understanding of the principal
functions regulated by TLRs in immune and
inflammatory responses has developed, so has
the appeal in applying that knowledge to
clinical problems.” |
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We found that TLR3 detects viral double-stranded RNA and polyI:C
(a synthetic analogue of double-stranded RNA) and that TLR3
signaling leads to NF-kappaB activation and production of type I
interferons and cytokines. TLR3-deficient mice were highly resistant
to polyI:C-induced septic shock. Moreover, we showed that in
response to polyI:C, NF-kappaB activation and dendritic cell
maturation was independent of MyD88, an adaptor molecule downstream
of most TLRs.
What
were the main findings of your study, and what were the implications for
the field?
Our major finding was that TLR3 detects viral double-stranded RNA
and that polyI:C can signal independently of MyD88. Today we know
that indeed TLR3 signals through an adaptor molecule called TRIF and
that viral double-stranded RNA can also be detected by the cytosolic
helicases RIG-I and MDA5. Moreover, we know that not only TLR3 but
also TLR7, TLR8, and TLR9 are able to sense distinct viral nucleic
acid structures, such as single-stranded RNA and unmethylated CpG
DNA.
Have
you done any follow-ups to this paper, or did this paper influence any
of your later publications?
One of our major follow-ups was to investigate the importance of
TLR3 in antiviral responses. As an infectious agent we used
West Nile virus, which is transmitted
to humans mainly through mosquito bites; however, the infection only
becomes consequential if the virus succeeds in crossing the
blood-brain barrier. Using the TLR3-deficient mice as our mouse
model, we showed that West Nile virus pathogenesis in the brain of
infected mice is dependent on TLR3, since TLR3-deficient mice are
more resistant to infection than their wild-type controls. TLR3
signaling initiates an early inflammatory response in the periphery,
including the production of TNF-alpha, which leads to the opening of
the blood-brain barrier and the entrance of the virus into the brain
that finally leads to brain inflammation (Wang T, et al.,
"Toll-like receptor 3 mediates West Nile virus entry into the brain
causing lethal encephalitis ,"
Nature Medicine, 10[12]:
1366-73, 2004).
Moreover, through collaboration with various research groups, we
tested the involvement of TLR3 signaling in different viral
infection models and found that TLR3 function can be either
beneficial or detrimental depending on the virus.
If
we were in an ideal world where you had unlimited resources, what
research would you pursue?
The recent appreciation of the role of pattern recognition
receptors (PRRs), including TLRs, on the initiation of innate
immunity and orchestration of adaptive immunity has opened new
avenues in our understanding of immune responses. It is important to
clarify the role of each individual PRR, but the big challenge is to
understand how in response to a specific pathogen the various PRRs
and their signaling pathways cooperate and orchestrate the
appropriate immune response in order to fight and eliminate the
pathogenic microorganism.
What
are your predictions for this field in the future, say in 10 years'
time?
Based on the intense research in the last decade on the
biological role of mammalian TLRs, we now know that TLR-mediated
innate and adaptive immune responses play an important role in a
variety of diseases including infectious diseases, sepsis,
autoimmune diseases, allergy, cancer, and atherosclerosis. As our
understanding of the principal functions regulated by TLRs in immune
and inflammatory responses has developed, so has the appeal in
applying that knowledge to clinical problems. Currently, various TLR
agonists are being developed as adjuvants for new vaccines to
prevent infectious diseases and cancer and for the treatment of
viral infections, allergies, and cancer. Interestingly, a few of
these promising drugs have already been approved and numerous others
are in the phase of preclinical or clinical trials. As the list of
disease states for which one or more TLRs and their associated
adaptor molecules are involved is growing rapidly, it is reasonable
that the TLRs will serve as a productive field for drug development
for various diseases in the future.
Lena Alexopoulou, Ph.D., CR1 CNRS
Centre d’Immunologie de Marseille-Luminy
Marseille, France
Richard Flavell, Ph.D., FRS
Howard Hughes Medical Institute
Yale University School of Medicine
New Haven, CT, USA
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Dr. Lena Alexopoulou and Dr. Richard Flavell's
most-cited paper with 1,166 cites to date: |
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Alexopoulou L, et al., "Recognition of
double-stranded RNA and activation of NF-kappa B by
Toll-like receptor 3," Nature 413(6857):
732-8, 18 October 2001.
Source:
Essential Science Indicators. |
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Related
Links: |
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Dr. Richard Flavell
is
featured in
ISIHighlyCited.com |
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ESI Special
Topics: August 2007
Citing URL: http://esi-topics.com/tlr/interviews/Alexopoulou_Flavell.html
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