Jules Hoffmann was born in Luxembourg where he gained his

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Jules Hoffmann was born in Luxembourg where he gained his Powered By Docstoc
					Jules Hoffmann was born in Luxembourg where he gained his bacchalaureate, after which he
left for the University of Strasbourg to study biology and chemistry. He did his Ph.D. work
with Professor Pierre Joly on the origins and roles of blood cells in the grasshopper Locustra
migratoria, a major pest in Northern and Western Africa. J. Hoffmann has subsequently
devoted his scientific life to the study of insects. Following his Ph.D. work, while still in
Strasbourg, he X-ray treated the hematopoïetic tissue which he had discovered in
grasshoppers and noted two dramatic effects which would thereafter orient his scientific
career: (1) the X-ray treated insects failed to molt if the treatment was performed before a
critical developmental period within the duration of the larval instars ; (2) the X-ray treated
insects developed spontaneously a lethal septicemia involving various opportunistic
microorganisms. The first effect pointed to a failure in the control of molting by the steroid
hormone ecdysome, which had just been discovered by the great German biochemist Peter
Karlson. J. Hoffmann went for an extended post-doctoral period to work with Karlson in
Marburg (Germany) on steroid hormones in development and reproduction, and he continued
this field of research with the renowned French chemist Guy Ourisson upon his return to
Strasbourg. Eventually, the biosynthesis and metabolism of ecdysome were worked out and
novel suicide-inhibitors were devised which were able to block the development of
grasshoppers and other pests. In the course of these studies, J.Hoffmann and colleagues made
the seminal discovery that massive ecdysone synthesis occurs in the ovaries of reproductively
competent female grasshoppers and that a phosphoconjugate storage form is transferred to the
oocyte and serves, after hydrolysis in the embryo, to control the cycles of embryonic
cuticulogenesis. Whilst the studies on ecdysone had priority over many years in the group,
experimental work on the immune system of grasshoppers continued by some of Hoffmann’s
co-workers and culminated in the discovery in late 80ies of several novel inducible
antimicrobial peptides in various insect species, namely the cysteine-rich defensins. In 1990,
J.Hoffmann and his group decided to solely focus on the origin and role of these inducible
antimicrobial peptides and to select Drosophila, as a genetically tractable model system, for
their studies.

In the early 90ies, J.Hoffmann and colleagues then succeeded in identifying in immune-
challenged flies seven distinct families of inducible antimicrobial peptides produced by the fat
body, an equivalent of the mammalian liver. Most of these peptides were found to be
membrane-active and their activities were directed against either fungi (named drosomycin
and metchnikowin by the group), Gram-positive bacteria (defensin) or Gram-negative bacteria
(diptericin, drosocin, cecropin, attacin). J.Hoffmann and his colleagues next addressed the
molecular regulation of the infection-induced expression of these antimicrobial peptides. A
major breakthrough in the mid-nineties was the discovery that two distinct pathways regulate
the response to infection at the transcriptional level. Remarkably, the pathway which responds
to fungal and Gram-positive bacterial infection was shown by the group to involve part of a
signaling cascade initially characterized for its role in the control of dorsoventral patterning in
the embryo. The cascade is activated through a transmembrane receptor, called Toll. This
receptor associates an extracellular domain similar to that of the by then known LPS-binding
membrane linked protein CD14 and an intracellular domain homologous to that of the
intracytoplasmic domain of the proinflammatory cytokine IL-1, which is a known activator of
NF-B. Loss of function flies failed to induce the synthesis of antifungal peptides and were
unable to resist fungal infections. The discovery that Toll was essential for innate resistance to
fungi in adult flies anticipated, and directly led to the discovery of the innate immune sensing
functions of the mammalian Toll-like receptors, and provoked a revolution in thought among
immunologists throughout the world. As in the fly, the mammalian Toll-like receptors were
shown to signal through NF-B family members and to lead to reprogramming of gene


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expression. Significantly, many of the newly-expressed genes in mammals encode cytokines,
co-stimulatory molecules, MHC proteins etc., which all concur to activate and orient the
adaptive immune responses. Whereas in the pre-Toll era, defense to microorganisms was
understood to be mediated primarily by phagocytosis or by the adaptive immune responses
based on rearranging receptors of B- and T-lymphocytes, a novel facet has nom become
apparent : a family of a dozen invariant Toll like receptors recognizes evolutionary conserved
microbial molecules and in response activates expression of immune-response genes many of
which are regulate efficient lymphocyte responses. Whereas in 1996 the Cell paper of the
Hoffmann laboratory was the first and only study linking Toll receptors to a defined host-
defense, more than 6,500 papers have been published in this field since and innate immunity
has now moved to the very forefront of immunology.

Hoffmann and his colleagues continued their studies by using genetic methods to identify the
component of the second immune signaling pathway in flies (which they had named Imd,
after a loss of function mutation resulting in immune-deficiency to Gram-negative bacteria).
Their studies have in large part deciphered the molecular events that lead from the activation
of the innate immune receptor to transcriptional control of gene expression.
Of particular interest is their recent functional dissection of a family of peptidoglycan
recognition receptors which bind to and are activated by various forms of peptidoglycan and
direct the immune responses either via the Toll or the Imd pathway. Proteins homologous to
these peptidoglycan recognition proteins have since been found in mammals where they
appear to exert a bactericidal action. Further, in a manuscript in press in Cell, the laboratory
now reports that proteases produced by invading filamentous fungi can also induce the Toll
pathway by activating zymogens in the circulating blood of the flies. The induction of an
immune response by microbial proteases is an important new concept which could prove in
the future to be of paramount importance in host-pathogen interactions, as most microbes,
including protozoan parasites, secrete proteases in their hosts.

J.Hoffmann has recently extended his interests and those of some of his co-workers to
antiviral defenses in Drosophila. So far, the results point to mechanisms distinct from those
devoted to fighting fungal or bacterial infections. For one, RNA interference appears as a
potent defense mechanism, which together with a STAT-JAK pathway dependent
reprogramming of gene expression accounts for much of the resistance of the flies to viruses.
The latter aspect can be regarded as a fac-simile of the mammalian interferon system. The
impressive array of tools that the Hoffmann laboratory has developed are now being used to
fully understand the antiviral response, which will also likely prove to be revealing for
mammalian systems.

With the purpose of applying the information gained on the Drosophila host defense to
medically important vector insects, Hoffmann has recently started a new group on the
postgenomic analysis on the immune defense of the mosquito Anopheles to the parasite
Plasmodium. The group has recently documented that a mosquito equivalent of the
Drosophila Toll pathway can abort infection by the malaria parasite in the mosquito. The
group has identified a complement-like protein as a mediator of this immune response. These
novel results are obviously of great potential and the molecular mechanisms of parasite killing
are under intense studies in the laboratory.

Hoffmann remains a highly active investigator in spite of his involvement in the French
Academy of Sciences and in other national and international boards. He is at present
particularly involved in the studies on antiviral and antiparasitic defenses of Drosophila and


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Anopheles, respectively. In addition, Hoffmann has very recently built up a new group with
three post-doctoral researchers which aims at studying at the genetic and biochemical levels
the role of the Imd and Toll pathways in inflammation. New, mostly unpublished, data now
indicate that the Imd pathway (and probably also the Toll pathway) is activated in the
absence of any infection, in flies in which a neurodegenerative phenotype has been induced as
well as in loss of function flies for the DNase genes (which scavenge DNA from apoptotic
cells during development). These phenotypes are evocative of inflammatory reactions, an
aspect not considered in flies to date. Hoffmann plans with this new group to make an in-
depth analysis of inflammation, using many of the tools and mutants which have been
generated in the course of the studies on antimicrobial defenses. This area represents a novel
frontier and given the parallels which exist between immune defenses of flies and mammals,
these studies may help understand inflammation in mammalian systems. They could also
bring significant insights into the crucial problem of identifying endogenous (non-microbial)
inducers of inflammation.

In conclusion, Hoffmann discovered the key pathways for resistance to infection in
Drosophila and paved the way to a revolution in the science of innate immunity. He continues
his work very actively to understand antiviral defense mechanisms and inflammatory
reactions to abnormal non-infectious self. He is also strongly involved in extending the
knowledge gained in immune defenses in Drosophila to the antiparasitic defense in the
malaria vector Anopheles.

Hoffmann is the founder of a school of internationally recognized group leaders, namely
Bruno Lemaitre (Lausanne), Julien Royet (Marseille), Jean-Luc Imler, Dominique Ferrandon,
Elena Levashina, Jean-Marc Reichhart, Charles Hetru and Maria Capovilla (Ferrara). He has
authored or co-authored more than 250 papers, many of which appeared in Cell, Science,
Nature, Nature Immunology, Immunity and other high ranking journals. He has received many
awards, in particular the William Coley Award of the Cancer Research Institute (2003), the
Koch Prize for Immunology of the Robert Koch Stiftung (2004) and the Grand Prix de la
Fondation pour la Recherche Médicale (2004). He is the President of the French Academy of
Sciences and a Member of the German Academy of Sciences Leopoldina, the Russian
Academy of Sciences, the European Molecular Biology Organization, Academia Europaea,
the American Academy of Arts and Sciences and the National Academy of the United States.




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