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The immune system is central to the survival of humans in a world replete with potentially deadly microbes. This system has two major components: (i) the familiar “adaptive” immune system, which is mobilized by previous infections or vaccines to protect us against subsequent encounters with the microbe for which the vaccine is specific, and (ii) the less well known, but more ancient, innate immune system, which is rapidly mobilized in response to infection and results in inflammatory responses. Both systems are essential for human survival. Infants born without a functioning adaptive immune system, such as those with severe combined immunodeficiency, require heroic measures, such as bone marrow transplantation, if they are to survive. But the lack of a normally functioning innate immune system can also be life-threatening, as is seen in the repetitive severe infections in those with mutations in key components of the innate immune system.

The 2011 Shaw Prize in Life Science and Medicine is awarded to Jules A Hoffmann, Professor at the University of Strasbourg, Ruslan M Medzhitov, David W Wallace Professor of Immunobiology at Yale University, and Bruce A Beutler, Chairman, Department of Genetics, The Scripps Research Institute. These three scientists have done path-breaking work that established the mechanisms of the innate system and have set the stage for a veritable torrent of work by others, leading to enormous progress and to the expectation of many practical applications of this knowledge to improve the overall function of the immune system.  

The story begins with Jules A Hoffmann, who recognized that study of the fruit fly, Drosophila melanogaster, had the potential to unlock the secrets of innate immunity. This was true since the innate immune system is an evolutionarily ancient one while adaptive immunity is only seen in vertebrates. Mutations in the fruit fly that disable innate immunity are straightforward to obtain and relatively easy to analyze, in contrast to studies in humans and other mammals such as mice. Hoffmann found mutations that prevented the fruit fly from making a protective immune response to the fungus, Aspergillus fumagatus. The normal response would have been the production of the anti-fungal peptide Drosomycin. By analyzing the genes in which the mutations that blocked anti-fungal immunity had occurred, Hoffmann showed that production of Drosomycin in infected fruit flies depended on the activation of a particular molecule termed Dorsal related immune factor (Dif). This result was particularly important because Dif is part of a system that is closely related to the key system in humans that activates inflammation. Even more important, Hoffmann showed that Dif activation depended on a molecule called Toll, which exists on the cell surface and is in the right position to detect pathogens. Interestingly, Toll had been previously known in flies for its important role in establishing the orientation of the Drosophila embryo. Its role in innate immunity in the fly was entirely unanticipated and this discovery immediately attracted the attention of scientists working on the innate immune responses of humans and experimental animals.

Ruslan M Medzhitov and his then research mentor Charles A. Janeway, Jr. (now deceased) recognized that humans might have a similar system for the initiation of the innate immune response. Indeed, Janeway had earlier predicted the existence of generalized mechanisms through which cells of the innate immune system could detect or “sense” a pathogen. Medzhitov and Janeway asked whether there were human molecules that resembled Drosophila Toll. By searching a database of human genes, they found a human homolog of Drosophila Toll that is now referred to as a Toll-like receptor (TLR). Within a year of Hoffmann’s report, Medzhitov showed that if TLR molecules on the surface of certain blood cells were brought into aggregates, they caused the cells to produce a series of potent molecules (cytokines) that were capable of initiating inflammatory responses and that would mobilize cells that would help to eliminate the pathogens.

Still unresolved after Medzhitov and Janeway’s work was what the TLR “sensed”.  That is, how did it “know” a potentially invasive microorganism was present.   Bruce A Beutler’s key contribution was to prove that the TLRs recognized specific molecules known to be stimulants of inflammatory responses. He had been studying responses of mouse cells to a potent bacterial product, the endotoxin lipopolysaccharide (LPS), a component of the outer membrane of one important class of bacteria. LPS was known to cause inflammatory responses in infected humans.  LPS had been shown to work by causing cells of the human and mouse innate immune system to make several inflammatory cytokines, which if produced in very large amounts can cause a fatal shock syndrome (endotoxin shock). In order to determine what molecules the cells of the innate immune system used to recognize LPS, he took advantage of the fact that certain mouse strains were unable to respond to LPS and their inability was known to be due to a single mutation. Identifying which gene was mutant was a daunting task in the early 1990s when Beutler undertook these studies but he persevered and, through elegant experiments, showed that the mutant gene was precisely the TLR that Medzhitov and Janeway had identified in the human database, a gene now known as TLR4. Beutler’s work showed that TLRs were physiologically important activators of the innate immune system of humans and other vertebrates and established that a known bacterial activator of the innate immune system, LPS, was recognized by TLR4. It established the paradigm that common bacterial products, and later viral and parasite products, mediated their activation of innate immunity by being recognized by TLRs and other sensors of the innate immune system.

These three scientists, Hoffmann, Medzhitov and Beutler, through their critical work, laid out the principles underlying the pathogen recognition/ response model of the innate immune system. Their work opened the floodgates leading to an enormous body of work and a deep and sophisticated understanding of the TLRs as microbial sensors important in innate resistance to pathogens and to further work outlining the existence of other microbial sensors found within cells that coordinate microbial sensing with inflammatory responses and with the elimination of pathogens. This body of work has revolutionized our understanding of the innate immune system and provides targets for drug development and for the development of new generations of vaccines.

Life Science and Medicine Selection Committee
The Shaw Prize

7 June 2011  Hong Kong