Section: Research

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Neal Silverman, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Infectious Diseases and Immunology
   Medicine

Other Affiliation(s):
   Center for AIDS Research
   Interdisciplinary Graduate Program
   Program in Immunology and Virology

Immune Signaling Pathways

The main goal of our lab is to decipher the molecular mechanisms responsible for transmitting a signal from the site of infection to the nucleus of an immune responsive cell. We are interested in how pathogens are distinguished, how related signaling pathways maintain specificity, and how various signals are integrated to produce the proper response. Research will focus on the immune response of the experimentally powerful fruit fly, Drosophila melanogaster. We are particularly interested in the mechanisms used in Drosophila that allow distinct pathogenic challenges to lead to specific immune responses by activating different signaling pathways and transcription factors. The immune signaling pathways in Drosophila have much in common with the pathways required for the activation of the mammalian innate immune response. In fact, the Toll-like receptor (TLR) family, which was discovered in Drosophila, plays a central role in pathogen recognition in both mammals and insects. A deeper understanding of these pathways in insects will undoubtedly lead to further advances in related mammalian fields.

The Drosophila antibacterial signaling pathway

In flies, infection causes the rapid production of a host of powerful antimicrobial peptides that are produced in the fat body (the insect liver) and ciruculate throughout the body. Pathogens are known to activate two separate and specific immune response signaling pathways, an antibacterial and an antifungal pathway, each of which culminates in the activation of different Drosophila NF-kB transcription factors. Fungal infection leads to the activation of Toll, which initiates a signal transduction cascade leading to the proteasome-mediated degradation of Cactus (the fly IkB), the nuclear translocation of two Drosophila NF-kB transcription factors, Dif and Dorsal, and the rapid expression of antifungal peptide genes. The Toll signaling pathway is also essential for the dorsoventral patterning of the developing embryo. The third Drosophila NF-kB protein, Relish, is required for antibacterial immunity. Relish is initially synthesized as a bipartite protein with an N-terminal NF-kB-like domain and C-terminal IkB-like domain, which inhibits its own nuclear translocation. Upon infection Relish is cleaved, freeing the NF-kB module to translocate to the nucleus where it activates antibacterial peptide gene expression.

Our lab is focused upon understanding the molecular mechanisms responsible for the activation of these two NF-kB pathways during the insect immune response. The antibacterial pathway, which is controlled by Relish, requires the Drosophila IkB kinase complex (IKK), a high molecular weight complex which contains a catalytic subunit, DmIKKb, and regulatory subunit, DmIKKg. Upon infection, the Drosophila IKK complex is activated and is required for the cleavage (and activation) of Relish. We are interested to know what lies upstream of the Drosophila IKK complex, what receptors are used to recognize pathogens and how does activation of these receptors, in turn, lead to the activation of the IKK complex. The mechanism of DmIKK-stimulated Relish cleavage is also a major focus in the laboratory.

The Drosophila Toll/antifungal signaling pathway

The antifungal pathway, which relies on the classic Toll signaling pathway, is also a focus of our research. Although we know a great deal about this signaling pathway, many important questions remain. In particular, we are interested in mechanisms of signal-induced Cactus degradation. Like mammalian IkBs, Cactus is phosphorylated upon signaling and this signaling leads to its proteasome mediated degradation. However, unlike IkB, Cactus degradation does not require the IKK complex, and the identity of the Cactus kinase is currently unknown.

Our goal is to uncover the molecular mechanism used by the innate immune system to recognize dangerous microbes and to rapidly mount a potent and specific response against them. Using Drosophila, with its powerful genetic, molecular, and biochemical tools, will enable us to gain a thorough understanding of the signal transduction pathways used by eukaryotes to fend-off their adversaries. This research has potential medical benefits beyond its primary goal of basic scientific understanding. A deeper understanding of the insect immune response will enable the design of new methods to combat the spread of infectious microbes by insects. Moreover, the similarities between the insect immune response and mammalian innate immunity will open-up new and exciting avenues of research into the mechanisms which control our more complicated immune response.

Office: LRB 313
Phone: 508-856-5826
Fax: 508-856-5463
E-mail: Neal.Silverman@umassmed.edu
Keywords: Immunology, Genetics, Organisms - Drosophila, Infectious Disease, Gene Regulation

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