Siddharth Balachandran, PhD
Office Phone: 215-214-1527
Lab Phone: 215-214-1528
Elucidating Interferon-Activated Survival and Cell Death Pathways
The IFNs were discovered 50 years ago as factors secreted by vertebrate cells that prevent virus infection. Since that time, however, it has emerged that IFNs also possess very potent antiproliferative and cytotoxic properties. Type I IFNs, particularly IFN-α, are FDA approved, or under trial, for the treatment of at least 20 different human cancers and over a dozen viral diseases. In particular, hematologic malignancies, such as hairy cell leukemia, chronic myelogenous lymphoma, multiple myeloma and AIDS-associated lymphomas are all susceptible to treatment, while malignant melanomas and renal cell carcinomas also respond favorably to IFN-α therapy. A key disadvantage to the continued use of IFNs in the clinic, however, is the spectrum of side-effects associated with its systemic administration at high doses. Thus, obtaining molecular insights into how the IFNs exert their antitumor effects is a particularly important imperative for the development of second-generation IFN-based therapeutics with increased specificity and potency.
We have recently discovered potential survival pathways that protect cells from IFNs, in the absence of which IFNs activate a powerful cell death program. We are particularly excited about these discoveries because they are expected to provide novel targets for the development of next-generation IFN-based therapeutics. Elucidating these novel IFN-activated signaling pathways and exploiting them for the treatment of human cancers forms the basis of the primary research project in our laboratory.
Role of NF-κB in Innate Immune Antiviral Responses
Innate immune responses are typically activated within minutes of exposure to the invading pathogen and serve the dual roles of thwarting the pathogen at the site of infection and galvanizing the pathogen-specific acquired immune response. The recognition of pathogenic microbes and the triggering of innate responses has become the subject of intense research over the last few years. Particular attention has focused on the role of toll-like receptors (TLRs), which have emerged as key trans membrane molecules that recognize conserved molecular motifs called ‘pathogen-associated molecular patterns’ (PAMPs) on invading pathogens. Examples of PAMPs include bacterial lipopolysaccharide and viral single-stranded RNA, which are recognized by TLR4 and TLR7, respectively.
Detection of viral PAMPs and consequent activation of a host response to viral infection occurs by both TLR-dependent and TLR-independent mechanisms. It has now emerged that two cytoplasmic RNA helicases, RIG-I and MDA-5 (collectively called the RIG-I-like helicases, or RLHs), are the primary sensors of cytosolic viral RNA in cells lacking TLRs. Both the TLR and RLH systems of viral recognition activate parallel signaling cascades that converge in the production of type I IFNs. Production of IFNs is considered the primary host innate immune response to viral infection.
Downstream of both TLRs and RLHs, at least three classes of transcription factors are activated: AP-1, NF-κB, and IRF-3/7. ‘NF-κB’ refers to a family of transcription factors formed by homo- and hetero-dimerization between members of the Rel group of proteins: RelA, RelB, c-Rel, p100/p52 and p105/p50. These Rel dimers are sequestered in the cytoplasm of un stimulated cells, for example through association with inhibitory proteins of the I-κB family. Stimulation of cells with a variety of agents, including virus infection, leads to the activation of protein kinases called IKKs (for I-κB kinases) that target cytoplasmic sequestration signals for destruction, thereby allowing the Rel dimers to enter the nucleus and turn on target genes.
Our laboratory is specifically interested in (1) determining the mechanism by which NF-κB is activated by virus infection, (2) identifying virus-activated NF-κB target genes, and (3) defining the role of NF-κB subunits in antiviral innate immunity.