Siddharth Balachandran, PhD
Office Phone: 215-214-1527
Lab Phone: 215-214-1528
The Balachandran lab is interested in how cells die during host innate-immune responses to viruses and bacteria, and in exploiting these mechanisms for the treatment of human disease, whether infectious, inflammatory or malignant.
A new form of programmed cell death, called ‘necroptosis’ and driven by the related kinases RIP1 and RIP3, has recently been described. Unlike apoptosis, which proceeds via a caspase cascade that results in the ordered disassembly of the cell, necroptosis is caspase independent largely driven by the RIP3 substrate MLKL. Once activated by RIP3, MLKL translocates to cellular membranes and induces their disruption, resulting in a form of cell death more reminiscent of necrosis. A whole-genome RNAi screen identified several innate-immune pathways as effectors of necroptosis, suggesting a key role for this form of cell death in anti-microbial host defense. Indeed several classes of innate-immune receptor (e.g., TLRs and cytokines such as TNF-α and interferons) and pathogen (e.g., DNA viruses, certain gram-negative bacteria) have since been shown to activate necroptosis. The Balachandran lab is interested in how viruses (particularly RNA viruses), gram-negative bacteria, and cytokines activate the necroptosis machinery, and how necroptosis functions during acute microbial infections to control pathogen spread.
The lab has recently outlined a pathway by which interferons (IFNs), a family of cytokines with well-known antiviral and immunomodulatory properties, activate RIP1/3 kinases and trigger necroptotitc death. The laboratory continues to work on how IFNs activate RIP1/3 kinases, and the regulatory mechanisms that normally restrain these kinases in unstimulated cells and only license necroptosis in susceptible cells. We have identified two such mechanisms that protect cells from IFNs: the adaptor protein FADD and the transcription factor NF-κB. Current projects in this area are centered on how FADD (and caspases) are disabled to allow IFNs to trigger necroptosis during an active infection. An allied area of interest is to test the feasibility of NF-κB blockade as a feasible combinatorial approach for the treatment of IFN-responsive human cancers.
More recently, the laboratory has identified RIP3-activated cell death as an important host defense mechanism that limits spread of RNA viruses, including influenza As. Downstream of RIP3, influenza A triggers the activation of both MLKL-dependent classical necroptosis as well as a parallel pathway of FADD/caspase 8-mediated apoptosis. The lab is interested in determining how RNA viruses activate RIP3 and how RIP3 activation results in MLKL activation versus apoptosis. Molecular- and animal model-based approaches are being used to identify additional determinants and regulators of virus-induced necroptosis, relevant cell types in vivo that die by RIP3-dependnent mechanisms, and the physiological contribution of discrete cell death pathways to control of an acute RNA virus infection.
Finally, the Balachandran laboratory is interested in targeting RIP1/3 kinases in human cancers that respond to IFN therapy, or possess well-established innate-immune and inflammatory etiologies. IFNs (esp. IFN-α) were approved by the Food & Drug Administration (FDA) in 1986 as the first ever commercial anticancer biotherapeutic, and are currently employed in the treatment of over twenty human cancers. In the years preceding their approval by the FDA, the IFNs were touted as a potential ‘silver bullet’ cure for many forms of cancer, even making the cover of Time magazine in 1980. Unfortunately, these cytokines have, in recent years, fallen out of favor with many oncologists because of their severe side-effects. Nevertheless, IFNs continue to be used in the clinic and provide spectacular cures of several highly malignant cancers (such as AIDS-associated lymphomas and metastatic renal cell carcinoma), highlighting their Janus-faced nature. The laboratory is interested in developing rational IFN-based combinations that seek to exploit IFN-triggered direct tumor cell death as a means to improve the efficacy of this cytokine and so lower its effective dose.Description of research projects
Fox Chase Programs
- Wang X, Wang J, Hopewell EL, Hussain S, Garcia-Sastre A, Balachandran S, Beg AA. Differential requirement for the IKKb/NF-kB signaling module in mediating TLR versus RLR-induced transcriptional responses. J Immunol. (In press).
- Haugh KA, Shalginskikh N, Nogusa S, Skalka AM, Katz RA, Balachandran S. The interferon-inducible antiviral protein Daxx is not essential for interferon-mediated protection against avian sarcoma virus. Virology J. 2014;11:100. PubMed
- Kaiser WJ, Daley-Bauer LP, Thapa RJ, Mandal P, Berger SB, Huang C, Sundararajan A, Guo H, Roback L, Speck SH, Bertin J, Gough PJ, Balachandran S, Mocarski ES. RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc Natl Acad Sci USA. 2014;111:7753-8. PubMed
- Peri S, Devarajan K, Wang DH, Knudson AG, Balachandran S. Meta-analysis identifies NF-κB as a therapeutic target in renal cancer. PLoS One. 2013;8:e76746. PubMed
- Thapa RJ, Nogusa S, Chen P, Maki JL, Lerro A, Andrake, M, Rall GF, Degterev A, Balachandran S. Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. Proc Natl Acad Sci USA. 2013;110:e3109-18. Highlighted in Nature Immunology (August 2013) and recommended to Faculty of 1000. PubMed
- Thapa RJ, Chen P, Cheung M, Nogusa S, Pei J, Peri S, Testa JR, Balachandran S. NF-κB inhibition by bortezomib permits interferon-γ-activated RIP1 kinase-dependent necrosis in renal cell carcinoma. Mol Cancer Ther. 2013;May 8 [Epub ahead of print]. PubMed
- Chen P, Nogusa S, Thapa RJ, Simmons H, Shaller C, Peri S, Adams GR, Balachandran S. Anti-CD70 immunocytokines for exploitation of interferon-γ-induced programmed necrosis in renal cell carcinoma. PLoS One 2013;8:e61446. PubMed
- Balachandran S, Adams GP. Interferon-γ-induced necrosis: an anti-tumor biotherapeutic perspective. J Interferon Cytokine Res. 2013;33:171-80. PubMed
- Balachandran S, Beg AA. Defining roles for NF-κB in antivirus responses: revisiting the interferon-β enhanceosome paradigm. PLoS Pathog. 2011;7:e1002165. PubMed
- Thapa RJ, Basagoudanavar S, Nogusa S, Irrinki K, Mallilankaraman K, Slifker MJ, Beg AA, Madesh M, Balachandran S. NF-κB protects cells from interferon-γ-induced RIP1-dependent necroptosis. Mol Cell Biol. 2011;31:2934-46. PubMed
- Basagoudanavar SH, Thapa RJ, Nogusa S, Wang J, Beg AA, Balachandran S. Distinct roles for the NF-kappa B RelA subunit during antiviral innate immune responses. J Virol. 2011;85:2599-610. PubMed
- Balachandran S, Thomas E, Barber GN. A FADD-dependent innate immune mechanism in mammalian cells. Nature. 2004;432:401-5. PubMed
- Balachandran S, Barber GN. Defective translational control facilitates vesicular stomatitis virus oncolysis. Cancer Cell. 2004;5:51-65. PubMed
- Balachandran S, Roberts PC, Brown LE, Truong H, Pattnaik AK, Archer DR, Barber GN. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity. 2000;13:129-41. PubMed
- Balachandran S, Kim CN, Yeh WC, Mak TW, Bhalla K, Barber GN. Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling. EMBO J. 1998;17:6888-902. PubMed