Innate immunity of an organism is the in born protection against invading pathogens. Innate immune receptors sense components of invading organisms and trigger immune and inflammatory responses to combat infectious agents. In this proposal we intend to target three human innate immune receptors which among others are involved in detecting virus infection. We will use high throughput screening to identify chemical and small interfering RNA modifiers, which will specifically modulate Toll-like Receptor 3, Retinoic acid Inducible gene I and Toll-like receptor 7 signaling pathways. During the course of this investigation, we would like to find efficient modifiers, test their specificity, and make them available to the research community. We have successfully developed and used high throughput screening experiments to target one of the innate immune receptor - Toll-like Receptor 3. Using a cell-based readout system to screen for inhibitors we have identified novel signaling pathways involved in TLR3 mediated IRF3 activation and cytokine induction. In this proposal we will collaborate with University of Pittsburgh Drug Discovery Institute (DDI) to take advantage of the high throughput screening and drug development expertise of DDI to expand our screening efforts. This project will not only generate novel reagents for studying innate immune receptor signaling pathways, but may also provide building blocks for future drug development, which can be used to treat inflammatory diseases caused by virus infection.

Public Health Relevance

Innate immune receptors are the first line of sensors to recognize various components of invading pathogens and trigger immune and inflammatory responses to combat the infectious agent. We propose to target a few of these receptors which are involved in sensing virus infections, and identify novel reagents capable of modulating the functions of these receptors. Our long-term goal is to use these specific reagents to treat inflammatory and auto-immune diseases, which are caused by over or under-action of these receptors.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Resource-Related Research Projects--Cooperative Agreements (U24)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-KE-I (J2))
Program Officer
Prabhudas, Mercy R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Forero, Adriana; McCormick, Kevin D; Jenkins, Frank J et al. (2014) Downregulation of IRF4 induces lytic reactivation of KSHV in primary effusion lymphoma cells. Virology 458-459:4-10
Forero, Adriana; Giacobbi, Nicholas S; McCormick, Kevin D et al. (2014) Simian virus 40 large T antigen induces IFN-stimulated genes through ATR kinase. J Immunol 192:5933-42
Zhu, Jianzhong; Zhang, Yugen; Ghosh, Arundhati et al. (2014) Antiviral activity of human OASL protein is mediated by enhancing signaling of the RIG-I RNA sensor. Immunity 40:936-48
Okada, Hideho; Scheurer, Michael E; Sarkar, Saumendra N et al. (2013) Integration of epidemiology, immunobiology, and translational research for brain tumors. Ann N Y Acad Sci 1284:17-23
Zhu, Jianzhong; Ghosh, Arundhati; Coyle, Elizabeth M et al. (2013) Differential effects of phenethyl isothiocyanate and D,L-sulforaphane on TLR3 signaling. J Immunol 190:4400-7
Forero, Adriana; Moore, Patrick S; Sarkar, Saumendra N (2013) Role of IRF4 in IFN-stimulated gene induction and maintenance of Kaposi sarcoma-associated herpesvirus latency in primary effusion lymphoma cells. J Immunol 191:1476-85
Umemura, Naoki; Zhu, Jianzhong; Mburu, Yvonne K et al. (2012) Defective NF-ýýB signaling in metastatic head and neck cancer cells leads to enhanced apoptosis by double-stranded RNA. Cancer Res 72:45-55
Zhu, Jianzhong; Coyne, Carolyn B; Sarkar, Saumendra N (2011) PKC alpha regulates Sendai virus-mediated interferon induction through HDAC6 and ýý-catenin. EMBO J 30:4838-49
Morosky, Stefanie A; Zhu, Jianzhong; Mukherjee, Amitava et al. (2011) Retinoic acid-induced gene-I (RIG-I) associates with nucleotide-binding oligomerization domain-2 (NOD2) to negatively regulate inflammatory signaling. J Biol Chem 286:28574-83
Beura, Lalit K; Sarkar, Saumendra N; Kwon, Byungjoon et al. (2010) Porcine reproductive and respiratory syndrome virus nonstructural protein 1beta modulates host innate immune response by antagonizing IRF3 activation. J Virol 84:1574-84

Showing the most recent 10 out of 11 publications