The concept of Pathogen-Associated Molecular Pattern (PAMPs) engaging Pattern Recognition Receptors (PRR) to initiate innate immunity has revolutionized immunology. We first reported the 22- member NLR (Nucleotide-binding and Leucine Rich repeat or NOD-like receptors) family. Most NLRs activate innate immunity, prime examples being NODI and N0D2 which recognize bacterial peptidoglycan and inflammasome NLRs that trigger caspase-1 activation leading to IL-1B and ILI8 maturation. Recently, we and several other groups documented a new NLR subfamily that reduces inflammatory and immune activation which is comprised of NLRP4, NLRP6, NLRP12, NLRC3, NLRC5 and NLRXI. These proteins largely operate by interacting with adaptors and signaling pathways in the innate immune system. In this proposal we will examine the intersection of some of these novel NLRs in regulating host response to a number of NIAID Priority RNA and DNA viruses. We will apply several cutting edge proteomic approaches to assess specific proteomes that are dependent on NLRs during infection with NIAID Priority viral pathogens. These directions are in precise concordance with the RFA which states that """"""""emphasis of research proposed in response to this FOA should be in defining novel cellular and molecular immune mechanisms involved in immunity to virus infection"""""""". Additionally, the mechanisms by which these NLRs regulate host response are broadly applicable to many viruses of relevance on the Priority Pathogens'list. It supports the overall goal of the Program by (a) investigating the role of novel PRRs as sensors or receptors of viral nucleic acid which affect subsequent innate immune responses to NIAID high priority viral pathogens in human;(b) applying cutting edge quantitative proteomic approaches for the identification of novel paradigm-shifting pathways of pathogen sensing;(c) assessing cross-talk between multiple PRRs;(d) using unique biochemical capabilities that are technically challenging to study the ligand-binding functions of PRRs, and (e) performing experiments with primary human materials. This project will involve extensive collaboration with Projects 2 and 3, as well as Cores A-C.

Public Health Relevance

NLRs are key intracellular PRRs, however their functional relevance in viral infection is just emerging. Furthermore, the mechanism by which NLRs sense pathogens is poorly understood and hotly debated. This work will focus on NLRs serve as brakes of innate inflammation. The work is relevant because (a) it studies PRRs that attenuate an inflammatory response, which is still a new concept;(b) these negative regulators affects multiple viral infections, thus the biologic implication is broadly applicable to multiple high priority viral pathogens.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-ZL-I (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Chapel Hill
United States
Zip Code
Hirai-Yuki, Asuka; Hensley, Lucinda; McGivern, David R et al. (2016) MAVS-dependent host species range and pathogenicity of human hepatitis A virus. Science 353:1541-1545
Erdoğan, Özgün; Xie, Ling; Wang, Li et al. (2016) Proteomic dissection of LPS-inducible, PHF8-dependent secretome reveals novel roles of PHF8 in TLR4-induced acute inflammation and T cell proliferation. Sci Rep 6:24833
Ma, Zhe; Damania, Blossom (2016) The cGAS-STING Defense Pathway and Its Counteraction by Viruses. Cell Host Microbe 19:150-8
Bhatt, Aadra Prashant; Wong, Jason P; Weinberg, Marc S et al. (2016) A viral kinase mimics S6 kinase to enhance cell proliferation. Proc Natl Acad Sci U S A 113:7876-81
Guo, Haitao; König, Renate; Deng, Meng et al. (2016) NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses. Cell Host Microbe 19:515-28
Gunawardena, Harsha P; O'Brien, Jonathon; Wrobel, John A et al. (2016) QuantFusion: Novel Unified Methodology for Enhanced Coverage and Precision in Quantifying Global Proteomic Changes in Whole Tissues. Mol Cell Proteomics 15:740-51
Damania, Blossom (2016) A Virological Perspective on Cancer. PLoS Pathog 12:e1005326
Chatterjee, Srirupa; Basler, Christopher F; Amarasinghe, Gaya K et al. (2016) Molecular Mechanisms of Innate Immune Inhibition by Non-Segmented Negative-Sense RNA Viruses. J Mol Biol 428:3467-82
Giffin, Louise; West, John A; Damania, Blossom (2015) Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration. MBio 6:e01499-15
Wang, Li; Xie, Ling; Ramachandran, Srinivas et al. (2015) Non-canonical Bromodomain within DNA-PKcs Promotes DNA Damage Response and Radioresistance through Recognizing an IR-Induced Acetyl-Lysine on H2AX. Chem Biol 22:849-61

Showing the most recent 10 out of 31 publications