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)
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Special Emphasis Panel (ZAI1)
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Mallia, Conrad M
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University of North Carolina Chapel Hill
Chapel Hill
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Huang, Juin-Hua; Liu, Chu-Yu; Wu, Sheng-Yang et al. (2018) NLRX1 Facilitates Histoplasma capsulatum-Induced LC3-Associated Phagocytosis for Cytokine Production in Macrophages. Front Immunol 9:2761
Zhang, Yugen; Dittmer, Dirk P; Mieczkowski, Piotr A et al. (2018) RIG-I Detects Kaposi's Sarcoma-Associated Herpesvirus Transcripts in a RNA Polymerase III-Independent Manner. MBio 9:
Anders, Penny M; Montgomery, Nathan D; Montgomery, Stephanie A et al. (2018) Human herpesvirus-encoded kinase induces B cell lymphomas in vivo. J Clin Invest 128:2519-2534
Feng, Hui; Lenarcic, Erik M; Yamane, Daisuke et al. (2017) NLRX1 promotes immediate IRF1-directed antiviral responses by limiting dsRNA-activated translational inhibition mediated by PKR. Nat Immunol 18:1299-1309
McKnight, Kevin L; Xie, Ling; González-López, Olga et al. (2017) Protein composition of the hepatitis A virus quasi-envelope. Proc Natl Acad Sci U S A 114:6587-6592
Swanson, Karen V; Junkins, Robert D; Kurkjian, Cathryn J et al. (2017) A noncanonical function of cGAMP in inflammasome priming and activation. J Exp Med 214:3611-3626
Freeman, Leslie; Guo, Haitao; David, Clément N et al. (2017) NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J Exp Med 214:1351-1370
Host, Kurtis M; Jacobs, Sarah R; West, John A et al. (2017) Kaposi's Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes. MBio 8:
Ma, Zhe; Hopcraft, Sharon E; Yang, Fan et al. (2017) NLRX1 negatively modulates type I IFN to facilitate KSHV reactivation from latency. PLoS Pathog 13:e1006350
Jha, Sushmita; Brickey, W June; Ting, Jenny Pan-Yun (2017) Inflammasomes in Myeloid Cells: Warriors Within. Microbiol Spectr 5:

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