A major conceptual advance for innate immunity has been the discovery of Pathogen-associated Molecular Pattern recognition receptors or sensors, a prime example being the toll-like receptor (TLR). More recently, we and others discovered a large family of pathogen sensors in humans and mice, called the NLR (nucleotide-binding domain, leucine-rich repeat containing) family, known previously as CATERPILLER, NACHT-LRR, or NOD-like receptor. An important function of NLR proteins is the formation of a biochemically-defined complex, called the inflammasome, which processes pro-caspase-1 and pro-IL-1b/IL- 18 to their mature forms. In addition to this role, some NLRs have a profound effect on T cell responses. This creates a new paradigm where NLRs can also influence adaptive immunity. Additional studies indicate that NLR proteins mediate type I interferon (IFN) production in response to viruses through an interference of the intracellular pathway mediated by the mitochondria! anti-viral signaling molecule (MAVS, a.k.a. IPS, VISA and CARDIF). This proposal will examine the divergent roles of NLR during flavivirus infection. Flaviviruses such as Dengue (DENV) and West Nile (WNV) have surfaced at the forefront of biodefense and emerging infections. Type I IFN is pivotal in anti-flaviviral host defense, and the intracellular pathway of viral RNA recognition is crucial for this response during DENV and WNV viral infection. Of equal importance, IL-1 Droduction has been observed by several groups as being a crucial outcome of human infection by Flaviviruses. Finally, adaptive immunity is unquestionably of importance to anti-flaviviral host response. However, the link between NLR members to any of these anti-viral host responses has not been explored. In this proposal, we plan to explore the roles of different NLRs in eliciting interferon response, inflammasome :unction, and adaptive immunity upon infection by WNV and DENV.

Public Health Relevance

This project examines novel innate immune pathways that are involved in anti-pathogen responses. These pathways are likely important for host defense against viral pathogens that pose as either potential biological warfare agents or as emerging infectious agents.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
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
Smartt, Chelsea T; Shin, Dongyoung; Alto, Barry W (2017) Dengue serotype-specific immune response in Aedes aegypti and Aedes albopictus. Mem Inst Oswaldo Cruz 112:829-837
Purcell, Erin B; McKee, Robert W; Courson, David S et al. (2017) A Nutrient-Regulated Cyclic Diguanylate Phosphodiesterase Controls Clostridium difficile Biofilm and Toxin Production during Stationary Phase. Infect Immun 85:
Ponnuswamy, Padmapriya; Joffre, Jeremie; Herbin, Olivier et al. (2017) Angiotensin II synergizes with BAFF to promote atheroprotective regulatory B cells. Sci Rep 7:4111
Silva, Laurie A; Dermody, Terence S (2017) Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J Clin Invest 127:737-749
Elong Ngono, Annie; Chen, Hui-Wen; Tang, William W et al. (2016) Protective Role of Cross-Reactive CD8 T Cells Against Dengue Virus Infection. EBioMedicine 13:284-293
Bowles, R D; Karikari, I O; VanDerwerken, D N et al. (2016) In vivo luminescent imaging of NF-?B activity and NF-?B-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy. Eur J Pain 20:365-76
Rowse, Michael; Qiu, Shihong; Tsao, Jun et al. (2016) Reduction of Influenza Virus Envelope's Fusogenicity by Viral Fusion Inhibitors. ACS Infect Dis 2:47-53
Ashbrook, Alison W; Lentscher, Anthony J; Zamora, Paula F et al. (2016) Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection. MBio 7:
Bates, John T; Pickens, Jennifer A; Schuster, Jennifer E et al. (2016) Immunogenicity and efficacy of alphavirus-derived replicon vaccines for respiratory syncytial virus and human metapneumovirus in nonhuman primates. Vaccine 34:950-6
Alayli, Farah; Scholle, Frank (2016) Dengue virus NS1 enhances viral replication and pro-inflammatory cytokine production in human dendritic cells. Virology 496:227-236

Showing the most recent 10 out of 387 publications