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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057157-11
Application #
8437251
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
11
Fiscal Year
2013
Total Cost
$235,810
Indirect Cost
$38,348
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Guo, Haitao; Gao, Jianmei; Taxman, Debra J et al. (2014) HIV-1 infection induces interleukin-1? production via TLR8 protein-dependent and NLRP3 inflammasome mechanisms in human monocytes. J Biol Chem 289:21716-26
Emery, Felicia D; Stabenow, Jennifer M; Miller, Mark A (2014) Efficient inactivation of Burkholderia pseudomallei or Francisella tularensis in infected cells for safe removal from biosafety level 3 containment laboratories. Pathog Dis 71:276-81
Pop, Laurentiu M; Barman, Stephen; Shao, Chunli et al. (2014) A reevaluation of CD22 expression in human lung cancer. Cancer Res 74:263-71
Rice, Amanda D; Adams, Mathew M; Lindsey, Scott F et al. (2014) Protective properties of vaccinia virus-based vaccines: skin scarification promotes a nonspecific immune response that protects against orthopoxvirus disease. J Virol 88:7753-63
Zellweger, Raphaƫl M; Eddy, William E; Tang, William W et al. (2014) CD8+ T cells prevent antigen-induced antibody-dependent enhancement of dengue disease in mice. J Immunol 193:4117-24
Agnihothram, Sudhakar; Yount Jr, Boyd L; Donaldson, Eric F et al. (2014) A mouse model for Betacoronavirus subgroup 2c using a bat coronavirus strain HKU5 variant. MBio 5:e00047-14
Krumm, Stefanie A; Yan, Dan; Hovingh, Elise S et al. (2014) An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model. Sci Transl Med 6:232ra52
Zhao, Jincun; Li, Kun; Wohlford-Lenane, Christine et al. (2014) Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci U S A 111:4970-5
de Alwis, Ruklanthi; de Silva, Aravinda M (2014) Measuring antibody neutralization of dengue virus (DENV) using a flow cytometry-based technique. Methods Mol Biol 1138:27-39
Blake, Lauren E; Garcia-Blanco, Mariano A (2014) Human genetic variation and yellow fever mortality during 19th century U.S. epidemics. MBio 5:e01253-14

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