The goal of this proposal is to determine the molecular mechanisms by which flaviviruses, notably the yellow fever vaccine strain YFV-17D and the pathogenic Asibi strain, as well as dengue virus (DENV), stimulate innate immunity to program adaptive immune responses. This broad goal will be pursued in 3 aims:
Specific Aim 1 : To determine the mechanisms by which ISR programs DCs to stimulate adaptive Immunity. Our recent use of systems biological approaches to understand immune responses to vaccination in humans has revealed an early transcriptional signature, consisting of mammalian general control nonderepressible-2 [GCN2], that is a strong correlate of the later CD8+ T cell response. GCN2 is a sensor of amino acid starvation, and mediates the integrated stress response (ISR) and translational control of mRNA. We will thus study the impact of the ISR and translational control in the innate control of adaptive immunity.
Specific Aim 2 : To evaluate the Innate and adaptive immune responses stimulated by YFV-17D, versus Aslbl. YFV-17D was derived from the Asibi strain, but very little is understood about the mechanisms of innate sensing and regulation of adaptive immunity by Asibi. Here we will use molecular clones of the two viruses to determine the signaling networks by which these two viruses program DCs and monocytes, and the impact of this on T and B cell immunity.
Specific Aim 3 : To determine the development and functions of human monocyte subsets In response to DENV. Our recent work demonstrates that during acute dengue infection, there is a substantial expansion in the CD14+CD16+ monocyte population. This subset seems to be efficient at inducing plasmablast differentiation from resting B cells. Here we will explore the immune stimulatory capacities and developmental programs of these cells. Sub-Aim 3a: To determine the Immune stimulatory capacity of monocytes stimulated by DENV; Sub-Aim 3b: Probing the gene regulatory networks driving differentiation of CD14+CD16+ monocytes The successful completion of these aims will offer novel insights into the mechanisms by which flaviviruses stimulate innate immunity, and guide the design of therapeutic and vaccination strategies.

Public Health Relevance

The proposed work builds on our previous work in which we have used systems biological approaches to define signatures that predict the immunogenicity of vaccines. Here we will explore the mechanistic basis of the genes contained in these signatures. Furthermore, we will dissect the molecular pathways by which 3 flaviviruses (YFV-17D, Asibi and DENV) program innate control of adaptive immunity. This work will provide new mechanistic insights and catalyze the design of therapeutics and vaccines against viral infections.

National Institute of Health (NIH)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
United States
Zip Code
Hohensinner, Philipp J; Goronzy, Jörg J; Weyand, Cornelia M (2014) Targets of immune regeneration in rheumatoid arthritis. Mayo Clin Proc 89:563-75
Suthar, Mehul S; Pulendran, Bali (2014) Systems analysis of West Nile virus infection. Curr Opin Virol 6:70-5
Pulendran, Bali (2014) Systems vaccinology: probing humanity's diverse immune systems with vaccines. Proc Natl Acad Sci U S A 111:12300-6
Janssens, Sophie; Pulendran, Bali; Lambrecht, Bart N (2014) Emerging functions of the unfolded protein response in immunity. Nat Immunol 15:910-9
Kwissa, Marcin; Nakaya, Helder I; Onlamoon, Nattawat et al. (2014) Dengue virus infection induces expansion of a CD14(+)CD16(+) monocyte population that stimulates plasmablast differentiation. Cell Host Microbe 16:115-27
Weyand, Cornelia M; Yang, Zhen; Goronzy, Jorg J (2014) T-cell aging in rheumatoid arthritis. Curr Opin Rheumatol 26:93-100
Yang, Rendong; Bai, Yun; Qin, Zhaohui et al. (2014) EgoNet: identification of human disease ego-network modules. BMC Genomics 15:314
Burke, Rachel M; Smith, Emily R; Dahl, Rebecca Moritz et al. (2014) The economic burden of pediatric gastroenteritis to Bolivian families: a cross-sectional study of correlates of catastrophic cost and overall cost burden. BMC Public Health 14:642
Chiu, Christopher; McCausland, Megan; Sidney, John et al. (2014) Broadly reactive human CD8 T cells that recognize an epitope conserved between VZV, HSV and EBV. PLoS Pathog 10:e1004008
Jagger, Ann; Shimojima, Yasuhiro; Goronzy, Jorg J et al. (2014) Regulatory T cells and the immune aging process: a mini-review. Gerontology 60:130-7

Showing the most recent 10 out of 127 publications