The immune response is a double-edged sword;it is absolutely required for host defense, but unregulated, causes inflammatory disease. A number of critical questions regarding the mechanisms that appropriately tailor these pathways remain unanswered. This proposal seeks to uncover novel regulatory mechanisms that control critical aspects of the innate and adaptive response to NIAID priority pathogens. This U19 proposes a novel and fully integrated approach to immunological research that we have termed Systems-Guided Forward Genetics. Here, we combine traditional forward genetics and systems biology methodologies, retaining the advantages of each strategy while eliminating several previous obstacles. The result of this synergy is a significant increase in both the scope and pace of gene discovery and of subsequent mechanistic studies. This program is enabled by the rapid advances in next-generation sequencing technology, which have transformed forward genetics by allowing the identification of ENU-induced mutations prior to phenotypic screening, and by new systems biology approaches that allow contextualization of the mutations within gene regulatory and signaling networks. The multiple Cores within this integrated U19 program will enable and support three complementary Projects that probe the immune system in several orthogonal directions. The UTSW group will conduct an unbiased screen for defective immune responses to a variety of PAMPs that are components of multiple NIAID Priority pathogens. This group will use knowledge of the mutations present in each pedigree to accelerate the identification of genes identified in these screens. The ANU group will selectively enrich the colony of mice to be screened for mutations in genes that have been predicted by systems biology analyses to play a role in adaptive immune responses, and analyze the role of these genes during infection with the NIAID Priority pathogens influenza and ectromelia viruses. The Seattle BioMed group will comprehensively screen macrophages and dendritic cells for in vitro defects in response to a wide-range of innate immune agonists. This group will focus on mice identified by exome sequencing to have ENU induced mutations in genes predicted by systems analysis to be critical regulators of immune ceil networks and will establish the role of these genes in the immune response to the NIAID Priority pathogens Salmonella, Listeria, and influenza.
The immune system is a two-edged sword;it is absolutely required for defense against infections, but unregulated, it causes inflammatory disease. This program combines several novel technologies and approaches in order to find new genes that control immune responses. Understanding the workings of this complex system will enable the design of vaccines, drugs, and other therapies to combat infectious disease and inflammation.
|Bendall, Sean C; Davis, Kara L; Amir, El-Ad David et al. (2014) Single-cell trajectory detection uncovers progression and regulatory coordination in human B cell development. Cell 157:714-25|
|Zak, Daniel E; Tam, Vincent C; Aderem, Alan (2014) Systems-level analysis of innate immunity. Annu Rev Immunol 32:547-77|
|Gaudillière, Brice; Fragiadakis, Gabriela K; Bruggner, Robert V et al. (2014) Clinical recovery from surgery correlates with single-cell immune signatures. Sci Transl Med 6:255ra131|
|Knijnenburg, Theo A; Ramsey, Stephen A; Berman, Benjamin P et al. (2014) Multiscale representation of genomic signals. Nat Methods 11:689-94|
|Gold, Elizabeth S; Diercks, Alan H; Podolsky, Irina et al. (2014) 25-Hydroxycholesterol acts as an amplifier of inflammatory signaling. Proc Natl Acad Sci U S A 111:10666-71|
|Yang, Yong; Kulka, Kathleen; Montelaro, Ronald C et al. (2014) A hydrolase of trehalose dimycolate induces nutrient influx and stress sensitivity to balance intracellular growth of Mycobacterium tuberculosis. Cell Host Microbe 15:153-63|
|Altin, John A; Daley, Stephen R; Howitt, Jason et al. (2014) Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4+ T cells. Proc Natl Acad Sci U S A 111:2067-74|
|Zeng, Ming; Hu, Zeping; Shi, Xiaolei et al. (2014) MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses. Science 346:1486-92|
|Angelo, Michael; Bendall, Sean C; Finck, Rachel et al. (2014) Multiplexed ion beam imaging of human breast tumors. Nat Med 20:436-42|
|Wang, James Q; Jeelall, Yogesh S; Beutler, Bruce et al. (2014) Consequences of the recurrent MYD88(L265P) somatic mutation for B cell tolerance. J Exp Med 211:413-26|
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