The goals of this project are to identify novel genes involved in innate immunity and to determine if polymorphisms in some of these genes regulate the innate immune response to lipopolysaccharide (LPS), Staphylococcus aureus, Gram negative sepsis, and Aspergillus fumigatus infection in humans. ? ? We have previously shown that polymorphisms in TLR4, the receptor for LPS, are associated with hyporesponsiveness to inhaled LPS in mice and humans. We have also shown that these same polymorphisms predispose humans to Gram negative sepsis and protect them from atherosclerosis. However, our previous findings also demonstrate that sequence variants of TLR4 account for only a portion of the LPS phenotype in either mice or humans and that other genes are also involved in regulating the response to LPS.? ? The role of host susceptibility in the initiation and severity of infections caused by Gram negative and Gram positive bacteria is incompletely understood. The overall goal of our sepsis project is to further understand why some individuals develop infection, and of those with bacteremia, why only some go on to have adverse outcomes. Similarly, very little is known about the hosts innate immune response to Aspergillus fumigatus, a fungal pathogen that causes invasive pulmonary aspergillosis in immunocompromized hosts.? ? The overall hypothesis of this research program is that polymorphisms of genes identified either by genetic or genomic techniques following a challenge with a microbial toxin or a live organism in model systems (mice, C. elegans, and cell culture) regulate the pathophysiologic response to innate immune stimuli in humans. To test this hypothesis, gene expression and positional cloning studies will be conducted in mice and their genetic relevance will be tested in humans. We will also use RNA interference (RNAi) in mammalian tissue culture and the nematode C. elegans to test the physiologic and biologic importance of these genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES101946-03
Application #
7594015
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2007
Total Cost
$1,023,640
Indirect Cost
City
State
Country
United States
Zip Code
Henao-Martinez, Andres F; Agler, Anne Hermetet; Laflamme, Daniel et al. (2013) Polymorphisms in the SUFU gene are associated with organ injury protection and sepsis severity in patients with Enterobacteriacea Bacteremia. Infect Genet Evol 16C:386-391
Henao-Martínez, Andrés F; González-Fontal, Guido R; Castillo-Mancilla, José R et al. (2013) Enterobacteriaceae bacteremias among cancer patients: an observational cohort study. Int J Infect Dis 17:e374-8
De Arras, Lesly; Seng, Amara; Lackford, Brad et al. (2013) An evolutionarily conserved innate immunity protein interaction network. J Biol Chem 288:1967-78
De Arras, Lesly; Yang, Ivana V; Lackford, Brad et al. (2012) Spatiotemporal inhibition of innate immunity signaling by the Tbc1d23 RAB-GAP. J Immunol 188:2905-13
Yang, Ivana V; Jiang, Weiwen; Rutledge, Holly R et al. (2011) Identification of novel innate immune genes by transcriptional profiling of macrophages stimulated with TLR ligands. Mol Immunol 48:1886-95
Alper, Scott; McBride, Sandra J; Lackford, Brad et al. (2007) Specificity and complexity of the Caenorhabditis elegans innate immune response. Mol Cell Biol 27:5544-53
Schwartz, David; Collins, Francis (2007) Medicine. Environmental biology and human disease. Science 316:695-6
Palmer, S M; Klimecki, W; Yu, L et al. (2007) Genetic regulation of rejection and survival following human lung transplantation by the innate immune receptor CD14. Am J Transplant 7:693-9
Snyder, Laurie D; Hartwig, Matthew G; Ganous, Tonya et al. (2006) Cytokine gene polymorphisms are not associated with bronchiolitis obliterans syndrome or survival after lung transplant. J Heart Lung Transplant 25:1330-5
Palmer, Scott M; Burch, Lauranell H; Mir, Saad et al. (2006) Donor polymorphisms in Toll-like receptor-4 influence the development of rejection after renal transplantation. Clin Transplant 20:30-6

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