INNATE IMMUNE GENE DISCOVERY USING MACROPHAGE RESPONSE TO PATHOGEN-ASSOCIATED MOLECULAR PATTERNS (PAMPS),

I.V. Yang, Ph.D1, L.A. Warg, BS1, E.J. Davidson, BS1, S.N.P. Kelada, PhD2, K. Kubalanza, BS2, F.S. Collins, MD, PHD2, E.J. Chesler, PhD3, G. Churchill, PhD4, D. Miller, BS5, D. Aylor, PhD5, F.P.-M. de Villena, PhD5, D.A. Schwartz, MD1

Author address: 

1Denver, CO/US, 2Bethesda, MD/US, 3Oak Ridge, TN/US, 4Bar Harbor, ME/US, 5Chapel Hill, NC/US

Abstract: 

RATIONALE: Host genetic factors play an important role in a variety of infections caused by bacterial, viral, and fungal pathogens. Our previous studies have focused on identification of novel genes that mediate the innate immune response to lipopolysaccharide (LPS), Gram negative, Gram positive organisms, and Aspergillus fumigatus in vivo. To complement and expand these previous in vivo studies, we are in the process of identifying genes that regulate the macrophage response to a panel of pathogen-associated molecular patterns (PAMPs). METHODS: Bone marrow derived macrophages (BMDMs) from 40 inbred strains of mice (inbred panel) and from a newly established panel of genetically diverse mice generated by the Collaborative Cross initiative (pre-CC panel) are stimulated with three different concentrations of six PAMPs: Pam3Cys (TLR1/2 ligand), lipotechoic acid (TLR1/2 ligand), poly(I:C) (TLR3 ligand), LPS (TLR4 ligand), zymosan (TLR2/6 ligand), and CpG DNA (TLR9 ligand). Concentrations of pro-inflammatory cytokines (IL-1b, IL-6, IL-12, and TNF-a) in the supernatant are measured 5 hours post-treatment. Genetic loci that control production of these cytokines by the macrophages are mapped using association mapping for inbred strains and quantitative trait loci (QTL) mapping for the mice from the Collaborative Cross based on high-density genotypes generated with the newly available Mouse Diversity array. RESULTS: Large variation in macrophage response to PAMP stimulation is observed in both the inbred and pre-cc mouse panels. A number of genomic loci are associated with inbred strain phenotypes at the significance level of p
2010

abstract No: 

Poster Board # D11

Full conference title: 

American Thoracic Society International Conference
    • ATS 2010