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Review
. 2016 Apr 26;5(2):39.
doi: 10.3390/pathogens5020039.

A Cellular GWAS Approach to Define Human Variation in Cellular Pathways Important to Inflammation

Samuel I Miller  1 , Anu Chaudhary  2
Affiliations
Review

A Cellular GWAS Approach to Define Human Variation in Cellular Pathways Important to Inflammation

Samuel I Miller et al. Pathogens. .

Abstract

An understanding of common human diversity in innate immune pathways should be beneficial in understanding autoimmune diseases, susceptibility to infection, and choices of anti-inflammatory treatment. Such understanding could also result in definition of currently unknown components of human inflammation pathways. A cellular genome-wide association studies (GWAS) platform, termed Hi-HOST (High-throughput human in vitro susceptibility testing), was developed to assay in vitro cellular phenotypes of infection in genotyped lymphoblastoid cells from genetically diverse human populations. Hi-HOST allows for measurement of multiple host and pathogen parameters of infection/inflammation including: bacterial invasion and intracellular replication, host cell death, and cytokine production. Hi-HOST has been used to successfully define a significant portion of the heritable human diversity in inflammatory cell death in response to Salmonella typhimurium. It also led to the discovery of genetic variants important to protection against systemic inflammatory response syndrome (SIRS) and protection against death and bacteremia in individuals with SIRS. Our laboratory is currently using this platform to define human diversity in autophagy and the NLPR3 inflammasome pathways, and to define new components that can impact the expression of phenotypes related to these pathways.

Keywords: GWAS; Hi-HOST; SIRS; host; lymphoblastoid; pathogen; pyroptosis.

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Figures

Figure 1
Figure 1
Schematic for the Hi-HOST autophagy screen. Genotyped lymphoblastoid cells (LCL) were treated with control buffer or rapamycin and then subjected to flow cytometric analysis after staining with LysoTracker. The two populations M1 and M2 in rapamycin treated LCL have differential autophagy as determined by western blotting. 500 LCL were thus screened and variation in the number of cells induced in M1 was used to perform genotype-phenotype association analysis using PLINK.
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