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

Area of Science:

• Immunology
• Genetics
• Infectious Disease

Background:

• Understanding human diversity in innate immunity is crucial for autoimmune diseases, infection susceptibility, and anti-inflammatory treatments.
• Identifying unknown components of human inflammation pathways is a key research goal.

Purpose of the Study:

• To develop and utilize a high-throughput platform (Hi-HOST) for assaying in vitro cellular phenotypes of infection in diverse human populations.
• To investigate heritable human diversity in inflammatory cell death and its genetic underpinnings.
• To discover genetic variants associated with protection against systemic inflammatory response syndrome (SIRS).

Main Methods:

• Development of the Hi-HOST (High-throughput human in vitro susceptibility testing) platform using cellular genome-wide association studies (GWAS).
• Assaying in vitro cellular phenotypes of infection in genotyped lymphoblastoid cells.
• Measuring bacterial invasion, intracellular replication, host cell death, and cytokine production.

Main Results:

• Successfully defined heritable human diversity in inflammatory cell death in response to Salmonella typhimurium.
• Discovered genetic variants crucial for protection against SIRS, death, and bacteremia in SIRS patients.
• Currently defining human diversity in autophagy and NLPR3 inflammasome pathways.

Conclusions:

• The Hi-HOST platform is effective for dissecting human genetic diversity in immune responses.
• This research contributes to understanding genetic factors influencing inflammatory diseases and infection outcomes.
• Future work will further elucidate pathways like autophagy and the NLPR3 inflammasome.