GWAS summary statistics for Y. pestis invasion in 961 LCLs generated using QFAM-parents in PLINK with adaptive permutation. For details of methods refer to manuscript Keener et al. 2024.
Yersinia pestis is the gram-negative bacterium responsible for plague one of the deadliest and most feared diseases in human history. This bacterium is known to infect phagocytic cells such as dendritic cells and macrophages but interactions with non-phagocytic cells of the adaptive immune system are frequently overlooked despite the importance they likely hold for human infection. To discover human genetic determinants of Y. pestis infection we utilized nearly a thousand genetically diverse lymphoblastoid cell lines in a cellular genome-wide association study method called Hi-HOST (High-throughput Human in-vitrO Susceptibility Testing). We identified a nonsynonymous SNP rs2282284 in Fc receptor like 3 (FCRL3) associated with bacterial invasion of host cells (p=9x10-8). FCRL3 belongs to the immunoglobulin superfamily and is primarily expressed in lymphocytes. rs2282284 is within a tyrosine-based signaling motif causing an asparagine-to-serine mutation (N721S) in the most common FCRL3 isoform. Overexpression of FCRL3 facilitated attachment and invasion of non-opsonized Y. pestis. Additionally FCRL3 colocalized with Y. pestis at sites of cellular attachment suggesting FCRL3 is a receptor for Y. pestis. These properties were variably conserved across the FCRL family revealing molecular requirements of attachment and invasion including an Ig-like C2 domain and a SYK interaction motif. Direct binding was confirmed with purified FCRL5 extracellular domain. Following attachment invasion of Y. pestis was dependent on SYK and decreased with the N721S mutation. Unexpectedly this same variant is associated with risk of chronic hepatitis C virus infection in BioBank Japan. Thus Y. pestis hijacks FCRL proteins possibly taking advantage of an immune receptor to create a lymphocyte niche during infection.
Yersinia pestis is the gram-negative bacterium responsible for plague one of the deadliest and most feared diseases in human history. This bacterium is known to infect phagocytic cells such as dendritic cells and macrophages but interactions with non-phagocytic cells of the adaptive immune system are frequently overlooked despite the importance they likely hold for human infection. To discover human genetic determinants of Y. pestis infection we utilized nearly a thousand genetically diverse lymphoblastoid cell lines in a cellular genome-wide association study method called Hi-HOST (High-throughput Human in-vitrO Susceptibility Testing). We identified a nonsynonymous SNP rs2282284 in Fc receptor like 3 (FCRL3) associated with bacterial invasion of host cells (p=9x10-8). FCRL3 belongs to the immunoglobulin superfamily and is primarily expressed in lymphocytes. rs2282284 is within a tyrosine-based signaling motif causing an asparagine-to-serine mutation (N721S) in the most common FCRL3 isoform. Overexpression of FCRL3 facilitated attachment and invasion of non-opsonized Y. pestis. Additionally FCRL3 colocalized with Y. pestis at sites of cellular attachment suggesting FCRL3 is a receptor for Y. pestis. These properties were variably conserved across the FCRL family revealing molecular requirements of attachment and invasion including an Ig-like C2 domain and a SYK interaction motif. Direct binding was confirmed with purified FCRL5 extracellular domain. Following attachment invasion of Y. pestis was dependent on SYK and decreased with the N721S mutation. Unexpectedly this same variant is associated with risk of chronic hepatitis C virus infection in BioBank Japan. Thus Y. pestis hijacks FCRL proteins possibly taking advantage of an immune receptor to create a lymphocyte niche during infection.