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Human genetic variation reveals FCRL3 is a lymphocyte receptor for Yersinia pestis

  • 1Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA; University Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA.
  • 2Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA.
  • 3Departments of Genome Sciences, Medicine, and Microbiology, University of Washington, Seattle, WA 98195, USA.
  • 4Department of Microbiology, Miami University, Oxford, OH 45056, USA.
  • 5Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA; University Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA; Division of Infectious Diseases, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA. Electronic address: dennis.ko@duke.edu.
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June 10, 2025

Abstract

Yersinia pestis is the bacterium responsible for plague, one of the deadliest diseases in history. To discover human genetic determinants of Y. pestis infection, we utilized nearly 1,000 genetically diverse lymphoblastoid cell lines in a cellular genome-wide association study. A nonsynonymous SNP, rs2282284 (N721S), in Fc receptor-like 3 (FCRL3) was associated with bacterial invasion of host cells (p = 9 × 10-8). Overexpressed FCRL3 facilitated attachment and invasion of Y. pestis and colocalized with Y. pestis at attachment sites. These properties were variably conserved across the FCRL family, revealing an immunoglobulin-like domain and signaling motifs shared by FCRL3 and FCRL5 to be necessary for attachment and invasion. Direct binding to FCRL5 extracellular domain was confirmed, and B cells (the primary cells that express FCRLs) were preferentially invaded by Y. pestis. Thus, Y. pestis hijacks FCRL proteins, possibly taking advantage of an immune receptor to create a lymphocyte niche during infection.