# Characterizing the impact of Yersinia Pestis to the phenotypic evolution of the human immune system

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $310,744

## Abstract

Project Summary
Pathogens are one of the strongest selective pressures on the human genome. As modern humans migrated
out of Africa, they encountered markedly different pathogenic environments, likely resulting in population-specific
selection of immune phenotypes. Consistent with this hypothesis, some of the most compelling evidence for
local positive selection in the human genome has been detected among genes involved in immunity and host
defense. Yet, our understanding of the role that local adaptation plays in shaping phenotypic variation in immune
responses across populations is still in its infancy. To better understand the complex relationship between
pathogens and host adaptation we propose to study the selective impact on the immune system of one of the
most devastating pathogens in history – Yersinia pestis, the agent of the Black Death. Since its emergence in
Eurasia 1500 to 6400 years ago Y. pestis has swept Eurasia and North and Central Africa in two major
pandemics (Justinian, 541-544; Black Death, starting 1347-1351) and has subsequently spread nearly worldwide
via a third ongoing pandemic. Although Y. pestis is proposed to have severely culled the Eurasian population,
how groups that differ in their historical exposure to plague respond to the pathogen is not known. Addressing
this gap is not only important for understanding the recent evolution of the human immune system, but may also
help reveal the molecular basis of ancestry-related differences in susceptibility to infectious diseases, chronic
inflammatory disorders, and autoimmune disorders. Using combined expertise in human genomics, immunology,
infectious diseases and ancient DNA, the parent R01 proposes: (i) to characterize inter-individual and inter-
population variability in immune responses to infection with Y. pestis in human macrophages; (ii) to map
expression quantitative trait loci (eQTLs) that are associated with variation in response to infection with Y. pestis;
and (iii) to identify genetic loci showing signatures of positive selection by Y. pestis by looking at “real-time”
fluctuations in allele frequencies among immune-related genes and immunological QTLs sequenced from
skeletal remains of European populations living before, during, and after the Black Death. As part of this
supplement, we propose (i) to expand the scope of the work to investigate the impact of genetic variation in
immune responses to Y. pestis across a larger array of immune cell types by leveraging the recent development
of single cell RNAseq approaches, and (ii) to investigate the impact of ERAP2 variants that were positively
selected during the Black Death to the repertoire of Y. pestis MHC-associated peptides (MAPs) and, ultimately,
host protection against Y. pestis.

## Key facts

- **NIH application ID:** 10631544
- **Project number:** 3R01GM134376-04S1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Luis Bruno Barreiro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $310,744
- **Award type:** 3
- **Project period:** 2019-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10631544

## Citation

> US National Institutes of Health, RePORTER application 10631544, Characterizing the impact of Yersinia Pestis to the phenotypic evolution of the human immune system (3R01GM134376-04S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10631544. Licensed CC0.

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