The Immune Ghosts of Pandemics Past

Abstract

Klunk J, Vilgalys TP, Demeure CE, et al. Evolution of immune genes is associated with the Black Death. Nature 2022;611:312–319. Our immune system exists to protect us from the external environment and specifically from the complex threat posed by microbial pathogens. It is well-known that microbes have rapidly evolved to either avoid, adapt, or co-opt host biology to survive and multiply. Conversely, infectious diseases are postulated to provide a strong selective pressure driving human genetic evolution, with exposure to pathogens driving immune system adaptation. However, exactly how and which specific loci and related immune genes have changed in response to a specific pathogen and functionally connecting signatures to protection or susceptibility in human populations has proved to be a challenging problem. The recent study by Klunk et al sets out to identify specific genes that may have directly evolved because of pathogen-induced selective pressure. To achieve this, they looked back at one of the most devastating pandemics in human history—the Black Death caused by the bacteria Yersinia pestis, which killed an estimated 30%–50% of the population in Europe. In a remarkable feat of molecular archeology, the study team identified human remains in two closely related European populations, in London and Denmark, devastated by the Black Death. To identify potential loci significantly selected for by this devastating disease, they obtained DNA samples from people who died before, during, and after the pandemic at various burial sites around London. After targeted DNA sequencing of a curated list of immune system genes and loci along with neutral regions of the genome as reference, they first verified that the pandemic did indeed induce a significant selection pressure on the immune system, with the identification of 245 significantly altered variants. After further filtering based on allele frequency patterns before and after the pandemic, they identified 35 potential target loci. Using their identified Denmark cohort to cross-validate these variants they eventually settled on 4 significant and validated loci related to 6 immune genes that potentially conferred either susceptibility or protection from Y. pestis infection. Although all 4 loci suggested interesting potential functional consequences, the clearest candidate was a putatively protective variant close to the gene ERAP2, an aminopeptidase important for antigen presentation, viral clearance, and cytokine responses and a known risk factor for Crohn’s disease. The study team went on to conduct a series of functional studies in monocyte-derived macrophages comparing the ERAP2 gene haplotype selectively favored by Y. pestis infection against the alternative deleterious prepandemic haplotype. Here, they found that macrophages from individuals possessing the selected ERAP2 allele exhibit a different cytokine response to Y. pestis infection and are better able to limit replication in cells, providing a functional corelate for the evolved host response. This study represents a wonderful journey into the history of the biological “arms race” between our immune system and the microbial environment, identifying some the specific changes brought about by a global disease pandemic. These findings illuminate our understanding of our immune responses to pathogens and highlight the evolution of immune system components such as ERAP2, CTLA4, and ICOS, which are associated with chronic inflammatory diseases including Crohn’s disease and autoimmune enteropathies. The study is also highly prescient in the setting of the global SARS-CoV-2 pandemic, and the current, likely highly accelerated, evolution of our immune system.