The immune system is responsible for maintaining a healthy state and preventing infection. For some people, however, immune system dysfunction results in increased susceptibility to infections, inflammation, autoimmunity or even development of cancer. The projects in the Barreiro lab aim to define in an evolutionary informed manner the genetic and environmental factors impacting immune responses to infection, through the integration of cutting-edge technologies in the fields of genomics, population genetics, immunology, molecular biology and bioinformatics. Examples of some ongoing projects are provided below.
Unveiling Immune Variation Across Diverse Human Populations
Susceptibility to infections, disease severity, and responses to therapies vary widely across individuals due to a combination of genetic and environmental factors. Most large-scale genomic studies have been overwhelmingly Eurocentric, leaving significant gaps in our understanding of immune responses in non-European populations. The limited transferability of genetic insights from European-ancestry individuals to other groups highlights the urgent need to expand research to a broader array of global populations.
Our initiative seeks to address this gap by constructing the first comprehensive, single-cell resolution map of immune system diversity across populations with varied genetic ancestries, environments, and lifestyles. Immune cells drive inflammatory pathways, a key and universal factor in non-communicable diseases associated with lifestyle. This project is not only a critical step toward personalized medicine but also a concerted effort to redress the historical biases in genomic research. By partnering with global investigators and leveraging a unique biobank of PBMCs from underrepresented and Indigenous groups, we are exploring the extremes, variation in lifestyle, environments and genetics – far beyond what we observe in European populations. Ultimately, we aim to create an inclusive and diverse resource that will transform our understanding of how genetic and environmental factors shape immune responses, and disease susceptibility worldwide.
Immune Cell Atlas of Indigenous South American Populations.
The unique immuno-genetic variation in present-day Indigenous American populations has been shaped over the last ~25,000 years since the founding population in eastern Asia split from related Siberian and East Asian lineages and journeyed into the Americas. After the arrival and subsequent radiation of Indigenous peoples to the rest of the Americas, they encountered multiple prehistoric and historic waves of admixture from Eurasian and African sources, experienced founder events and genetic bottlenecks (e.g. European colonization), and were exposed to novel selective pressures (e.g. pathogens, diets). Comparing shared and unique biological variation between various Indigenous American and other populations is key to understanding the evolution of the immuno-genomic landscape of Indigenous Americans and ways in which it is distinct to that of other ancestry groups. To do so, our lab started a collaborative network with several PIs from South America, which was recently funded by the Chan Zuckerberg Initiative. Focusing on eight distinct Indigenous populations from the Amazon, Andes, and coastal regions of South America, we are using a range of single-cell technologies to identify how diverse ancestries impact gene expression, epigenetic profile and the composition and responsiveness of immune cells to immune challenges.
Cross-species comparisons of immune responses.
Humans and our close evolutionary relatives respond differently to a large number of infections. While AIDS, malaria, and cancer kill millions of humans around the world every year, several non-human primates appear to be naturally protected against these diseases. Such differences between humans and other primates are thought to be the result, at least in part, of inter-species differences in immune response to infection. However, due to the lack of comparative functional data across species, the ways in which the immune systems of humans and other primates differ remain unclear. In the laboratory, we are studying the phenotypic evolution of immune responses in primates by combining in-vitro immunological assays with cutting-edge genomic techniques. Our projects promise to identify inter-species differences in early response to infection that may explain differences in susceptibility to diseases among primates
Epigenetic regulation of immune response to infection.
Innate immune cells have classically been considered to have no immunological memory. However, recent studies have challenged this dogma by demonstrating that innate immune cells, particularly monocytes and macrophages, can mount long-term memory and resistance to reinfection. These observations led to the concept of “trained immunity” – a phenomenon in which innate immune cells, like monocytes/macrophages and NK cells, develop a faster and more robust immune response upon secondary infection by the same organism, or even an unrelated pathogen. Epigenetic reprogramming is thought to be central to the induction of trained immunity. Yet, there is still a profound lack of knowledge of what are the specific epigenetic determinants required to induce long-lasting trained immunity in humans. Using combined expertise in functional genomics, computational biology, human immunology, and infectious diseases, our lab is working towards addressing the following questions: What is that nature of the epigenetic changes induced by “trained immunity adjuvants” in human progenitor cells? What trained immunity-induced epigenetic changes can be transmitted from pluripotent stem cells to their differentiated counterparts in humans? What are the genetic and molecular determinants of inter-individual variation in trained immunity? This line of research benefits from close collaborations with the labs of Dr. Maziar Divangahi, Dr. Mihai Netea , and Dr. Shabaana Khader .
The evolutionary history of hunter-gatherer populations.
Prior to the emergence of agriculture ~10,000-12,000 years ago most human populations practiced locally-adapted forms of hunting and gathering. While most hunter-gatherer societies gradually adopted some variation of subsistence agriculture and others have been replaced entirely by agriculturalist migrants, an estimated 229 hunter-gatherer populations remain worldwide based on ethnographic data. The long-term goal of this project is to build a comprehensive picture of the demographic and evolutionary events that contributed to the evolutionary history of hunter-gatherer population across the globe. Our lab is particularly interested in understanding how the advent of agriculture impact on our relation with pathogens. Indeed, it has been proposed that the advent of agriculture at the beginning of the Neolithic period, 10,000 years ago, resulted in an increased burden of infectious diseases. We are formally testing this hypothesis by performing comparative studies of immune response between hunter-gathers and their neighboring agriculturalist population. This work is done in collaboration with Dr. George Perry’s lab .
iPSC-derived macrophages as a model to study the genetic basis of inter-individual variation in immune responses to pathogens.
Despite the recent advent of vaccines and antibiotics, infectious diseases cause nearly 15 million deaths every year. Although a significant proportion of inter-individual variation in susceptibility to microbes can be attributed to environmental factors, a substantial portion is also due to host genetic factors. The importance of host genetic factors on susceptibility to infectious diseases has been shown by comparative studies involving twins and adopted persons. Yet, very little is known about the underlying genetic factors contributing to differences in susceptibility to infectious diseases at the population level. By combining expertise in functional genomics, computational biology, human immunology, population genetics, and infectious diseases, we aim to identify genes and regulatory pathways that contribute to variability of immune response to two of the deadliest infectious agents of our days: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, and influenza virus. Specifically, we propose to leverage the power of induced pluripotent stem cells (iPSC)-derived macrophages to: (i) characterize inter-individual and inter-population variability in immune responses to infection with (Mtb) and influenza viruses in humans; (ii) study the contribution of epigenetic variation to inter-individual variation in immune responses; and (iii) map quantitative trait loci (QTL) that are associated with variation in the immune response to infection with Mtb and influenza, and evaluate the impact of natural selection at shaping their allele frequencies across populations.