The death toll imposed by microbes has been of paramount importance during human evolution, with genes involved in immune functions being recurrent targets of natural selection. As they dispersed across the world, human populations interacted with deadly, endemic pathogens, suggesting that present-day population differences in immune responses are, at least partly, the product of natural selection. Yet, despite the critical impact of infectious diseases on human health, how host genetic factors drive immune response variation at the population level remains poorly investigated. Over the last decade, we have shown that adopting an evolutionary thinking is an indispensable complement to clinical and immunological approaches for delineating genes and functions that are key for host defense. However, given the complex, dynamic nature of host-pathogen interactions, the role of host genetic variation as the sole mechanism contributing to immune phenotypic differences is unsatisfactory. Indeed, epigenetic modifications can provide an additional source of immune variation, which may act as a fast-acting driver of human resistance to pathogens. Tropical rainforests are among the harshest environments for human life. Besides adverse climatic conditions, tropical regions harbor one of the world’s highest pathogenic loads; i.e., human pathogenic diversity is ~70% higher in rainforests than in temperate areas, resulting in unusually high mortality among rainforest communities. Yet, studies on biological adaptations among rainforest communities such as those habiting the South American Amazon rainforest are currently lacking. Moreover, South American populations offer the unique opportunity to investigate how microbial pathogens introduced through European contact over the last 500 years, many of which had never been encountered before, resulted in recent biological adaptation. We hypothesize that the high pathogenic burden of the Amazon rainforest has exerted strong selective pressures that left detectable footprints on human genome diversity. As indigenous Americans are severely underrepresented in genetic studies, we expect that studying the genomic signatures of positive selection in these populations will identify novel genes that affect human resistance to infections. We also hypothesize that the challenge of infectious diseases brought by Europeans resulted in a rapid adaptation process; the analysis of admixed Amazonians offers an excellent setting to test this hypothesis. Moreover, given that some Amazonian groups have recently adopted an urban lifestyle, we further hypothesize that differences in immune response across rainforest- and urban-based communities result, at least partly, from epigenetic modifications. In this context, studying the immunogenomic diversity of rainforest- and urban-based Amazonian provides an excellent model to elucidate the factors driving individual and population differences in immune responses, allowing to discover key immunological mechanisms of host defense, including those that may contribute to current biological and disease-risk patterns of present-day Amazonians. To test these hypotheses, we propose to use a multi-disciplinary approach that combines population genomics, epigenomics, and systems immunology, to determine, in autochthonous populations from the Amazonia, the genetic, epigenetic and evolutionary factors driving biological diversity across the viral exposome and the immune response to various pathogenic stimuli. In doing so, the PATHO-NAT project will bring new data and knowledge on two fundamental questions related to host-microbe interactions: how humans have adapted to pathogens over time, in particular in the understudied ecosystem of the Amazonia, and which mechanisms have contributed to population differences in immune responses against infectious agents.