Pathogens are a major selective force driving the evolution of species. Multiple pathogens have been identified as exerting selective pressure on primate immune loci for millions of years. The objective of this study is to clarify the role of novel pathogens, encountered as hominin landscape departed from that of chimpanzees, in the divergence of the Pan and Homo lineages. This study will examine possible functional divergence of chimpanzee (Pan troglodytes) and modern human immune receptors that may explain the disparate immune response of these species to shared infectious pathogens, including immunodeficiency viruses. Chimpanzees are the natural host of Simian Immunodeficiency virus - chimpanzee (SIV-cpz), the progenitor virus of Human Immunodeficiency Virus type 1 (HIV-1). Unlike HIV-1 infected humans, SIV/HIV-1 infected chimpanzees do not, typically, progress to Acquired Immune Deficiency Syndrome (AIDS). A primary difference in human and chimpanzee immunodeficiency virus infection is pan-immune activation, a destructive widespread activation of immune cells in humans. Its occurrence in immunodeficiency virus infections is strongly associated with descent into AIDS and death. Recent research suggests that HIV-1 interaction with a human immune receptor, Toll-like Receptor 2 (TLR2), contributes to pan-immune cell activation. Extensive use of savannah landscapes exposed hominins to novel pathogens not found in forested regions (i.e. Mycobacterium and Trypanosoma) that interact with TLR2. This study will test the hypothesis that human AIDS is caused by TLR2 cell signaling adaptations that have been acquired since the evolutionary divergence of humans and chimpanzees from a last common ancestor 6- 7 million years ago. This research will correlate chimpanzee and human TLR2 genetic differences between chimpanzee and human TLR2 to receptor responses to TLR2-detected pathogens to which species in either the Pan or Homo lineages have historically been exclusively exposed (i.e. immunodeficiency viruses, Trypanosoma sp and Mycobacterium tuberculosis). Cell response to pathogens will be evaluated via Fluorescent-activated Cell Sorting (FACS) analysis and Enzyme-linked Immunosorbant Assay (ELISA). Given the different pathogen exposure history of chimpanzees and humans, TLR2/pathogen interactions are expected to differ between the species.
This research will contribute to a better understanding of human origins by clarifying the role of TLR2-sensed pathogens, with special attention paid to immunodeficiency viruses, in the divergence of the Pan and Homo lineages. It will also better define mechanisms associated with primate/pathogen co-evolution and AIDS progression in humans. The cell-based comparative experimental models used here will offer new avenues in the study of human origins and enable direct observation of functional outcomes of genetic change in a simple well controlled system. Results will be published in scholarly journals and Genbank. The project is the doctoral dissertation research of a female Co-Pi and will train and advance a female student in a science field. The same Co-PI will train high school and undergraduate students in conducting similar research in a cell and molecular biology laboratory through this study.
