Summary Bacterial sepsis is a serious and difficult-to-treat condition with high mortality in part due to initial overactive innate immunity followed by immunosuppression that leaves the host vulnerable to new infections. Inhalational anthrax, a known and expected outcome of bioterrorism-related release of Bacillus anthracis (Ba) spores, inevitably leads to sepsis and high mortality without early intervention. Anti-inflammatory sepsis therapies developed in mice have failed in humans, indicating that improved understanding of molecular mechanisms of human immune cell involvement in Ba sepsis is needed. Prior work in our center showed that unchecked inflammation and sepsis pathology is worsened by elevated circulating nucleosomes released from dying cells. Clearance of apoptotic cells is mediated by macrophages via the process of efferocytosis. A major site of lymphocyte apoptosis in sepsis is in secondary lymphoid organs. Efferocytic function by tissue macrophages in these lymphoid organs is likely crucial for apoptotic lymphocyte clearance during sepsis. Our preliminary data show that Ba and its toxins impair human monocyte-derived macrophage efferocytosis, although the mechanism is unclear. In Aim 1, we will test the hypothesis that Ba and its toxins inhibit human tissue macrophage efferocytosis by decreasing expression of efferocytic machinery and impairing efferocytic receptor signaling. Extensive lymphocyte apoptosis also contributes to immunosuppression, a major complication following sepsis survival. Long term immunosuppression correlates with the accumulation of hyporesponsive T cells bearing markers of exhaustion, suggesting the involvement of epigenetic changes. Our preliminary data show lymphopenia and T cells bearing exhaustion markers in a primate model of Ba induced sepsis. In Aim 2, we will test the hypothesis that live Ba and its toxins promote T lymphocyte apoptosis and exhaustion, leading to immunosuppressed T cell phenotypes enforced by epigenetic changes after sepsis. Lipid-activated nuclear receptors such as peroxisome proliferator activated receptors (PPARs) and liver X receptors (LXRs) respond to lipids of efferocytosed apoptotic cells by increasing transcription of efferocytic machinery. However, few studies have assessed the impact of PPAR or LXR activity on human tissue macrophage gene expression or lymphocyte apoptosis. Synthetic agonists of these receptors have shown efficacy in diabetes and recurrent stroke but no studies to our knowledge have used such modulators to treat sepsis in humans or primates. In Aim 3, we will test the hypothesis that synthetic agonists of PPAR and LXR lipid-activated nuclear receptors can mitigate negative impacts of Ba and its toxins on macrophages and T cells during sepsis. The results of these studies will lead to a better understanding of mechanisms of acute pathology and subsequent immunosuppression in sepsis and may accelerate the development of new therapeutic strategies for the treatment of septic patients.