# Immune cell mechanisms of Bacillus anthracis sepsis

> **NIH NIH U19** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2020 · $482,388

## Abstract

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 trea...

## Key facts

- **NIH application ID:** 9927975
- **Project number:** 5U19AI062629-17
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** A Darise Farris
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $482,388
- **Award type:** 5
- **Project period:** 2004-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927975

## Citation

> US National Institutes of Health, RePORTER application 9927975, Immune cell mechanisms of Bacillus anthracis sepsis (5U19AI062629-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9927975. Licensed CC0.

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