# Hyperglycemia and increased severity to Staphylococcus aureus infections. > **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $688,727 ## Abstract PROJECT SUMMARY Chronic hyperglycemia has been linked to systemic inflammation, which may underlie several comorbidities, and infection is a significant concern for persons with diabetes. Based on our published and preliminary data, the scientific premise of this proposal is rooted in the finding that hyperglycemia-enhanced low-grade inflammation prompts phagocytes to hyper-respond to pathogens, amplifying the severity of unchecked inflammatory responses, the risk of multiple organ dysfunction syndrome (MODS) and mortality from sepsis in persons with diabetes. Also, the lack of understanding of the pathogenesis of systemic infection during diabetes poses a major barrier to developing effective treatments. We and others have shown that the lipid mediator leukotriene B4 (LTB4) is a critical component of the inflammatory response. However, we have also shown that excessive amounts of this bioactive lipid enhance systemic inflammation and promote susceptibility to infection in diabetic animals. However, 1) we did not determine the mechanisms involved in aberrant LTB4 receptor 1 (BLT1; the high-affinity receptor for LTB4) activation in diabetic animals; 2) we did not assess whether preventing BLT1 actions after sepsis had protective effects during sepsis and diabetes. Here, we aim to determine how epigenetic alterations caused by high glucose exposure accelerate the transcription of genes involved in LTB4/BLT1 actions that render diabetic mice more vulnerable to systemic infections. This proposal is based on the surprising preliminary data showing that peritoneal macrophages from diabetic mice exhibit high basal histone acetyltransferase (HAT) activity and increased acetylation of H3 histone, favoring gene transcription. HAT inhibition decreases exaggerated Ltb4r1 mRNA expression in diabetic animals. We also discovered that treating diabetic mice with a BLT1 antagonist 6 h after i.v. infection increased survival and decreased bacterial load in diabetic mice. Notably, the relevance of our findings is underscored by our preliminary observation that LTB4 levels and BLT1 expression are higher in people with diabetes and sepsis than in individuals with sepsis and nondiabetes. These data led to our hypothesis that hyperglycemia primes HAT activation to promote sustained and amplified BLT1 activation, leading to an intense but ineffectual inflammatory response to systemic infection, resulting in severe MODS and enhanced death rates. We propose two Specific Aims, which will use innovative approaches to test our hypothesis, including cutting-edge murine systems, testing newly generated concepts (metabolic memory) in the pathogenesis of sepsis, and new potential treatment protocols that might help translate our findings to the bedside. Aim 1 will determine whether hyperglycemia promotes metabolic memory to sustain aberrant BLT1 activation. Aim 2 will test the hypothesis that the threshold of BLT1 activation dictates the severity of the infection and MODS in hum... ## Key facts - **NIH application ID:** 10989200 - **Project number:** 1R01AI180777-01A1 - **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER - **Principal Investigator:** C. Henrique Serezani - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $688,727 - **Award type:** 1 - **Project period:** 2024-07-01 → 2029-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10989200 ## Citation > US National Institutes of Health, RePORTER application 10989200, Hyperglycemia and increased severity to Staphylococcus aureus infections. (1R01AI180777-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10989200. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*