# PROJECT 2 - Mechanisms of Hypervirulence in the Pathogenesis of Sepsis

> **NIH NIH P01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2021 · $460,733

## Abstract

Project Summary
The aims address the central hypothesis of the overall program: Protein glycosylation and glycoprotein
remodeling alter the coagulopathy and inflammation of sepsis. Proposed research is based on the emerging
hallmark of sepsis whereby natural selection imposed by the immune system results in the generation of
hypervirulent strain variants with increased risk of invasive disease. Hypervirulence is believed to arise from a
combination of pathogen-specific determinants and host responses. Over the last grant cycle, we have
demonstrated that host responses to experimental sepsis occur by multiple mechanisms including alterations
in blood glycoprotein remodeling. Proposed research focuses on the role of hypervirulent bacteria and host
glycoprotein remodeling responses leading to accelerated onset and progression of coagulation abnormalities
and inflammation of sepsis. This project utilizes the combined expertise of the Project Leaders and Core
Directors in the pathophysiology of sepsis, including coagulation, inflammation, proteomics and glycobiology
and engages all of the core facilities of the program. The Project Leader discovered hypervirulent Salmonella
Choleraesuis (SC) clinical isolates that are among the most virulent Salmonella found in nature. SC typically
causes sepsis or extra-intestinal infections in humans yet is closely related to the common food-poisoning
pathogen Salmonella Typhimurium (ST). We have shown that in experimental ST and E. coli sepsis, reduced
blood levels of anti-inflammatory alkaline phosphatase (AP) enzymes result from pathogen-selective host
responses – induction of neuraminidase activities (Neu) and resultant AP desialylation, and clearance by the
Ashwell-Morell receptor (AMR). AP reductions diminish LPS de-toxification thereby increasing inflammation
and mortality. In contrast, our recent findings indicate that SC does not induce Neu activities nor AP clearance,
but AMR deficiency remains protective, implicating the involvement of other host glycoproteins, and their
identification may reveal new pathways and mechanisms modulating hypervirulence and sepsis. Additional
preliminary data suggest that SC elicits an increased pro-inflammatory state due to diminished levels of host
induction of IL-10, an immune modulatory cytokine that affects sepsis disease outcome. Further, stratification
of experimental and human sepsis caused by Gram-negative pathogens may include pathogen-selective
modulation of Factor XI activity in circulation. Proposed research will identify and investigate environmental,
genetic, and proteomic mechanisms determining hypervirulence including the AMR, IL-10, and coagulation
Factor XI, and their utility in the stratification and prognosis of experimental and human sepsis. The
overarching goal is to identify components and mechanisms of both the pathogen and host determining
virulence and sepsis pathogenesis, leading to diagnostic biomarker discovery and rational design of
therapeutic ...

## Key facts

- **NIH application ID:** 10171429
- **Project number:** 2P01HL131474-06
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** MICHAEL J MAHAN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $460,733
- **Award type:** 2
- **Project period:** 2016-07-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171429

## Citation

> US National Institutes of Health, RePORTER application 10171429, PROJECT 2 - Mechanisms of Hypervirulence in the Pathogenesis of Sepsis (2P01HL131474-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10171429. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*