# Project 2: Host-Pathogen Interactions in Blood Glycoprotein Modulation of Sepsis

> **NIH NIH P01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $434,357

## Abstract

SUMMARY
Sepsis is one of the most common and life-threatening syndromes faced by patients and clinicians. It is often
fatal due to the coagulopathy and inflammation that arises in multiple tissues from the host response, while
survivors may face a lifetime of disability from the resulting vascular and organ damage. This project is focused
on this major health problem while addressing the central hypothesis of this program, that protein glycosylation
and glycoprotein remodeling modulate the coagulopathy and inflammation of sepsis. It has recently been
determined that hepatocytes of the liver control the abundance of circulating secreted proteins that modulate
thrombosis and inflammation during sepsis. This occurs by a mechanism of secreted protein aging and
turnover that includes the endocytic Ashwell-Morell receptor (AMR). Unlike the previously described protective
role of the AMR in sepsis caused by Gram-positive pneumococcal infection, preliminary data have recently
determined that AMR function is deleterious to the host during sepsis caused by the Gram-negative bacterial
pathogen Salmonella enterica Typhimurium (ST). These findings suggest that the AMR is positioned at a
nexus determining host susceptibility to different microbial pathogens. These findings further indicate that the
pathogenesis of sepsis may be stratified by different host responses to different pathogens, which would
advance the understanding of sepsis beyond that of a singular disease mechanism. This project will investigate
the mechanisms of AMR function involving Asgr1 and Asgr2 in host interactions that participate in the
pathogenesis of Gram-negative bacterial sepsis to include ST and Escherichia coli (EC), with parallel studies
of the underlying Systemic Inflammatory Response Syndrome (SIRS). Other preliminary data indicate a role of
AMR function in host outcomes following infection by the hypervirulent strain Salmonella Choleraesuis (SC), a
serovar recently discovered to be among the most virulent microbes encountered of this species. Preliminary
data indicate that secreted alkaline phosphatase isozymes are regulated by the AMR and that this regulation
determines the progression and outcome of Gram-negative bacterial sepsis, perhaps by dephosphorylation
and detoxification of bacterial lipopolysaccharide. The roles of AP isozyme regulation in host-pathogen
interactions of sepsis caused by ST, SC, and EC infection will be determined by research that includes all of
the core facilities proposed. Studies proposed will further determine whether the AMR functions to modulate
mechanisms of microbial hypervirulence in aims that include comparing sepsis caused by SC infection. This
project will further identify the repertoire of secreted proteins regulated by the AMR in sepsis and SIRS, which
may disclose novel biomarkers and proteins that are implicated in additional mechanisms that modulate the
coagulopathy and inflammation of sepsis. These studies may stratify host responses...

## Key facts

- **NIH application ID:** 9916815
- **Project number:** 5P01HL131474-05
- **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:** 2020
- **Award amount:** $434,357
- **Award type:** 5
- **Project period:** — → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916815

## Citation

> US National Institutes of Health, RePORTER application 9916815, Project 2: Host-Pathogen Interactions in Blood Glycoprotein Modulation of Sepsis (5P01HL131474-05). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9916815. Licensed CC0.

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