# BASIS FOR CELLULAR SUSCEPTIBILITY TO BACTERIAL TOXINS

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 1993 · $224,035

## Abstract

Pseudomonas exotoxin A (ETA), one of several potential virulence products
produced by Pseudomonas aeruginosa is a three domain bacterial toxin that
kills mammalian cells by gaining entry to the cytosol and inhibiting
protein synthesis.  The toxin binds to a surface receptor on susceptible
cells, is internalized via coated pits and endosomes, and enters the
cytosol.  During this journey, the toxin is cleaved to generate an
enzymatically active fragment which ADP-ribosylates elongation factor 2.
The pathway ETA takes to reach its target is only partially elucidated.
Recently the ETA receptor has been isolated and shown to be similar to
the alpha2macroglobulin receptor/LDL related protein (alpha2MR/LRP)  The
long-term goals of this research are to fully understand the cellular
action of ETA, including how it is processed, and to determine its
interaction with its receptor on toxin-sensitive cells.

The specific aims of this proposal are:  10 Confirm the relationship
between the ETA receptor and the alpha2MR/LRP.  The investigator will
identify sequences in human alpha2MR/LRP.  The investigator will identify
sequences in human alpha2MR/LRP.  The investigator will identify
sequences in human alpha2MR/LRP receptor that correspond to ETA binding
sites; 2) Determine the basis for cellular susceptibility to toxins.
This includes a) determining ETA receptor level in toxin sensitive (LM
and Chang) and resistant cells (OVCAR and Hela); b) establishing the
level of alpha2MR/LRP receptor associated protein (RAP) in various
mammalian cells; c) identifying and localizing the compartments where ETA
is proteolytically processed, is activated, and enters the cytosol.
Where feasible, these  studies will include diphtheria toxin (DT), to
determine if a second bacterial toxin is processed in a manner similar
to ETA.  3) Define the intracellular pathway taken by the ETA receptor
in sensitive cells.  This work is significant because it will increase
understanding of the pathophysiology of pseudomonas infections, help in
the construction of efficient chimeric toxins, and help to answer the
question of how toxins have adapted to take advantage of well conserved
cellular components such as the alpha2MR/LRP.
GRANTS=R29AI35994
Primary biliary cirrhosis (PBC)  and autoimmune hepatitus (AI-CAH) ar two
chronic diseases of the liver, believed to be autoimmune in nature, with
etiologies and pathogenesis that remain unknown.  These disorders affect
predominantly women, mostly in th prime of their life.  For example, over
90% of patients with PBC are women between the ages of 20-70.  Liver
transplantation ha s proven to be an effective treatment for both AI-CAH
and PBC.  However, disease recurrence remains an important concern.

The goal of this project is to elucidate the role of cytokines and
cytotoxic mediators in autoimmune liver disease.  Specifically, we
propose to: 1) characterize the cytokine profiles within the liver of
patients with PBC and AI-CAH 20 identify the cytotoxi...

## Key facts

- **NIH application ID:** 3127261
- **Project number:** 2R01AI017529-11A2
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **SAM.gov UEI:** DZ4YCZ3QSPR5
- **Principal Investigator:** CATHARINE B SAELINGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $224,035
- **Award type:** 2
- **Project period:** 1980-12-01 → 1996-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3127261

## Citation

> US National Institutes of Health, RePORTER application 3127261, BASIS FOR CELLULAR SUSCEPTIBILITY TO BACTERIAL TOXINS (2R01AI017529-11A2). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3127261. Licensed CC0.

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