# CONTROL OF BACTERIAL TOXINS BY VIRUSES AND PLASMIDS

> **NIH NIH R01** · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · 1990 · $187,227

## Abstract

DESCRIPTION:  (Adapted from the applicants abstract) Diphtheria toxin (DT)
and the family of heat-labile enterotoxins (LTs) are well studied virulence
factors of Corynebacterium diphtheriae and Escherichia coli, respectively.
Each toxin has a B domain that binds to plasma membrane receptors and an A
domain that mediates toxicity.  DT ADP-ribosylates elongation factor 2,
thereby inhibiting protein synthesis and killing target cells.  LTs
ADP-ribosylate the regulatory protein G, and activate adenylate cyclase.
The long term objectives are to understand the genetics, regulation, and
mode of action of these toxins at the molecular level.  Such knowledge is
essential for understanding pathogenesis of diphtheria and enterotoxic E.
coli diarrhea and for development of improved vaccines, immunotoxins,
hybrid toxins, or related biologic products involving these toxins.  The
specific aims of this proposal are to:  1) determine the mechanisms by
which iron regulates production of DT and the activity of the iron uptake
system in C. diphtheriae.  The investigators will analyze the tox promoter
sequence that interacts with the E. coli Fur protein, clone and
characterize the tox repressor from C. diphtheria, isolate and characterize
ferric uptake regulation (fur) mutants of C. diphtheriae, and determine
whether tox repressor activity is mediated by the putative fur gene product
in C. diphtheriae.  2) characterize the interactions of DT with its
cellular receptor.  Dr. Holmes and colleagues have developed monoclonal
antibodies to membrane components of human cells that block intoxication by
DT and they will characterize their mode of action.  They will also purify
DT receptor molecule(s), clone and characterize and corresponding cDNA(s),
determine whether DT-resistant cells that lack functional receptors have
genes or membrane components homologous with those for DT receptors, and
characterize the binding domains of DT and its receptor.  3) analyze
structure-function relationships of LTs.  They will compare purified type I
and type II LTs in intestinal assays in several animal species to determine
whether their different receptor specificities correlate with differences
in biologic activity.  They will use genetic complementation with cloned A
and B subunit genes, directed mutagenesis of cloned genes, chemical
modification of purified toxins, and synthetic oligopeptides to analyze the
molecular determinants of biologic activity of representative type I and
type II LTs.

## Key facts

- **NIH application ID:** 3125643
- **Project number:** 2R01AI014107-14
- **Recipient organization:** HENRY M. JACKSON FDN FOR THE ADV MIL/MED
- **SAM.gov UEI:** UYLKBRENAPG5
- **Principal Investigator:** Randall K Holmes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1990
- **Award amount:** $187,227
- **Award type:** 2
- **Project period:** 1976-09-30 → 1995-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3125643

## Citation

> US National Institutes of Health, RePORTER application 3125643, CONTROL OF BACTERIAL TOXINS BY VIRUSES AND PLASMIDS (2R01AI014107-14). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3125643. Licensed CC0.

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