# The Role of STa in ETEC Pathogenesis

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2020 · $376,250

## Abstract

Enterotoxigenic Escherichia coli (ETEC) is one of the major causes of childhood morbidity and mortality in
developing countries. In 2010, annual mortality from illness due to ETEC was estimated at 157,000 deaths (9
percent of all deaths attributed to diarrhea) and approximately 1 percent of all deaths in children 28 days to 5
years of age. ETEC cause disease by colonizing the small intestine with colonization factor antigens and cause
secretory diarrhea through the actions of heat-labile (LT) or heat-stable (ST) enterotoxins. Development of
natural immunity to ETEC requires years of recurrent infections, which raises the question as to what about
this organism prevents the development of immunity.
LT is highly immunogenic and induces antibodies to itself when given to human volunteers. On the other hand
ST is a small non-immunogenic secreted peptide. We have recently begun to investigate the contribution of ST
on ETEC pathogenesis. Our preliminary data indicate (1) ST expression is higher in defined 4AA media as
compared to LB, sta1 gene (encoding STh) is up-regulated under anaerobic conditions, as could be found
within the host intestinal tract, and iron-depletion decreases ST expression (2) ST binds both iron and iron-
sulfur (FeS) clusters under these anaerobic conditions, in vitro (3) iron-bound forms of ST elicit less secretion
than native ST in an in vivo model and less cGMP from intestinal epithelial cells in cell culture than native ST,
and (4) ST suppresses fecal IgA and Th17 immune responses against ETEC H10407 (whole cell and O78-
LPS).
Based on the preliminary data, the hypotheses are that (1) sta1 is up-regulated in response to anaerobic
conditions by specific cis and trans factors (2) ST can bind iron and FeS clusters, which regulate its toxicity,
and (3) ST suppresses mucosal immunity to ETEC antigens thereby maintaining susceptibility of the host to
recurrent infections by the same organism mediated by iron sensing. The specific aims are 1) Determine the
environmental conditions that regulate transcription of genes encoding ST, 2) Characterize the iron and iron-
sulfur cluster binding properties of ST and how this controls ST enterotoxicity, and 3) Determine how ST
modifies mucosal immune responses to ETEC antigens.
At the conclusion of these studies, growth conditions that result in enhanced ST expression and secretion will
be elucidated. In addition, the role of iron and FeS clusters on ST toxicity will be clarified. Lastly, mechanisms
concerning ST-mediated suppression of mucosal immune responses to ETEC antigens will provide compelling
evidence for why it takes years of recurrent ETEC infections to develop natural immunity and inform vaccine
development.

## Key facts

- **NIH application ID:** 9962280
- **Project number:** 5R01AI125542-04
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Jacob P. Bitoun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,250
- **Award type:** 5
- **Project period:** 2017-08-11 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962280

## Citation

> US National Institutes of Health, RePORTER application 9962280, The Role of STa in ETEC Pathogenesis (5R01AI125542-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9962280. Licensed CC0.

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