# Epithelial Responses to Bacterial Invasion

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $381,250

## Abstract

Summary
The intestinal mucosa serves as a barrier to infection from pathogens and normal gut flora. This barrier is
defended by the mucosal immune system through a variety of innate and adaptive immune mechanisms.
However, mucosal immune responses must be tightly regulated to maintain tolerance to resident normal flora
and food antigens. Because peripheral tolerance cannot be explained completely by immunological ignorance
or negative selection in the thymus, various mechanisms have been proposed for how lamina propria
macrophages (MPs) and dendritic cells (DCs) capture and present luminal antigen in the steady-state to
promote intestinal homeostasis. Recently, we described a novel luminal antigen transport mechanism that
we've termed goblet cell associated antigen passages (GAPs). The role of GAPs in peripheral tolerance vs.
immunity is relatively unexplored, but GAPs deliver small soluble antigens preferentially to CD103+ DCs, which
have tolerogenic potential. A key question is whether pathogen invasion mechanisms have evolved to target
steady-state antigen acquisition pathways (e.g., GAPs) as a strategy to evade the acute immune response.
 These studies will use a common and often deadly bacterial pathogen, Listeria monocytogenes (Lm), to
investigate how initial host-bacterial interactions (minutes to hours) affects mucosal immunity and link invasion
pathways to downstream infection outcomes. Our hypothesis is that bacterial invasion via GAPs will lead to
inefficient innate and adaptive immune responses and increase bacterial persistence in the host. This
hypothesis will be tested in vivo using a murinized Lm strain (Lm InlAMt) mouse that can infect mice orally and
complemented by studying Lm InlAWt infection in explanted human intestinal tissues. These studies build on
important recent developments including the murinized Lm oral infection model, in vivo two-photon imaging of
the intestine and mesenteric lymph nodes, the development of a human explant infection system and state-of-
the-art RNA sequencing approaches to characterize epithelial responses. This work is conceptually innovative
in that it examines the first few minutes of an infection, which is rarely studied in vivo and impractical to study in
human patients, but which may ultimately determine infection outcomes.

## Key facts

- **NIH application ID:** 9828486
- **Project number:** 5R01AI077600-09
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MARK James MILLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2009-08-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828486

## Citation

> US National Institutes of Health, RePORTER application 9828486, Epithelial Responses to Bacterial Invasion (5R01AI077600-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828486. Licensed CC0.

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