# Microbial Control of Host Intercellular Communication

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $306,174

## Abstract

PROJECT SUMMARY/ABSTRACT
Multicellular organisms use intercellular communication to coordinate cell function and maintain tissue
homeostasis. Recent work suggests that this communication is driven in part by the exchange of organelles (via
trans-endocytosis) and mechanical cues directly across cell-cell junctions. Dysregulation of this communication
leads to cancer and cardiovascular diseases. Despite its importance, we lack a fundamental molecular
understanding of how intercellular communication occurs because of the limited number of cell biological tools
capable of probing the molecular mechanisms at cell-cell contacts. This proposal seeks to elucidate the
regulatory mechanisms of the pathways thought to control intercellular communication by studying how they are
manipulated when under microbial control. The bacterium Listeria monocytogenes disseminates through human
tissues using a process called cell-to-cell spread, which is a vesicular-mediated form of intercellular exchange
that mimics host trans-endocytosis. Listeria spreads from cell to cell by mobilizing the host’s actin cytoskeleton
for intracellular motility and transport to the cell-cell junction. Once at the junction, it pushes against the
membrane and forms a double-membrane protrusion that is engulfed by a neighboring cell. Studying this
distinctive spreading process will allow us to examine several outstanding cell biological questions. First, are
specific endocytic pathways used at cell-cell junctions to engulf large cargo like microbes? Second, are
mechanically-sensitive membrane domains or membrane curvature proteins activated as Listeria pushes against
the junction during spread? To answer these questions, we used a high-content, image-based siRNA screen to
test if Listeria requires host intercellular communication pathways during spread. We discovered that the
endocytic and mechanoresponsive caveolar proteins CAV1, CAV2, and PACSIN2 promote Listeria spread. We
also revealed a putative role for 19 other host proteins, including those that regulate membrane curvature, trans-
endocytosis, and adhesion. Our preliminary findings suggest the overall hypothesis that Listeria subverts multiple
intercellular communication pathways to promote cell-to-cell spread. In Aim 1, we will determine how PACSIN2
and caveolins coordinate their activities to promote the engulfment stage of cell-to-cell spread. In Aim 2, we will
reveal which of the remaining hits regulate Listeria spread specifically, how they function, and if they work
independently or together with caveolae. In the end, our proposed studies will improve our fundamental
understanding of host-microbe interactions and basic cell biology, and may uncover how intercellular
communication goes awry in human disease.

## Key facts

- **NIH application ID:** 10875285
- **Project number:** 5R01GM141025-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** REBECCA L LAMASON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $306,174
- **Award type:** 5
- **Project period:** 2022-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875285

## Citation

> US National Institutes of Health, RePORTER application 10875285, Microbial Control of Host Intercellular Communication (5R01GM141025-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10875285. Licensed CC0.

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