# Host factors in Shigella flexneri infection

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $575,734

## Abstract

Project summary. Host interactions play critical roles during infection with bacterial pathogens. For many
bacterial pathogens, type 3 secretion systems (T3SSs) mediate numerous interactions with the host. Host
interactions, in turn, regulate the activation of the T3SSs. Once activated, T3SS effectors are delivered into
host cells via pores in mammalian plasma membranes (translocons) that consist of two T3SS translocases.
T3SS effectors modulate host cells in ways that promote infection. We found that engagement of host factors
leads to specific conformational changes in the translocon that are required for activation of effector secretion.
We found that residues in the host cytosolic domains of the bacterial translocases reside at least transiently
within the pore channel. We found that Shigella OspB manipulates mTORC1, the mammalian central regulator
of cell growth and proliferation, leading to OspB alteration of cell proliferation during Shigella infection.
 We propose to investigate the mechanisms by which cellular interactions with natively delivered plasma
membrane-embedded Shigella flexneri translocons contribute to translocon activation prior to cell invasion,
with the goal of uncovering mechanisms of pre-invasion roles of plasma-membrane embedded translocons,
including the mechanisms of pore opening, activation of effector secretion, effector translocation, and
membrane ruffling. Additionally, we propose to plan to leverage our recent findings to determine the
mechanisms of OspB manipulation of mTORC1, specifically identifying mammalian substrate(s), characterizing
the mechanism of mammalian substrate cleavage, and interrogating the mechanism by which OspB
mammalian substrate(s) alter mTORC1 activity.
 Our overall goal is to determine how mammalian cell proteins and interactions modulate bacterial infection
and pathogenesis, specifically the activation of the T3SS, and how T3SS effectors interact with and alter
mammalian cells. Given the conservation of T3SSs and OspB among medically important bacterial pathogens,
it is highly likely that our insights will have broad implications for host-pathogen interactions more generally,
therefore be of considerable interest to the pathogenesis community.

## Key facts

- **NIH application ID:** 10778561
- **Project number:** 5R01AI081724-12
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Marcia B Goldberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $575,734
- **Award type:** 5
- **Project period:** 2010-01-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10778561

## Citation

> US National Institutes of Health, RePORTER application 10778561, Host factors in Shigella flexneri infection (5R01AI081724-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10778561. Licensed CC0.

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