# Mechanisms of SFG Rickettsia-Host Interactions

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $558,165

## Abstract

PROJECT SUMMARY/ABSTRACT
A subset of emerging, but poorly characterized tickborne diseases in the U.S. are caused by Spotted Fever
Group (SFG) Rickettsia. These obligate intracellular bacterial pathogens cause mild-to-life-threatening vascular
diseases in humans and have a limited set of diagnostics and therapeutic interventions. To promote widespread
disease, SFG Rickettsia species have evolved dynamic strategies to invade host cells, escape into the cytosol,
and spread from cell to cell. We hypothesize that SFG Rickettsia coordinate their complex life cycle by delivering
an arsenal of secreted bacterial proteins (i.e., effectors) that reprogram host cell processes. Unfortunately, the
identity and host targets of these secreted effectors have remained largely unknown. Furthermore, direct analysis
of the secretion systems and putative effectors have been hampered due to challenges in growing and
genetically manipulating these pathogens in the lab. To overcome this barrier, we recently adapted forward
genetics and plasmid-based complementation to the model SFG member Rickettsia parkeri, allowing for
powerful functional-genetic studies of SFG Rickettsia pathogenesis. Using these tools, we discovered that the
secreted effector Sca4 promotes a late stage of cell-to-cell spread by manipulating host cell-cell adhesion.
Additionally, transposon mutagenesis of a secreted effector of unknown function (RARP-1) and a component of
the anomalous Rickettsia Type 4 secretion system (VirB6e) impairs distinct stages of R. parkeri infection. This
proposal will leverage these key advances to examine how a secretion system and secreted effectors promote
different steps of the R. parkeri infectious life cycle. Here, we combine our functional-genetic strategies and
expertise in host cell biology, with modern biochemical techniques to reveal critical, mechanistic insights into
SFG Rickettsia pathogenesis. In Aim 1, we will examine the function and secretome of the T4SS component
VirB6e. In Aim 2, we will determine how the secreted effector RARP-1 promotes R. parkeri infection. In Aim 3,
we will elucidate how Sca4 specifically targets host cell-cell adhesion complexes during R. parkeri cell-to-cell
spread. Collectively, the proposed research will dramatically improve our fundamental understanding of
Rickettsia biology and Rickettsia-host interactions and reveal therapeutic targets to prevent or treat tickborne
diseases.

## Key facts

- **NIH application ID:** 10891429
- **Project number:** 5R01AI155489-04
- **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:** $558,165
- **Award type:** 5
- **Project period:** 2021-08-12 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891429

## Citation

> US National Institutes of Health, RePORTER application 10891429, Mechanisms of SFG Rickettsia-Host Interactions (5R01AI155489-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10891429. Licensed CC0.

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