# Mechanisms of Rickettsia invasion, intracellular survival, and actin-based motility

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $380,650

## Abstract

PROJECT SUMMARY/ABSTRACT
The Rickettsiae are obligate intracellular bacterial pathogens that cause serious diseases, such as spotted
fever and typhus. We study the model spotted fever group (SFG) species Rickettsia parkeri, which causes an
eschar-associated human rickettsiosis, is experimentally tractable, and has emerging mouse models of
pathogenesis, making it ideal for revealing molecular mechanisms of SFG Rickettsia infection and virulence.
During infection, SFG Rickettsia invade host cells by mobilizing the actin cytoskeleton, escape from the
phagosome into the cytosol, replicate while avoiding degradation by autophagy, and harness actin
polymerization to promote intracellular motility and cell-cell spread. However, there are fundamental gaps in
our knowledge of the molecular mechanisms by which SFG Rickettsia exploit or disrupt host cell components
to promote their infection cycle. To bridge these gaps, in the current funding period we have pioneered an
innovative combination of bacterial genetics and host cell biology to identify key Rickettsia factors that
manipulate host cells. In unpublished work, we discovered that outer membrane protein OmpB is crucial for
both invasion and avoidance of autophagy. We also observed that patatin-like phospholipase Pat1 plays a role
in phagosome escape and/or autophagy evasion. Additionally, in published work, we demonstrated that
Rickettsia use two actin-polymerizing surface proteins to direct sequential phases of motility – with RickA
driving early motility and surface cell antigen Sca2 driving late motility. However, key outstanding questions
remain, including: How do Rickettsia engage host receptors to promote invasion? How do Rickettsia degrade
membranes during phagosome escape or inhibit membrane engulfment to avoid autophagy? And how do
Rickettsia coordinate and use two actin assembly factors in distinct phases of motility? Our preliminary and
published findings suggest the overall hypothesis that OmpB, Pat1, RickA, and Sca2 are multifunctional
proteins that mobilize or disrupt host cell components and play a crucial role in infection in vivo. This
hypothesis will be tested in three Aims focused on uncovering the mechanisms through which OmpB, Pat1,
RickA, and Sca2 influence invasion, intracellular survival, and motility. The Aims are to: (1) define the role of
Rickettsia surface protein OmpB in invasion and intracellular survival; (2) investigate the role of Pat1
phospholipase in phagosome escape and intracellular survival; and (3) determine how and why Rickettsia use
two distinct actin-based motility mechanisms. The proposed studies will advance the field by revealing crucial
molecular mechanisms used by Rickettsia and other pathogens to manipulate host cells and the importance of
these mechanisms to infectivity. Our studies may also lead to improved diagnostics and treatments for
rickettsial and other infections.

## Key facts

- **NIH application ID:** 9987487
- **Project number:** 5R01AI109044-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Matthew D Welch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,650
- **Award type:** 5
- **Project period:** 2014-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987487

## Citation

> US National Institutes of Health, RePORTER application 9987487, Mechanisms of Rickettsia invasion, intracellular survival, and actin-based motility (5R01AI109044-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9987487. Licensed CC0.

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