# Rickettsia-host interface and multiple paths to invasion

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $560,764

## Abstract

The global impact of rickettsial infections is illustrated by the resurgence of long-known
pathogens, as well as the emergence of newly recognized pathogens. Infections with
Rickettsia rickettsii (Rocky Mountain Spotted Fever) continue with severe consequences in
South and Central America. The resurgence of R. conorii (Mediterranean Spotted Fever) in
Europe, the Middle East and Africa, as well as a recent worldwide rise in murine typhus (R.
typhi), highlights the threats of rickettsial diseases. Despite the public health importance of
pathogenic Rickettsia spp.,, our limited knowledge of ricketsial biology has been an
impediment to progress towards more effective intervention modalities. Our phylogenomics
analyses have highlighted considerable variation across Rickettsia genomes, providing a
framework to link particular genotypes with their associated disease phenotypes. For several
bona fide secretory proteins that have been characterized in universal rickettsial processes
(i.e., host cell adhesion, invasion and intracellular growth and survival), a patchy genomic
distribution indicates that the mechanisms underpinning these processes are inherently
different across rickettsial groups. For instance, our recent work on R. typhi (Typhus Group)
identified a novel invasin, RalF, which interacts with host Arf6 in a process dependent on host
phosphoinositide PIP2. Curiously, RalF genes are absent from species of Spotted Fever
Group (SFG). Conversely, two well-characterized surface proteins (Sca0 and Sca2) of SFG
pathogens are either absent (Sca0) or highly divergent (Sca2) in non-SFG rickettsial species.
Thus, mechanisms of Rickettsia host cell invasion are more complex than previously
appreciated, necessitating the need to employ a comparative approach for investigating the
factors underpinning pathogenesis. Under this proposal, our work will focus on identifying the
mammalian and invertebrate host cell targets of Sca3 and divergent Sca2 (d-Sca2) proteins
from non-SFG species (Aim 1). Additionally, we will investigate the manner by which non-
SFG species trigger phosphoinositide (PIP) metabolism to facilitate membrane ruffling and
rickettsial endocytosis, with identified host proteins and PIPs present on the early endosome
further explored as docking sites for rickettsial phospholipases that mediate phagosome
escape (Aim 2). The successful outcome of this work will provide important clues on how
divergent Rickettsia species utilize different molecules to achieve the universal rickettsial
process of host cytoplasmic infection via induction of phagocytosis. We anticipate this
knowledge to yield disease-specific therapeutic approaches to combat fatal rickettsioses.

## Key facts

- **NIH application ID:** 9931126
- **Project number:** 5R01AI126853-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Abdu F Azad
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $560,764
- **Award type:** 5
- **Project period:** 2016-06-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931126

## Citation

> US National Institutes of Health, RePORTER application 9931126, Rickettsia-host interface and multiple paths to invasion (5R01AI126853-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9931126. Licensed CC0.

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