# Murine Typhus

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $726,758

## Abstract

Arthropod-borne Rickettsia species are among the most virulent and lethal human pathogens
and are of significant global Public Health concern. Our work over the past 3.5 years resulted in
significant progress in understanding of R. typhi pathogenesis, and in particular, the role of the
rickettsial secretome during host cell invasion. For this proposal, we will address fundamental
questions in two understudied yet highly significant topics in rickettsial pathogen biology. First,
we will determine the mechanisms by which R. typhi modulates cat flea (Ctenocephalides felis)
innate immunity, microbiota and other factors to establish infection and facilitate transmission to
the vertebrate host; and second, defining the functional spectrum and immunogenic potential of the
R. typhi armory of secreted phospholipases that alter host membrane physiology to facilitate
phagosomal escape and intracellular replication. We will implement a transdisciplinary approach
(e.g., phylogenomics, bacteriology, entomology, and cellular/molecular biology) to thoroughly
investigate these focal areas, as outlined by the following Specific Aims. In Aim I, we will
decipher the modulatory factors R. typhi employs to colonize C. felis and facilitate transmission
via 1) a robust tissue-specific, time-course expression analysis, 2) silencing IMD and Toll
pathway gene expression, 3) testing the immunomodulatory propensities of isolated R. typhi
peptidoglycan, and 4) characterizing the impact of the C. felis microbiome on infection. In Aim II,
we will characterize the function and immunogenicity of R. typhi secretory phospholipases. We will
take two approaches to characterize R. typhi phospholipases: 1) functional characterization of Pat1,
Pat2 and Pld via determining their subcellular localization, lipid recognition and interactome within
host cells, with downstream analyses designed to reveal the significance of these interactions in
mediating bacterial access to the host cytosol; and; 2) identification of inflammasome components
necessary for IL-1β secretion by R. typhi, and determining the impact of Pat1, Pat2, and Pld activities
on inflammasome activation. Together these studies will significantly advance our understanding
of the complex Rickettsia/vector/host relationship, shedding light on how rickettsial parasites of
arthropods transition to vertebrate pathogens throughout the obligatory Rickettsia life cycle.
Thus, we anticipate that our work will take us closer to generating more prudent therapeutics to
combat fatal rickettsioses.

## Key facts

- **NIH application ID:** 9931109
- **Project number:** 5R01AI017828-37
- **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:** $726,758
- **Award type:** 5
- **Project period:** 1982-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931109

## Citation

> US National Institutes of Health, RePORTER application 9931109, Murine Typhus (5R01AI017828-37). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9931109. Licensed CC0.

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