# Rickettsia-host interface and multiple paths to invasion

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $662,481

## Abstract

PROJECT SUMMARY
 Species in the genus Rickettsia are Gram-negative obligate intracellular bacteria with both symbiotic and
pathogenic lifecycles. The global impact of rickettsial infections is illustrated by the resurgence of infections
of humans with R. rickettsia (etiologic agent of Rocky Mountain Spotted Fever) in South and Central America,
or R. conorii (Boutonneuse fever) in Europe, the Middle East, and Africa. Strikingly, tick- and flea-borne
rickettsial diseases are also on the rise in the United States, as exemplified by recent outbreaks of R. rickettsii
in Arizona and R. typhi (etiologic agent of murine typhus) in California and Texas, further highlighting the
threats of rickettsial diseases. There are currently no vaccines to prevent rickettsioses and our insufficient
understanding of rickettsial intracellular lifestyle hinders the progression towards the development of effective
therapeutics against these increasingly recognized bacterial pathogens. Over the past four years, we identified
a complex mechanism by which pathogenic rickettsiae utilize secreted effectors to facilitate colonization by
manipulating ER structures or by modulating intracellular trafficking to subvert host defense pathways.
However, the precise mechanisms by which virulent Rickettsia species utilize this effector arsenal to subvert
host innate defense pathways to support intracellular lifestyle in endothelial cells or macrophages (MΦ)
remains ill-defined. To address these knowledge gaps, this renewal application proposes to: i) decipher how
virulent Rickettsia species utilize their effector repertoire to manipulate autophagic responses to colonize host
cells, and ii) determine the mechanism(s) by which effectors of virulent, but not avirulent, Rickettsia species
suppress inflammasome activation and manipulate MΦ polarization to promote host dissemination. Our
overall goal is to test the hypothesis that effectors from virulent species of Rickettsia, like Risk1, induce
autophagy to negatively regulate inflammasome activation and skews MΦ polarization from a M1 to M2 bias
to facilitate host colonization. To test our hypothesis, in Aim 1, we will define the mechanism(s) by which
pathogenic Rickettsia subvert autophagosomal maturation to promote host colonization. In Aim 2, we will
decipher the mechanism(s) underlying subversion of inflammasome responses and manipulation of MΦ
polarization by pathogenic Rickettsia species. These Aims are intended to unveil a link by which effectors of
pathogenic Rickettsia species manipulate autophagy to subvert inflammasome-dependent proinflammatory
cytokine signaling and skew MΦ polarization from a microbicidal milieu (M1-MΦ) to a more favorable pro-
microbial environment (M2-MΦ). These studies will lead to the identification of a link that could be exploited
for anti-virulence strategy.

## Key facts

- **NIH application ID:** 10359124
- **Project number:** 5R01AI126853-07
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Abdu F Azad
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $662,481
- **Award type:** 5
- **Project period:** 2016-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359124

## Citation

> US National Institutes of Health, RePORTER application 10359124, Rickettsia-host interface and multiple paths to invasion (5R01AI126853-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10359124. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*