# Redefining the Interaction Between Extracellular Immune Mechanisms and Intracellular Rickettsia Infections

> **NIH NIH R21** · UNIV OF MARYLAND, COLLEGE PARK · 2021 · $193,125

## Abstract

PROJECT SUMMARY
Bacteria of the genus Rickettsia are obligate intracellular endosymbionts and the causative agents of many significant
human and animal infections. These bacteria are transmitted to humans by hematophagous arthropods. Pathogenic
Rickettsia species parasitize endothelial cells of the circulatory system, causing vascular leakage with significant
morbidity and mortality. Rickettsia species are amongst the most important pathogens in history, with millions of human
fatalities associated with these infections.
 The complement system is a well-known potion of the mammalian immune system that has classically been
considered a secreted patroller of the extracellular spaces of the vasculature. Until recently it was considered unlikely
that extracellular immune components like the complement system would encounter intracellular pathogens like
Rickettsia; let alone that evolution would drive these systems into an adversarial relationship. Consequently, we are
only beginning to appreciate how complement can control intracellular bacterial infections. Emerging data from
Rickettsia and other organisms has begun to identify some of the molecular and cellular mechanisms of complement
efficacy against intracellular pathogens. As the newly-emerging concept of “intracellular complement” is rapidly gaining
traction, the experiments outlined in this proposal will be central to redefining an innate immune component that was
discovered over a century ago.
 Based on both clinical and experimental evidence, we have hypothesized that complement activation is essential
for the effective immune response to obligate intracellular Rickettsia infections. However, experimental data suggests
that complement efficacy does not result directly from the antibacterial components of complement. Instead,
complement efficacy against Rickettsia is derived from secondary interaction with other portions of the immune system.
We therefore aim to 1) assess the contribution of the proinflammatory components of complement to the anti-Rickettsia
immune response, and 2) define complement-induced components of the immune system that specifically target
intracellular pathogens. By studying the interaction between complement and clinically relevant pathogens, the
achieved results will advance our collective understanding of basic complement biology, further define the specific
immune response to Rickettsia infection, directly influence the design of anti-Rickettsia vaccines, and provide the
premise for future studies to analyze complement manipulation as a preventative or therapeutic intervention for
intracellular bacterial pathogens.

## Key facts

- **NIH application ID:** 10303369
- **Project number:** 1R21AI156069-01A1
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Sean Phillip Riley
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $193,125
- **Award type:** 1
- **Project period:** 2021-05-25 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10303369

## Citation

> US National Institutes of Health, RePORTER application 10303369, Redefining the Interaction Between Extracellular Immune Mechanisms and Intracellular Rickettsia Infections (1R21AI156069-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10303369. Licensed CC0.

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