# Exploring the role of type I interferon in Rickettsia pathogenesis

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $235,500

## Abstract

PROJECT SUMMARY / ABSTRACT
The Rickettsiae are a diverse group of Gram-negative, obligate intracellular bacterial pathogens that cause
human diseases, including typhus and spotted fever. Among the causative agents of spotted fever group
(SFG) rickettsiosis in the U.S., Rickettsia parkeri has proven to be a uniquely powerful model for studying
pathogenicity at the cellular level, because it causes a non-lethal eschar-associated disease and therefore can
be grown under biosafety level 2 conditions, facilitating cell biological studies. However, progress toward
developing R. parkeri as a model for studying the innate immune response to SFG Rickettsia infection has
been hindered by a dearth of studies employing mutant mice. As such, key questions regarding the innate
immune response to SFG Rickettsia remain unanswered, including how the bacteria respond to type I
interferon (IFN-I), an important cytokine of the innate immune system. Our new preliminary data indicate that
intradermal infection of mice lacking both receptors for IFN-I and type II interferon (IFN-g) with R. parkeri
results in a necrotic lesion at the site of infection and occasional lethality, whereas mice lacking each individual
receptor exhibit no symptoms. This demonstrates a role for IFN-I (and IFN-g) in restricting R. parkeri growth in
vivo. Moreover, the pathology of the double mutant is similar to (but more severe than) that occurring during
human infection, suggesting it may represent a new animal model of human disease. We have also observed
that IFN-I severely restricts R. parkeri growth in primary mouse macrophages, and that this is partially due to
killing by the IFN-I regulated gene products, including antimicrobial guanylate binding proteins (GBPs). Despite
these advances, there remain two key gaps in knowledge: (1) it is unclear how IFN-I restricts R. parkeri growth
at the organ/tissue/cellular level in vivo; and (2) it is not known how gene products upregulated by IFN-I kill R.
parkeri at the cellular/molecular level. We hypothesize that that IFN-I plays an important role in restricting
Rickettsia growth in vivo and in vitro via the upregulation of cytosolic antibacterial molecules. We will test this
hypothesis in two aims. In Aim 1, we will characterize the kinetics of intravenous and intradermal infection, the
resulting organ and tissue pathologies, and the cell types infected by R. parkeri in mice lacking both receptors
for IFN-I/IFN-g. These studies will reveal how IFN-I restricts growth of R. parkeri in vivo and will establish a
robust murine model for investigating SFG Rickettsia pathogenesis. In Aim 2, we will test the effect of
activating or mutating candidate antimicrobial factors (identified by RNAseq) on bacterial killing downstream of
IFN-I signaling, and will test whether the GBPs restrict R. parkeri growth in endothelial cells in vitro and mice in
vivo. Our findings will reveal how IFN-I restricts the growth of R. parkeri, and perhaps other microbes, in vit...

## Key facts

- **NIH application ID:** 9888303
- **Project number:** 5R21AI138550-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Matthew D Welch
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $235,500
- **Award type:** 5
- **Project period:** 2019-03-06 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9888303

## Citation

> US National Institutes of Health, RePORTER application 9888303, Exploring the role of type I interferon in Rickettsia pathogenesis (5R21AI138550-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9888303. Licensed CC0.

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