# Role of caspase-8 in innate immunity to infection

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $181,371

## Abstract

PROJECT SUMMARY
Although inflammatory responses play a key role in controlling infection, dysregulated inflammation is
associated with inflammatory and immune-mediated diseases. IL-1b is a cytokine that functions in host
defense as an initiator of inflammation, and the pathways of IL-1b synthesis and release by myeloid cells have
been described. In the classical pathway of activation, signals through Toll-like receptors (TLRs) trigger NF-kB
activation and IL-1b transcription, and pro-IL-1b is proteolytically cleaved to mature, bioactive IL-1b by
caspase-1 functioning in the inflammasome. This pathway is best characterized in mouse macrophages.
Interestingly, however, human cells regulate the inflammasome differently than mouse cells, and the
molecular basis for the functional differences in these inflammatory pathways are relatively poorly understood.
The long-term goal of my research is to define molecular mechanisms of human innate immunity during
infection with the intracellular protozoan parasite Toxoplasma gondii. Although T. gondii infects an estimated
one-third of humans worldwide and causes fatal disease in immune-compromised individuals, relatively little is
known about human innate recognition of the parasite, since the TLRs that recognize T. gondii in mice
(TLR11/TLR12) are not functional in human cells. We recently reported that infection of human peripheral
blood monocytes with T. gondii results in IL-1b release via Syk-CARD9-NF-kB signaling and NLRP3
inflammasome activation. In preliminary studies using genetic knockout cells and pharmacological inhibitors,
we found that caspase-8 deficiency resulted in reduced IL-1b release from T. gondii-infected human
monocytes. We hypothesize that caspase-8 is involved in IL-1b release downstream of inflammasome
activation during T. gondii infection of human monocytes. Caspase-8 is critical for inflammation and monocyte-
mediated host defense against T. gondii in mice. However, it remains unknown how caspase-8 functions in
inflammatory pathways during T. gondii infection of human monocytes. The objective of this proposal is to
determine the role of caspase-8 in the regulation of IL-1b release from T. gondii-infected human monocytes.
This research is significant because pathways of inflammation in human immune cells are relatively poorly
defined, and understanding these processes may contribute to efforts to develop therapeutics to modulate or
dampen inflammation. In Aim 1, we will determine the role of caspase-8 in IL-1b release from infected
monocytes. In Aim 2, we will define the functional requirements of caspase-8 activity, including its processing
and association with cellular partners, during T. gondii infection. This proposal seeks to decipher the molecular
determinants of inflammatory signaling during T. gondii infection of human monocytes and will contribute to
defining innate immune pathways activated in response to infection with a human pathogen of global health
importance.

## Key facts

- **NIH application ID:** 10331886
- **Project number:** 5R21AI156452-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Melissa Bruckner Lodoen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $181,371
- **Award type:** 5
- **Project period:** 2021-01-22 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10331886

## Citation

> US National Institutes of Health, RePORTER application 10331886, Role of caspase-8 in innate immunity to infection (5R21AI156452-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10331886. Licensed CC0.

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