# Pharmacological Modulation of IL-1beta/Inflammasome Signaling and Host Immunity to Bacterial Pathogens

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $153,035

## Abstract

Project Summary/Abstract
A review of post-marketing surveillance reveals that humans receiving IL-1β inhibitors (e.g. Anakinra) have
strikingly high (> 800 fold-increased risk) reporting of invasive group A Streptococcus (GAS) infections,
including 11 fatal cases of necrotizing fasciitis. We found that Anakinra treatment, but not treatment a novel
direct NLRP3 inflammasome inhibitor MCC950, increased mouse susceptibility to GAS. Surprisingly, GAS
induced macrophage IL-1β production independently from canonical inflammasome regulatory components.
Secreted GAS cysteine protease SpeB was necessary and sufficient for induction of non-canonical IL-1β
signaling. Thus IL-1β acts a sensor to directly detect pathogen-associated proteolysis, an independent
innate immune pathway running in tandem with the conventional inflammasome response, and which is
blocked with Anakinra treatment. Based on this striking discovery, the goals of this program are three-fold.
In Aim 1, we will understand how pharmacological modulation of IL-1β signaling, and consequent changes
in macrophage and neutrophil innate immune and inflammatory function, can influence the pathogenesis
and outcome of severe bacterial infections – pneumonia and sepsis. Leading IL-1β receptor-blocking drug,
Anakinra will be compared directly to an investigational small molecule NLRP3 inhibitor MCC950. We
predict from our own clinical and experimental studies that higher IL-1β responses may be detrimental in
lung infection but beneficial in systemic infection, and differ between pathogens inducing noncanonical IL-1β
processing (GAS and Pseudomonas aeruginosa) compared a pathogen that only activates canonical
NLRP3 inflammasome, methicillin-resistant Staphylococcus aureus (MRSA). In Aim 2, we provide data that
IL-1β and IL-10 responses to MRSA predict risk of prolonged bacteremia and mortality, and that different
contemporary antibiotic treatments influence MRSA virulence factor expression and the magnitude and
pattern of cytokines including IL-1β and IL-10 produced by macrophages. Surveying all the common anti-
MRSA drugs currently in clinical use, will provide a comprehensive analysis of how these “indirect” effects of
antibiotic treatment may influence disease pathogenesis and how immunomodulatory pharmacodynamics
parameters identified in vitro and ex vivo with phagocytic cells translate to in vivo infection/treatment
models. Finally, the caution that we raise with Anakinra from the FDA adverse event reporting has inspired
us to carefully examine the full suite of anti-inflammatory therapies currently used in KD. Aim 3 provides a
comprehensive pharmacodynamics analysis of the infectious risks associated with different KD therapeutics
that may support the preferred use certain agents or guide adjunctive interventions such as prophylactic
antibiotics to guarantee patient safety. The Nizet Lab is a leader in the study of microbial pathogenesis and
innate immunity to inform novel approaches for treatment...

## Key facts

- **NIH application ID:** 9970238
- **Project number:** 5P50HD090259-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Victor Nizet
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $153,035
- **Award type:** 5
- **Project period:** 2016-09-20 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970238

## Citation

> US National Institutes of Health, RePORTER application 9970238, Pharmacological Modulation of IL-1beta/Inflammasome Signaling and Host Immunity to Bacterial Pathogens (5P50HD090259-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9970238. Licensed CC0.

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