Noncanonical inflammasome sensing of LPS in the cytosol has emerged as a central mechanism of innate immune activation during Gram-negative bacterial infections. While optimal engagement of the cytosolic LPS sensing pathway can be host protective during bacterial infections, its excessive and prolonged activation is highly deleterious and involved in sepsis. A comprehensive understanding of how cytosolic LPS sensing by noncanonical inflammasome contributes to host defense and sepsis is lacking. Innate immune detection of LPS in the cytosol via inflammatory caspases (4,5 and 11) elicits three distinct outcomes; proteolytic maturation of caspase-1, IL-1?, and IL-18, pyroptosis, unconventional secretion of intracellular proteins, which lack leader sequence for secretion via classical endoplasmic reticulum (ER)-Golgi route. Upon extracellular release, several of these proteins are believed to act as alarmins or damage associated molecular patterns (DAMPs), and can both incite and modulate ongoing immune responses. Thus, alarmins and DAMPs play substantial roles in shaping inflammatory responses and tissue repair during infectious diseases, sepsis and trauma. However, the unconventional protein secretion as a consequence of caspase-11 activation by cytosolic LPS is poorly characterized. The overall goal of this study is to profile alarmins released as a consequence of caspase-11 activation by cytosolic LPS. Importantly, we will characterize the secretion and function of a novel alarmin identified in our preliminary studies in regulating innate immune responses during bacterial infections and sepsis. Overall, the findings of this study will provide critical insights into pathogenic mechanisms in sepsis and potentially identify new biomarkers and targets to intervene in sepsis.

Public Health Relevance

Sepsis is the leading cause of death in the intensive care units and is responsible for more than 250,000 deaths in the United States annually. By uncovering new effector mechanisms of caspase-11, the findings from this study could offer new immunomodulatory targets to block detrimental inflammation in sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI135528-02
Application #
9625607
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Singleton, Kentner L
Project Start
2018-01-15
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06032
Russo, Ashley J; Rathinam, Vijay A K (2018) Lipid Peroxidation Adds Fuel to Pyr(optosis). Cell Host Microbe 24:8-9