[R01] Regulation of neutrophil endoplasmic reticulum stress response by IRE1a
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2031-05-31
Importo max: 599.480 EUR
Paese: US
Descrizione
Project Summary/Abstract:
The lungs are exposed to pathogens and environmental toxins that trigger stress and cause numerous
respiratory diseases. Effective host defenses against lung infection by bacterial pathogens, including methicillin-
resistant Staphylococcus aureus (MRSA), rely on innate immune cells including neutrophils, prominent early
responders to sites of infection. If host defenses are ineffective, MRSA causes serious lung infection, resulting
in severe morbidity and a significant economic burden on healthcare facilities, where it is endemic. MRSA
infections have a mortality rate of up to 14% and an estimated $500 million in healthcare costs in the US alone.
Increasing resistance to vancomycin, the last resort antibiotic for MRSA infections, underscore the urgent need
for innovative treatment approaches. Although directly targeting pathogens with antibiotics has been a successful
approach for treating infections, many pathogens, including MRSA, eventually will become resistant to these
drugs. As an alternative, immunomodulatory strategies to enhance host defenses, such as those shown to be
effective against cancer cells, have the potential for treating drug-resistant pathogen infections. Recently, we
showed that the inositol-requiring enzyme 1-α (IRE1α), an endoplasmic reticulum (ER) stress sensor, is required
for clearance of MRSA in a murine skin abscess model, where neutrophils are robustly recruited to the site of
infection. Further, IRE1α coordinates signaling events upstream of calcium (Ca2+) mobilization, histone
citrullination, and production of mitochondrial reactive oxygen species (mitoROS), all of which are important for
neutrophil inflammatory responses including the formation of antimicrobial neutrophil extracellular traps (NETs).
Because excessive neutrophil activation and NET release can be detrimental to vital organs, it is not clear
whether neutrophil IRE1α-mediated stress responses aid or impede the resolution of infection in the lungs. While
IRE1α activation has been linked to the development of lung fibrosis through the regulation of alveolar epithelial-
to-mesenchymal transition in the context of chronic inflammatory diseases, its role in pulmonary neutrophil
defenses is unknown. Thus, there is a gap in our knowledge of how cellular stress responses modulate
pulmonary neutrophil defenses and infection outcomes in the lungs. The overarching goal of this proposal is to
elucidate the mechanisms by which neutrophil IRE1α signaling influences production of mitoROS and Ca2+
mobilization to drive NET release, injure lungs, and regulate pulmonary host defense against MRSA. We will
accomplish the following Aims: (1) Define the molecular mechanisms underlying IRE1α-mediated mitoROS
hyperactivation of human and mouse primary neutrophils and excessive NET release, and (2) Elucidate the role
of neutrophil IRE1α signaling in excessive NET release, lung injury, and immunity in vivo using a MRSA
pneumonia infection mouse model.
Istituzione: LOUISIANA STATE UNIV A&M COL BATON ROUGE
PI: Basel Hanna Abuaita
Progetto: 1R01AI193067-01A1
Settori: National Institute of Allergy and Infectious Diseases
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