Specific Inhibition of Orai1-mediated Calcium Signalling Resolves Inflammation and Clears Bacteria in an Acute...

Area of Science:

• Immunology and Pharmacology
• Respiratory Medicine

Background:

• Acute respiratory distress syndrome (ARDS) has a high mortality rate (35%) and lacks effective therapies.
• Orai1 calcium channels regulate inflammation and are a potential drug target, but specific inhibitors are unavailable.

Purpose of the Study:

• To investigate the efficacy of ELD607, a novel Orai1 antagonist, in treating ARDS induced by bacterial pneumonia in preclinical models.
• To evaluate ELD607's pharmacological properties and its effects on immune cells and bacterial load.

Main Methods:

• Assessed ELD607's inhibition of store-operated Ca2+ entry (SOCE) in HEK293T cells and immune cells from ARDS patients.
• Utilized a murine model of ARDS induced by various bacterial pathogens (Pseudomonas aeruginosa, Staphylococcus aureus, MRSA).
• Administered ELD607 intranasally and evaluated its impact on neutrophilia, survival, bacterial load, and cytokine levels.

Main Results:

• ELD607 demonstrated potent and specific inhibition of SOCE (IC50 = 9 nM) and was stable in ARDS airway secretions.
• In vivo, inhaled ELD607 significantly reduced neutrophilia, improved survival rates, and unexpectedly decreased bacterial lung burden, including MRSA.
• ELD607 acted as an immunomodulator, reducing cytokines and promoting macrophage-mediated bacterial clearance, an effect dependent on alveolar macrophages.

Conclusions:

• Specific Orai1 inhibition with ELD607 presents a novel therapeutic strategy for ARDS, reducing systemic inflammation.
• ELD607 exhibits potential in treating antibiotic-resistant bacterial infections by enhancing host immune responses.
• Targeting Orai1 offers a promising approach for managing ARDS and combating multidrug-resistant pathogens.