PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections

Area of Science:

• Immunology
• Pharmacology
• Infectious Diseases

Background:

• Severe infectious agents like SARS-CoV-2 and MRSA cause tissue damage, leading to immune cell infiltration and organ damage.
• Neutrophils, monocytes, and macrophages in infected lungs express PI3Kγ, a key regulator of myeloid cell trafficking and immune suppression.

Purpose of the Study:

• To investigate the role of PI3Kγ in inflammatory lung diseases caused by virulent pathogens.
• To evaluate the therapeutic potential of PI3Kγ inhibition using eganelisib in infectious disease models.

Main Methods:

• Studied PI3Kγ expression in myeloid cells during SARS-CoV-2 and MRSA infections.
• Utilized PI3Kγ deletion and inhibition with eganelisib in animal models of infectious diseases.
• Assessed outcomes including survival, inflammation, vascular leak, and organ damage.

Main Results:

• PI3Kγ deletion and eganelisib treatment significantly promoted survival in SARS-CoV-2 and MRSA infection models.
• Inhibition of PI3Kγ suppressed inflammation, reduced vascular leak, mitigated organ damage, and controlled cytokine storm.

Conclusions:

• PI3Kγ plays a critical role in the pathogenesis of severe infectious lung diseases.
• PI3Kγ inhibitors, such as eganelisib, represent a promising therapeutic strategy for managing severe infectious diseases.