Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19

Area of Science:

• Virology
• Immunology
• Pharmacology

Background:

• Coronavirus disease 2019 (COVID-19) disproportionately affects aged populations.
• Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants necessitate novel therapeutic strategies, particularly for the elderly.
• Age-dependent severity in murine models of SARS involves elevated prostaglandin D2 (PGD2) and phospholipase A2 group 2D (PLA2G2D).

Purpose of the Study:

• To investigate the role of the PLA2G2D-PGD2/PTGDR pathway in age-related COVID-19 severity.
• To evaluate the therapeutic potential of a PTGDR antagonist in aged, SARS-CoV-2-infected animals.

Main Methods:

• Isolation and use of a virulent mouse-adapted SARS-CoV-2 model.
• Assessment of disease severity in aged mice lacking PTGDR or PLA2G2D expression.
• Treatment of aged, infected mice with the PTGDR antagonist, asapiprant.

Main Results:

• Mice lacking PTGDR or PLA2G2D expression were protected from severe disease.
• Asapiprant treatment significantly protected aged mice from lethal SARS-CoV-2 infection.
• The PLA2G2D-PGD2/PTGDR pathway was identified as a key contributor to severe, age-dependent COVID-19 outcomes.

Conclusions:

• The PLA2G2D-PGD2/PTGDR pathway represents a viable therapeutic target for COVID-19 in aged individuals.
• PTGDR antagonism, exemplified by asapiprant, demonstrates specific protective effects in elderly SARS-CoV-2-infected animals.