Targeting Doublecortin-Like Kinase 1 (DCLK1)-Regulated SARS-CoV-2 Pathogenesis in COVID-19.

Area of Science:

• Virology and Immunology
• Host-pathogen interactions
• Molecular mechanisms of viral pathogenesis

Background:

• Host factors significantly influence SARS-CoV-2 infection severity and COVID-19 pathology.
• Chronic liver disease is a comorbidity associated with high COVID-19 mortality.
• Understanding host-driven mechanisms is crucial for developing effective COVID-19 treatments.

Purpose of the Study:

• To systematically analyze the roles of SARS-CoV-2-induced host factors, doublecortin-like kinase 1 (DCLK1) and S100A9, in viral pathogenesis.
• To investigate the therapeutic potential of targeting DCLK1 and S100A9 in COVID-19.

Main Methods:

• Analysis of DCLK1 and S100A9 expression in autopsied subjects with and without COVID-19 and chronic liver disease.
• Quantification of circulating DCLK1+S100A9+ mononuclear cells in hospitalized COVID-19 patients.
• In vitro validation using co-culture models, gain/loss of function studies, and treatment with DCLK1 kinase and S100A9 inhibitors.

Main Results:

• High DCLK1 and S100A9 expression, along with immunosuppressive M2-like macrophages and N2-like neutrophils, were observed in lungs and livers of COVID-19 patients with chronic liver disease.
• Increased circulating DCLK1+S100A9+ mononuclear cells correlated with COVID-19 disease severity.
• DCLK1 kinase activity amplified SARS-CoV-2 production and promoted pro-inflammatory cytokine secretion; inhibition of DCLK1 and S100A9 normalized cytokine profiles and reduced viral load in vitro.

Conclusions:

• DCLK1 plays a previously unrecognized role in augmenting SARS-CoV-2 viremia and inflammatory responses via β-catenin/DCLK1/S100A9/NF-κB signaling.
• DCLK1 and S100A9-expressing immune cells are associated with increased COVID-19 severity.
• DCLK1 represents a potential therapeutic target for COVID-19, particularly in patients with comorbid conditions like chronic liver disease.