SARS-CoV-2 spike protein expression drives post-acute coagulopathy

Area of Science:

• Virology
• Immunology
• Pathology

Background:

• Emergence of SARS-CoV-2 variants with distinct pathogenicity during the COVID-19 pandemic.
• Focus on the viral spike (S) protein's role in disease progression and post-acute sequelae.

Purpose of the Study:

• Investigate the role of the SARS-CoV-2 spike (S) protein, particularly from the Delta variant, in disease progression and long COVID.
• Determine if S protein expression can induce post-COVID-like symptoms in a mouse model.
• Explore potential therapeutic interventions targeting S protein-associated pathology.

Main Methods:

• Transient expression of Ancestral and Delta S proteins in K18-hACE2 transgenic mice using a recombinant vesicular stomatitis virus (VSV) vector.
• Monitoring for pulmonary inflammation, neutrophil activation, microthrombosis, mortality, splenic atrophy, and systemic inflammation markers (IGFBP-1, CXCL13).
• Analysis of serum samples from long COVID patients for IGFBP-1 and CXCL13 levels.
• Assessment of aspirin's efficacy in mitigating S protein-induced pathology in mice.

Main Results:

• Transient S protein expression induced mild pulmonary inflammation, neutrophil activation, microthrombosis, and ~40% mortality in mice.
• Diseased mice exhibited splenic atrophy and elevated serum IGFBP-1 and CXCL13.
• Elevated IGFBP-1 levels were observed in long COVID patients, with higher CXCL13 in severe cases.
• Aspirin treatment significantly reduced mortality and weight loss in mice exposed to Delta S protein.

Conclusions:

• SARS-CoV-2 S protein-associated coagulation and systemic inflammation may contribute to the development of post-acute sequelae of COVID-19 (long COVID).
• The study provides evidence for delayed pathological effects of S protein expression, relevant to long COVID pathogenesis.
• Findings support further research into S protein-driven mechanisms and potential antiplatelet therapies for long COVID.