How Spike-Associated Material May Prepare the Way for Its Own Delivery: A Systems-Level Hypothesis of Endothelial–Immune Feed-Forward Amplification

This manuscript proposes an evidence-integrated, systems-level and falsifiable hypothesis concerning how SARS-CoV-2 spike-associated material may participate in a self-amplifying vascular–immune feed-forward architecture. The model integrates endothelial activation, ACE2- and NRP1-associated pathways, leukocyte recruitment, monocyte/macrophage activation, vascular injury, and persistent inflammatory cargo. CD147 (BSG) is incorporated as a candidate immune–vascular signaling interface rather than as an established direct spike receptor. Persistent viral or spike-associated inflammatory cargo is treated as a second-order hypothesis and is conceptually distinguished from persistent productive viral replication. The proposed architecture is: S → E → R → M → V → E where S represents spike-associated inflammatory stimulation, E endothelial activation/dysfunction, R immune-cell recruitment, M myeloid-cell activation, and V vascular injury. The manuscript presents experimentally testable predictions and explicitly distinguishes evidence-supported biological relationships from higher-order systems-level inference. It does not claim a universal mechanism for Long COVID. The central limitation is that evidence exists for several individual components of the proposed network, but evidence that these components form a persistent, causally closed feed-forward loop in humans remains insufficient.