Long COVID has been considered the “Next National Health Disaster” in the US (Phillips and Williams, 2021). As many as 50 per cent of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may develop Long-COVID (Thaweethai et al., 2023), especially Neuro-COVID (Ali et al., 2022; Almulla and Al-Hakeim, 2023) characterized cognitive dysfunction (Hadad et al., 2022). Long COVID may last up to two years.(Shanley et al., 2022) However, the precise pathogenesis of Long COVID has yet to be fully elucidated (Proal and VanElzakker, 2021). SARS-CoV-2 enters cells via its coronavirus spike protein binding to its cell surface receptor, angiotensin-converting enzyme 2 (ACE2) (Tai et al., 2020). SARS-CoV-2 Spike protein may enter the brain from the nose through the nasal neural mucosa following the olfactory nerve tract (Meinhardt et al., 2021). While the exact brain pathogenetic mechanisms remain unclear, evidence points to the involvement of neuroinflammation (Sodagar et al., 2022; Tremblay et al., 2022), especially perivascular inflammation (Lee et al., 2021) and blood-brain barrier (BBB) disruption (Bonetto et al., 2022; Lee et al., 2021), leading to neuronal damage (Zingaropoli et al., 2022).
Autopsy studies of patients with COVID-19 showed severe neuronal loss in the capillaries of the choroid plexus (Yang et al., 2021), as well as neuronal necrosis and glial cell hyperplasia (Xu et al., 2024). A two-year longitudinal study using plasma proteomics to probe Long-COVID reported that pathways related to neuron generation and differentiation were persistently suppressed (Gu et al., 2023).
A critical component of neuronal connectivity is the extracellular matrix (ECM) that can be disrupted by matrix metalloproteinases (MMPs). MMP-9 has emerged an important molecule in neuropsychiatric (Kaczmarek et al., 2023; Lopez-Navarro and Gutierrez, 2022) and neurodegenerative disorders (Beroun et al., 2019). MMP-9 can disrupt the polysaccharide scaffolding of the brain matrix and digest tight junction proteins, thus disrupting neuronal connectivity (Stawarski et al., 2014). MMP-9 can cause vascular inflammation and increase BBB permeability (Dhanda and Sandhir, 2018). MMP-9 levels were elevated in the serum of COVID-19 patients and were associated with disease severity (Ding et al., 2023; Savic et al., 2022).
We investigated serum levels of MMP-9 in Long-COVID patients, and whether recombinant SARS-CoV-2 Spike protein could stimulate release of MMP-9 from cultured human microglia and mast cells.