Long COVID elevated MMP-9 and release from microglia by SARS-CoV-2 Spike protein, 2024, Kempuraj, Klimas, Theoharides+

[SNT Gatchaman]

Long COVID elevated MMP-9 and release from microglia by SARS-CoV-2 Spike protein
Duraisamy Kempuraj; Irene Tsilioni; Kristina K. Aenlle; Nancy G. Klimas; Theoharis C. Theoharides

OBJECTIVES
Long COVID is a major health concern because many patients develop chronic neuropsychiatric symptoms, but the precise pathogenesis is unknown. Matrix metalloproteinase-9 (MMP-9) can disrupt neuronal connectivity and be elevated in patients with long COVID.

METHODS
In this study, MMP-9 was measured in the serum of long COVID patients and healthy controls, as well as in the supernatant fluid of cultured human microglia cell line stimulated by recombinant severe acute respiratory syndrome coronavirus 2 Spike protein, as well as lipopolysaccharide (LPS) and neurotensin (NT) used as positive controls. MMP-9 was measured by commercial enzyme-linked immunosorbent assay.

RESULTS
MMP-9 was significantly elevated in the serum of long COVID patients compared to healthy controls. Moreover, there was significant release of MMP-9 from a cultured human microglia cell line stimulated by LPS, NT, or Spike protein. We further show that pretreatment with the flavonoids luteolin and tetramethoxyluteolin (methlut) significantly inhibited the release of MMP-9 stimulated by the Spike protein.

CONCLUSIONS
MMP-9 from Spike protein-stimulated microglia could contribute to the development of long COVID and may serve as a target for treatment including the use of luteolin.

Link | PDF (Translational Neuroscience) [Open Access]

 

[SNT Gatchaman]

Patients (n = 13, 6 females and 7 males, mean age was 57 years old) were recruited from Southern Florida.

The inclusion/exclusion criteria for unrecovered individuals were fatigue, as well as one additional symptom that began after positive SARS-CoV-2 test and that the participant self-reported experiencing “a good bit of the time,” “most of the time,” or “all of the time” during the past month.

 

[Murph]

I've encountered references to matrix metalloproteinaise a few times recently.

https://en.wikipedia.org/wiki/MMP9

Its functions relate to the extracellular matrix, and [speculation follows] perhaps one reason science has struggled to find the answers to mecfs in the cell is that the issues are extracellular? JUst an idea... Here's the abstract of a recent review on metalloproteinases.

Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology
Luiz G N de Almeida 1 , Hayley Thode 1 , Yekta Eslambolchi 1 , Sameeksha Chopra 1 , Daniel Young 1 , Sean Gill 1 , Laurent Devel 1 , Antoine Dufour 2
Affiliations

• PMID: 35738680
• DOI: 10.1124/pharmrev.121.000349

Abstract
The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix.

More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix.

In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases.

There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases.


Significance Statement :
Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated.

After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.

 

[SNT Gatchaman]

Theorides in 2023 Recombinant SARS-CoV-2 Spike Protein and Its Receptor Binding Domain Stimulate Release of Different Pro-Inflammatory Mediators via Activation of Distinct Receptors on Human Microglia Cells (2023, Molecular Neurobiology) —

In this study, we show that recombinant SARS-CoV-2 full-length S protein stimulates release of pro-inflammatory IL-1b, CXCL8, IL-6, and MMP-9 from cultured human microglia via TLR4 receptor activation. Instead, recombinant receptor-binding domain (RBD) stimulates release of TNF-α, IL-18, and S100B via ACE2 signaling.

These results provide evidence that SARS-CoV-2 spike protein contributes to neuroinflammation through different mechanisms that may be involved in CNS pathologies associated with long-COVID.