How IsoPlexis’ Unique Functional Proteomics is Critical to Understanding the Vascular Effects of COVID-19
COVID-19 was first thought to be largely a disease affecting only the lungs, like pneumonia, however, recent studies report that many patients present with mysterious blood clots or strokes stemming from the virus. Additionally, painful red or purple toes surfaced as another symptom. These symptoms may suggest an issue with blood circulation. Notably, 40% of deaths resulting from COVID-19 have been ruled as cardiovascular-related, furthering the notion that this disease may potentially be primarily a vascular infection rather than a respiratory one.
Proteins Affect Every Part of the Body, From the Immune System to Inflammation and Vessel Damage
A paper recently published in The Lancet presented evidence that the SARS-CoV-2 virus has the ability to infect endothelial cells, which line the inside of blood vessels. A recent article interviewing top COVID-19 researchers stated that these cells “protect the cardiovascular system, and they release proteins that influence everything from blood clotting to the immune response. In the paper, the scientists showed damage to endothelial cells in the lungs, heart, kidneys, liver, and intestines in people with COVID-19.”1
The diverse set of symptoms from COVID-19 patients spanning the entire body makes the theory that it’s an infection in the blood vessels more likely. The symptoms doctors were seeing not only seemed unconnected, but were not typically seen in infectious diseases like SARS or H1N1:1
- Blood clots
- Kidney damage
- Encephalitis (brain swelling)
- Inflammation of the heart
When connecting these symptoms, it seems likely that it is a blood vessel virus. “[The virus] enters the lung, it destroys the lung tissue, and people start coughing. The destruction of the lung tissue breaks open some blood vessels,” Mandeep Mehra, MD, medical director of Brigham and Women’s Hospital Heart and Vascular center explains. “Then it starts to infect endothelial cell after endothelial cell, creates a local immune response, and inflames the endothelium.”1 Respiratory viruses don’t infect blood cells and then circulate throughout the body—it’s virtually unheard of.1
Authors Varga, et al. reported in The Lancet that “SARS-CoV-2 infects the host using the angiotensin converting enzyme 2 (ACE2) receptor, which is expressed in several organs, including the lung, heart, kidney, and intestine. ACE2 receptors are also expressed by endothelial cells. Whether vascular derangements in COVID-19 are due to endothelial cell involvement by the virus is currently unknown. Intriguingly, SARS-CoV-2 can directly infect engineered human blood vessel organoids in vitro.”2
Professor of Microbiology at the Icahn School of Medicine at Mount Sinai, Benhur Lee, MD, spoke about how SARS-CoV-2 and SARS are different and why the former is much more dangerous. The difference “likely stems from an extra protein each of the viruses requires to activate and spread. Although both viruses dock onto cells through ACE2 receptors, another protein is needed to crack open the virus so its genetic material can get into the infected cell. The additional protein the original SARS virus requires is only present in lung tissue, but the protein for SARS-CoV-2 to activate is present in all cells, especially endothelial cells.”1 Dr. Lee went on to add “[SARS-CoV-2] is cleaved by a protein called furin, and that’s a big danger because furin is present in all our cells, it’s ubiquitous.”1
Inflammatory Drivers of Complications in COVID-19: How Functional Phenotyping Can Reveal Insight
The Lancet article by Varga, et al. discusses several cases, one case of excess endothelium inflammation which led to multi-organ failure, two other cases involved multi-system organ failure and prominent inflammation of endothelial cells (endotheliitis).
Authors Varga, et al. report in The Lancet a buildup of inflammatory cells, viral components inside endothelial cells, and signs of inflammatory and endothelial cell death. This suggests that SARS-CoV-2 makes it easier to induce endotheliitis. “COVID-19 endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilize the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins. This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction…associated with adverse outcomes in COVID-19.”2 Functionally characterizing this inflammatory response in both COVID patients and within blood vessels will be critical to understanding the mechanisms of this inflammation as well as developing better vaccines and therapies. IsoPlexis’ single-cell proteomics and ultra-small sample solutions have been used to reveal inflammatory cytokine signatures from multiple different cell types, such as T cells, NK cells, and monocytes, patient plasma, and CSF in various studies.
IsoPlexis’ Functional Proteomics Uncovers the Mechanisms of Neurological Manifestations of COVID-19 in Patients
The ability to detect specific cytokines with single-cell proteomics or cytokines within ultra-small sample plasma and CSF is critical toward understanding disease mechanisms as well as developing vaccines and therapies. Researchers Farhadian, et al. used IsoPlexis’ functional proteomics to examine CSF and plasma from COVID-19 patients presenting with neurological complications, such as seizure and confusion, revealing unique cytokine signatures from very small sample volumes. Researchers have used IsoPlexis’ CodePlex Secretome technology to discover increased inflammation in plasma and CSF in these patients, where the SARS-CoV-2 virus was present in the plasma but not the CSF. This increase in inflammation can extend to numerous organs and being able to identify these signatures can help to develop treatments for COVID-19 and potentially prevent the associated cytokine storm response that some patients experience.
IsoPlexis’ Functional Proteomics Identified Senescent Fibroblast Proteomic Signatures in Microvessel Environment
The inflammation present in endothelial cells is significant as through blood vessels, there is a pathway for potential infection throughout the body. Because COVID-19 is being discussed as a potential blood vessel virus, it is important to be able to measure vascular cytokine signatures. In a recent study, Xiao et al used IsoPlexis’ CodePlex Secretome technology to measure these types of cytokine signatures within the microvessel environment. “Microvascularization if of pivotal importance in tissue engineering. It is controlled by a host of soluble and immobilized signals, including growth factors, cytokines, and extracellular matrix.”3 Xiao, et al. engineered senescent primary human lung fibroblasts to be a “living source of cytokines and growth factors to promote in vitro growth of microvasculature as well as demonstrate the potential applications, such as vascularizing pancreatic islets ex vivo and enhancing blood flow for wound repair in vivo.”3
This study found that “senescent fibroblasts not only accelerate the formation of microvasculature in vitro but also promote maturation and stabilization.”3 When used in vivo in wound repair in a diabetic mouse model, increased blood flow resulted. “Together, this work points to a new direction for modeling the delivery of cytokines and growth factors that promote microvascular tissue engineering and tissue repairs.”3 IsoPlexis’ CodePlex Secretome technology has been involved in identifying inflammation in COVID-19 patients, looking at cytokine signatures in microvessel environments, and IsoPlexis’ single-cell solutions have been able to uncover disease mechanisms and correlates with various cell types.
Download the Infectious Disease eBook to learn more about how the IsoLight system provides a solution for the single cell and accelerated population level functional proteomics required to overcome common challenges within infectious disease research, vaccine development, and more.
- Smith DG. Coronavirus May Be a blood Vessel Disease, Which Explains Everything. Elemental May 29, 2020.
- Varga Z, et al. Endothelial cell infection and endotheliitis in COVID-19. The Lancet 395: 1417-1418, 2020.
- Xiao Y, et al. Senescent Cells with Augmented Cytokine Production for Microvascular Bioengineering and Tissue Repairs. Advanced Biosystems 3, 1900089, 2019.