Posts Tagged ‘ACE2’

Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells

Reporter: Adina Hazan, PhD


Kaneko, et al.  from UCLA aimed to explore why SARS-CoV-2 infection is associated with an increased rate of cerebrovascular events, including

  • ischemic stroke and
  • intracerebral hemorrhage

While some suggested mechanisms include an overall systemic inflammatory response including increasing circulating cytokines and leading to a prothrombotic state, this may be only a partial answer. A SARS-CoV-2 specific mechanism could be likely, considering that both angiotensin-converting enzyme-2 (ACE2), the receptor necessary for SARS-CoV-2 to gain entry into the cell, and SARS-CoV-2 RNA have been reportedly detected in the human brain postmortem.

One of the difficulties in studying vasculature mechanisms is that the inherent 3D shape and blood flow subject this tissue to different stressors, such as flow, that could be critically relevant during inflammation. To accurately study the effect of SARS-CoV-2 on the vasculature of the brain, the team generated 3D models of the human middle cerebral artery during intracranial artery stenosis using data from CT (computed tomography) angiography. This data was then exported with important factors included such as

  • shear stress during perfusion,
  • streamlines, and
  • flow velocity to be used to fabricate 3D models.

These tubes were then coated with endothelial cells isolated and sorted from normal human brain tissue resected during surgery. In doing so, this model could closely mimic the cellular response of the vasculature of the human brain.

Surprisingly, without this 3D tube, human derived brain endothelial cells displayed very little expression of ACE2 or, TMPRSS2 (transmembrane protease 2), a necessary cofactor for SARS-COV-2 viral entry.


  • horizontal shear stress increased the expression of ACE2 and
  • increased the binding of spike protein to ACE2, especially within the stenotic portion of the 3D model.

By exposing the endothelial cells to liposomes expressing the SARS-CoV-2 spike protein, they also were able to explore key upregulated genes in the exposed cells, in which they found that

  • “binding of SARS-CoV-2 S protein triggered 83 unique genes in human brain endothelial cells”.

This included many inflammatory signals, some of which have been previously described as associated with SARS-COV-2, and others whose effects are unknown. This may provide an important foundation for exploring potential therapeutic targets in patients susceptible to cerebrovascular events.

Overall, this study shows important links between the

  • mechanisms of SARS-CoV-2 and the
  • increase in ischemic events in these patients. It also has important implications for
  • treatment for SARS-CoV-2, as high blood pressure and atherosclerosis may be increasing ACE2 expression in patients, providing the entry port for viral particles into brain endothelia.



Other related articles published in this Open Access Online Scientific Journal include the following:

The Impact of COVID-19 on the Human Heart

Reporters: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN



SAR-Cov-2 is probably a vasculotropic RNA virus affecting the blood vessels: Endothelial cell infection and endotheliitis in COVID-19

Reporter: Aviva Lev-Ari, PhD, RN – Bold face and colors are my addition



Diagnosis of Coronavirus Infection by Medical Imaging and Cardiovascular Impacts of Viral Infection, Aviva Lev-Ari, PhD, RN  Lead Curator – e–mail: avivalev-ari@alum.berkeley.edu

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Novel SARS-CoV-2 sybodies

Reporter: Irina Robu, PhD

Absolute Antibody Ltd., a leader of the market in recombinant antibody products announced a partnership with University of Zurich to offer synthetic nanobodies against the receptor binding domain (RBD) of SARS-CoV-2. Under the partnership, the original nanobodies and recently engineered formats are now accessible to the global research community for use as serological controls and in COVID-19 therapeutic development. The synthetic nanobodies hold a particular potential for the development of inhalable drugs, which could suggest a convenient treatment option for the COVID-19 pandemic.

The laboratory of Markus Seeger at University of Zurich designs a rapid in vitro selection platform to generate synthetic nanobodies, sybodies, against the receptor binding domain (RBD) of SARS-CoV-2. Within a two-week timeframe, the lab had recognized more than 60 unique anti-RBD sybodies from combinatorial display libraries. The sybodies are “designed to mimic the natural shape diversity of camelid nanobodies, consequently allowing for an optimal surface complementarity to the limited hydrophilic epitopes on membrane proteins. Due to their high thermal stabilities and low production costs, sybodies demonstrate a promise for diagnostic and therapeutic applications.

Sybodies are perfectly suited to trap intrinsically flexible membrane proteins and thereby facilitate structure determination by X-ray crystallography and cryo-EM. Additional research indicate that six of the sybodies bound SARS-CoV-2 spike protein with very high affinity, while five of those also inhibited ACE2, the host cell receptor to which SARS-CoV-2 binds to initiate the COVID-19 infection. Furthermore, two of the sybodies can at the same time bind the RBD, which could permit the construction of a polyvalent antiviral drug. The SARS-CoV-2 sybodies are therefore valuable tools for coronavirus research, diagnostics and therapeutic development.

Moreover, Absolute Antibody has used antibody engineering to fuse the nanobodies to Fc domains in different species, isotypes and subtypes. Absolute Antibody also offers supporting coronavirus research such as the production of gram quantities of human antibodies sequenced from recovering COVID-19 patients.




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Placenta lacks molecules required for COVID-19 infection

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected more than 10 million people, including pregnant women. To date, no consistent evidence for the vertical transmission of SARS-CoV-2 has been found. The placenta serves as the lungs, gut, kidneys, and liver of the fetus. This fetal organ also has major endocrine actions that modulate maternal physiology and, importantly, together with the extraplacental chorioamniotic membranes shield the fetus against microbes from hematogenous dissemination and from invading the amniotic cavity.


Most pathogens that cause hematogenous infections in the mother are not able to reach the fetus, which is largely due to the potent protective mechanisms provided by placental cells (i.e. trophoblast cells: syncytiotrophoblasts and cytotrophoblasts). Yet, some of these pathogens such as Toxoplasma gondii, Rubella virus, herpesvirus (HSV), cytomegalovirus (CMV), and Zika virus (ZIKV), among others, are capable of crossing the placenta and infecting the fetus, causing congenital disease.


The placental membranes that contain the fetus and amniotic fluid lack the messenger RNA (mRNA) molecule required to manufacture the ACE2 receptor, the main cell surface receptor used by the SARS-CoV-2 virus to cause infection. These placental tissues also lack mRNA needed to make an enzyme, called TMPRSS2, that SARS-CoV-2 uses to enter a cell. Both the receptor and enzyme are present in only miniscule amounts in the placenta, suggesting a possible explanation for why SARS-CoV-2 has only rarely been found in fetuses or newborns of women infected with the virus, according to the study authors.


The single-cell transcriptomic analysis presented by the researchers provides evidence that SARS-CoV-2 is unlikely to infect the placenta and fetus since its canonical receptor and protease, ACE2 and TRMPSS2, are only minimally expressed by the human placenta throughout pregnancy. In addition, it was shown that the SARS-CoV-2 receptors are not expressed by the chorioamniotic membranes in the third trimester. However, viral receptors utilized by CMV, ZIKV, and others are highly expressed by the human placental tissues.


Transcript levels do not always correlate with protein expression, but the data of the present study indicates a low likelihood of placental infection and vertical transmission of SARS-CoV-2. However, it is still possible that the expression of these proteins is much higher in individuals with pregnancy complications related with the renin-angiotensin-aldosterone system, which can alter the expression of ACE2. The cellular receptors and mechanisms that could be exploited by SARS-CoV-2 are still under investigation.
















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The Seasonality of COVID-19

Reporter: Irina Robu, PhD

There are several similarities between SARS-CoV-2 and SARS-CoV, because both viruses share a high degree of homology to SARS-like coronaviruses isolated from bats. The entire genome of SARS-CoV-2 has 86% similarity with SARS-CoV. COVID-19, SARS-CoV-2 has a higher transmissibility than SARS-CoV, where more patients with COVID-19 have mild symptoms that contribute to spread because the patients are usually missed and not isolated.

Even in terms of disease dynamics, the similarities include transmission route via respiratory droplets. The angiotensin-converting enzyme 2 (ACE2), found in the lower respiratory tract of humans, has been identified as the receptor used for cell entry for both SARS-CoV and SARS-CoV-2.

So even though the viruses seem similar, there are some strong differences as well. Patients reports from China, Europe and United states show that some patients have also cardiac issues. The scientist do not truly understand what is happening at this point, whether people are having heart attacks (myocardial infarction) or whether the virus is actually invading the heart tissue to cause inflammation (myocarditis)

The great concern is that many people are asymptomatic with this condition, have no symptoms. This is what makes the virus so complicated is because you can have a group of patients severely sick and in the intensive care unit and in some cases, there are older individuals and some with underlying diabetes and heart disease, hypertension, renal disease.

Even though, the US has a large number of cases of over one million and at least 84,000 deaths, but due to undertesting, the true numbers of cases are probably far higher. The big unknown is that there is no clear understanding what is going to happen in the next coming months or years with the virus. However, the investigation models indicate that the virus has a probably of returning seasonally in the coming years.

Yet, people have to be mindful and recognize that even if we begin relaxing social distancing and transmission diminishes, that it could come back in these periodic waves, as suggested by the model.




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