key: cord-0958136-b8tdug93
authors: Beddingfield, Brandon J.; Bix, Gregory J.
title: In the Age of CoVID: Genomic Changes Over the Lifespan Help Explain Severe SARS-CoV-2 Disease
date: 2020-10-23
journal: JACC Basic Transl Sci
DOI: 10.1016/j.jacbts.2020.10.004
sha: 9a3a815f90fd089f17024eb22393200f0497af20
doc_id: 958136
cord_uid: b8tdug93

[Figure: see text]

Angiotensin Converting Enzyme 2 (ACE2), a metalloprotease functioning in vasoactive peptide cleavage, was characterized as the entry receptor for the first Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) in 2003. It has since been implicated in the entry of the causative agent of the current pandemic, SARS-CoV-2. Along with ACE2, the serine protease TMPRSS2 was found to be needed for viral entry into host cells. With that elucidated, potentially effective therapeutic approaches for viral entry inhibition could be investigated.

Because additional receptor interactions have been implicated in host cell invasion by previous coronaviruses, other receptors have been investigated for their potential role in SARS-CoV-2 infection. Basigin (CD147) is one of the putative receptors being investigated. This receptor has some positive evidence for its role in this infection (1), even though some may disagree (2) . This lack of consensus notwithstanding, a clinical trial is in place utilizing an anti-CD147 antibody, Meplazumab, with some promising results (3) . Previous studies have also The potential entry gene BSG was found to be in higher abundance in cardiorenal tissues than in the lung, though it was well expressed in all tissues examined. This is in contrast to ACE2, which was found to be expressed at low levels in lung, but higher levels in cardiorenal tissues (kidney, heart and blood vessels) across the individuals examined. Genes responsible for processing viral spike protein or ACE2 to allow for viral entry, ADAM17 and FURIN were found to be high in lung tissue. Taken together, this could explain the higher levels of viral replication in lung tissue for SARS-CoV-2, even if the receptor itself is not highly expressed. Next, the authors explored how these genes changed with respect to age in these individuals. Individuals were categorized as under 40, and 40 years of age and above. ACE2 expression decreased linearly with age in arterial tissue, and was decreased in colon and blood, but was not differentially expressed in heart or kidney. This adds to a prior study that found decreased expression of ACE2 in the airways of children, indicating a bell curve of expression over a lifetime (5) . ACE was also reduced in the nasal epithelium in the over 40 category. By contrast, BSG expression increased with age in endothelial cells. Males also had an increased expression of BSG, PPIA, PPIB in endothelial cells, and higher levels of ACE2 and TMPRSS2 in the coronary artery. This may help explain the higher mortality seen in male patients.

The BSG/PPIA(B) pathway and its differential expression, if it does play a role in SARS-CoV-2 infection, provides a potential mechanism by which infection affects cardiovascular function, rather than this infection being one confined solely to the airways. This study highlights that the typical ACE2/TMPRSS2 receptor expression does not positively correlate to increased risk of severe CoVID-19 disease. More work must be done to elucidate the likely multitude of reasons why this is not the case, though BSG may be a part of that puzzle. 

SARS-CoV-2 invades host cells via a novel route: CD147-spike protein

No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor

Meplazumab treats COVID-19 pneumonia: an openlabelled, concurrent controlled add-on clinical trial

The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors

Airways Expression of SARS-CoV-2 Receptor, ACE2, and TMPRSS2 Is Lower in Children Than Adults and Increases with Smoking and COPD