The new coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused severe morbidity and mortality across the world. In addition to the flu-like symptoms of respiratory disease, infection with SARS-CoV-2 can also cause systemic manifestations, leading to a wide range of pathologies, including thrombosis and microvascular damage and stroke, disturbance of the vascular system, gastrointestinal complications, ocular and dermatological symptoms cardiac and renal pathologies, neurological manifestations, male infertility and Kawasaki-type blood and cardiac disorders in children.

A serious and often fatal immune response called a “cytokine storm” can occur following infection with SARS-CoV-2. Some patients suffer from a series of complications several months after testing negative for SARS-CoV-2, and this is called COVID-19 “ Long Distance ” or “ Long ”. The causes of this phenomenon are not well understood.

The human ACE2 receptor and its role in the entry of SARS-CoV-2 into host cells

Angiotensin-converting enzyme 2 (ACE2), the main entry receptor for SARS-CoV-2 in human cells, also plays a role in the regulation of blood pressure and vasodilation by the renin system. angiotensin and protein digestion in the intestine. Binding of SARS-CoV-2 to ACE2 leads to downregulation of ACE2 function, which may be associated with systemic damage.

“The angiotensin-converting enzyme 2 (ACE2) is of obvious interest because it is a primary receptor for entry of SARS-CoV-2 into human cells.”

Elevated levels of soluble ACE2 have been found in critically ill COVID-19 patients, explaining the reduced expression of membrane-bound ACE2. According to a recent study, sACE2 may have a role in the entry of SARS-CoV-2 via other receptors.

Unidirectional reciprocal rank ACE2 network (URR). The 10 major unidirectional ERC proteins of ACE2 for a reciprocal rank connection network (RR20). The network is particularly enriched for cytokine signaling and immunity. Highly interconnected proteins include COL4A5, F5, GEN1, and IFNAR2. ACE2 is highlighted in purple and the intensity of the blue shading indicates the level of reciprocal connectivity for different proteins.

A new approach – evolutionary inference – to understand protein-ACE2 interactions

A better understanding of the type of proteins with which ACE2 interacts may shed light on disease manifestations and potential treatment pathways. American researchers have tried a new approach to predict candidate proteins interacting with ACE2. They used evolutionary inference to identify a group of mammalian proteins that “co-evolve” with ACE2. This study is published on the bioRxiv* pre-print server.

The new approach is called evolutionary rate correlation (ERC), and it detects proteins with highly correlated evolution rates in mammalian evolution. These proteins may be good candidates for biological interactions with ACE2.

Overall, the concept behind the concept of evolutionary rate coevolution (also known as evolutionary rate covariance or evolutionary rate coevolution) is that coevolutionary proteins will show correlated rates of change through evolution and that this reflects functional interactions.

The approach revealed many fundamental ACE2-protein interactions that may be relevant for COVID-19 pathologies. While some proteins reported to be related to severe COVID-19 are currently not known to interact directly with ACE2, some other new proteins interacting with ACE2 may be relevant for COVID-19.

ACE2 has strong links to coagulation pathway proteins relevant to COVID-19 pathologies

Using reciprocal rankings of protein RCTs, researchers identified highly interconnected protein networks associated with ACE2 that are relevant to COVID-19 pathologies. The results show that ACE2 has strong links with proteins in the coagulation pathway, including coagulation factor V and the fibrinogen components FGG, FGB and FGA.

Components of fibrinogen can mediate through ACE2 connections to clusterin, which removes misfolded extracellular proteins, and to GPR141, the functions of which are relatively unclear.

SARS-CoV-2 disrupts new protein-ACE2 interactions contributing to COVID-19 pathologies

In addition, ACE2 has links with proteins that are part of cytokine signaling and the immune response such as IFNAR2, XCR1 and TLR8, and with the androgen receptor. The ERC pre-screening approach also clarified the potential functions of some previously uncharacterized proteins and additional functions for some already well characterized proteins.

The study also discussed validation approaches for ACE2-interacting proteins predicted by ERC. The authors propose that infection with SARS-CoV-2 disrupts new protein interactions of ACE2, which contributes to the wide range of COVID-19 pathologies.

“Finally, if it is proven that RCTs can be informative in predicting protein interactions, the approach can be applied more widely as an additional tool to detect protein interaction networks involved in biological processes and diseases. . “

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behaviors, or be treated as established information.