After ACE2 receptors, NRP1 emerges as another pathway for COVID-19 virus to enter the human body

By now we all know that the COVID-19 causing novel coronavirus, SARS-CoV-2, enters the human body through the nose, mouth or eyes. It is also well established that the virus binds with ACE 2 receptors on the lungs, blood vessels and other parts of the body, to infect healthy cells. Now, researchers have found yet more ways the SARS-CoV-2 virus can enter healthy cells in the body, and cause this respiratory disease.

Two separate and independent researches from Europe have found yet another way the new coronavirus, that first originated in Wuhan, China in late 2019, enters human cells, infects them and begins to replicate in the human body.

Viral entry is the earliest stage of infection which happens through adsorption, the process of how a host cell that holds a receptor a virus can attach itself to, in order to fuse with the host cell. The virus then blends with the membrane of the cell to release its infectious contents and begins to multiply.

A protein on the surface of human cells, known as ACE2 receptors, is the gateway for the SARS-CoV-2 virus entering the human body. But new research emerging from two separate studies indicates another cell-surface protein, known as neuropilin-1 or NRP1, may be another potential gateway from where the virus can break into the cell and attach itself in a fashion similar to how it happens to the ACE2 receptors. (Read more: Role of ACE2 receptors in COVID-19)

Both studies have been carried out in Europe and have been published online on the preprint server BioRxiv, and provide more evidence on the rapid spread of the COVID-19 infection that has gripped countries all over the world. More than 7.6 million people have been affected globally by this infection and over 425,000 people have died around the world, with India also facing a spike in the number of cases in recent months, having become the fourth-most affected country in the world.

What are NRP1 receptors?
The role of NRP-1 receptors in COVID-19

What are NRP1 receptors?

Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) are a type of glycoproteins that help in the development of the cardiovascular and central nervous systems. They serve as receptors for the atrial and brain natriuretic peptide. Natriuretic means getting rid of excess sodium through urine, and natriuretic peptides are hormones that tell the kidneys to do this.

According to an article published in Frontiers in Immunology, NRP1 receptors are said to be involved in various biological processes including cell survival, cell migration, neuronal development or the development of neurons, as well as the development of new blood vessels also known as angiogenesis.

Neuropilin-1 is also known to be a target for anti-cancer therapies by regulating the development of endothelial cells, the thin layer of squamous cells lining the surface of blood and lymphatic vessels.

Experiments done on human cells in laboratories have found that an antibody that can bind to the surface of NRP1 can also prevent the SARS-CoV-2 virus from binding and prevent the eventual infection. (Read more: Passive antibody therapy)

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The role of NRP-1 receptors in COVID-19

Since the time of the outbreak of COVID-19, researchers have more or less zeroed in on the role of the ACE2 receptors in the spread of the new coronavirus infection in humans. ACE2 is a protein on the surface of many cells in the human body, and an enzyme that regulates the functions of the cells.

The spike-like protein structure on the surface of the SARS-CoV-2 virus can bind to the ACE2 receptors, to enter and infect healthy cells. And because the ACE2 receptors are mainly located in the lungs, kidneys, liver, heart, blood vessels and the gastrointestinal tract, it has been known to cause all the symptoms associated with the disease thus far.

However, according to the two new studies, the NRP1 is also a protein that has a spike-like structure which the SARS-CoV-2 virus binds itself to as a potential gateway, to break into the cell and replicate quickly to infect the human body.

Researchers in the study titled "Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system" generated replication-deficient lentiviruses "pseudotyped with SARS-CoV-2 spike protein" to determine whether the new coronavirus used NRP1 for entry into human cells. Samples of the virus were isolated from COVID-19 patients admitted at the Helsinki University Hospital in one study.

The study confirmed that while a majority of research into the spread of the infection thus far has focused on the role of ACE2 receptors, viruses like SARS-CoV-2 can use multiple routes to infect the human body. The researchers did establish that NRP1 receptors can also act as an entry point for the virus, but there is more work needed to understand how the NRP1 receptors facilitate the entry of the SARS-CoV-2 virus.

The second study, titled "Neuropilin-1 is a host factor for SARS-CoV-2 infection", further explains how the structure of neuropilin-1 and NRP2 receptors enable entry and subsequent mutation of the SARS-CoV-2 virus in the human body.

The C-end Rule (CendR) is the structural process of how a receptor-binding domain functions when a pathogen binds to the cellular surface of the body—CendR is also seen repeated in the case of the SARS-CoV-2 virus binding with the NRP1 and NRP2 receptors.

The study suggests that "the SARS-CoV-2 S-protein binds to cell surface receptor NRP1 via the S1 CendR motif generated by the furin cleavage of S1/S2. This interaction promotes infection by SARS-CoV-2 in physiologically relevant cell lines widely used in the study of COVID-19." Basically, the S proteins on this new coronavirus can also bind with NRP1 to cause infection. For this to happen, the S protein has to be cleaved or cut properly to form this S1 CendR.

The C-terminus is the end of an amino acid chain which constitutes proteins or peptides, explaining the structure of proteins and it is this tail-end of the structure that the SARS-CoV-2 virus—in this case—is able to latch on to. Once the virus enters the cell, it activates the formation of proteins to suppress or disable the defence mechanism of cells.

The study was also able to conclude that due to this process, "neuropilins are emerging targets in the urgent research and treatment of COVID-19," which means more research could be dedicated to the development of drugs and vaccines against COVID-19.