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SARS-CoV-2 Find Other Route to Infect Cells

SARS-CoV-2, the virus that causes COVID-19, has the ability to enter cells through an alternative route other than ACE2, shows a new study.

It has been shown that SARS-CoV-2 the virus that causes COVID-19, can enter cells through an alternative route, which is not the same as ACE2.

In previous studies, scientists have shown how the novel coronavirus SARS-CoV-2 that emerged in Wuhan, China, gets into the host cells to cause infection. Like its predecessors—SARS-CoV—the novel coronavirus also uses the same ACE2 receptor to get into the cells (Li et al., 2003, Xu et al., 2020).

Most of the current vaccines were designed to block the ACE2 route so that the virus can’t get into the cells. However, the ability of the virus to use an alternative path to get into the cells increases the possibility of evading the vaccine or the antibodies that the vaccine generates.

New research from Washington University School of Medicine in St. Louis has found that a mutation gives SARS-CoV-2 the ability to enter cells via an alternative route. The discovery shows the virus, when get blocked from using its known ACE2 gate, finds new ways to get into the cells. The results are published on June 23 in Cell Reports (Puray-Chavez et al., 2021).

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Mutation and SARS-CoV-2

Mutation occurs in the genome sequence of an organism or virus. When a gene multiplies, changes may happen in the base sequences of genes, either DNA or RNA.

Environmental factors such as UV and certain chemicals are the major contributors to gene mutation, but it may occur accidentally or through the inherited evolutionary process. Once transformation happens, the mutated gene encodes new proteins with novel properties.

SARS-Cov-2’s spike protein that attaches to the ACE2 receptor of the host cells is often found to be altered due to mutation. According to WHO, at least five mutant variants have emerged since the first identification of the virus in Wuhan, China. Notable are the UK variants (alpha), South African Variants (beta), and Indian variants (delta).

In the new research, scientists from Washington University School of Medicine used a mutant variant. The virus was originally obtained from a person in Washington state with COVID-19, but the virus had acquired a mutation while growing over time in the laboratory. The mutation caused the virus a change at position 484 position of the amino acid sequence in the spike protein.

SARS-CoV-2 uses spike protein to attach to ACE2. The position 484 is a hot spot for mutations. At the same position, a variety of mutations have been found in viral variants grown in the lab, obtained from people and mice.

The viral variants that the researchers Kutluay and Major found in the lab are very similar to the mutations found in the samples taken from people. For example, the Alpha (UK) and Beta (South Africa) variants of concern have mutations at position 484, although those mutations are different.

Study Design and Major Findings

To study SARS-CoV-2, most researchers use kidney cells because the virus grows well in these cells. Also, ACE2 receptors are abundant in kidney cells like the myocardium and gastrointestinal tract cells. But the fact is, the virus SARS-CoV-2 mainly affects the lung tissue despite the low expression of ACE2 receptors compared to other cell types.

Therefore, the researchers used lung cells, considering the fact that the cells are naturally affected the most. To investigate if the mutant variant has the ability to enter lung cells using a route other than the ACE2 gate, the researchers in their investigation blocked the cells’ ACE2 receptors using ACE2-blocking antibodies.

Surprisingly, they observed differential results: ACE2 blocking antibody significantly decreased the amount of cell-associated viral RNA in Calu-3 cells, but the antibody did not impact SARS-CoV-2 viral RNA levels in H522 cells.

Next, the researchers used the gene-editing tool CRISPR and inactivated ACE2 gene locus in cell lines, Calu-3 cells, and H522 cells to confirm the results. Then, they monitored viral replication. While viral RNA levels increased at similar levels in H522, the lack of ACE2 significantly reduced SARS-CoV-2 replication in Calu-3 cells.

These data establish that the mutant variants can enter some cells even when the ACE2 receptor is not available.


The findings researchers described as serendipitous, as they discovered an alternative way to infect a human lung cell and that the virus acquired this ability via a mutation.

‘This is something we need to know more about, stated co-senior author Sebla Kutluay, Ph.D., an assistant professor of molecular microbiology.

“It is possible that the virus uses ACE2 until it runs out of cells with ACE2, and then it switches over to using this alternative pathway,” Kutluay said.

“This might have relevance in the body, but without knowing the receptor, we cannot say what the relevance is going to be.”

Major added, “That’s where we’re going right now. What is the receptor? If it’s not ACE2, what is it?”

Related Publication and Further Readings

Li, W., M. J. Moore, et al. (2003). “Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.” Nature 426(6965): 450-454.

Puray-Chavez, M., K. M. LaPak, et al. (2021). “Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell.” bioRxiv.

Xu, J., S. Zhao, et al. (2020). “Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV.” Viruses 12(2).

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