News & Views: ACE2 and COVID-19 — What We Know and What We Are Learning

Many people are aware that SARS-CoV-2, the virus that causes COVID-19, attaches to a cellular receptor, called angiotensin-converting enzyme 2 or, more commonly, ACE2. Viral attachment to ACE2 is the first of two steps necessary for cell entry and infection. The second step is fusion of the viral and cellular membranes.

So, let’s take a closer look at what is known about ACE2 biology and what that might mean for the course of COVID-19 infections.

ACE2: The basics

ACE2 is a transmembrane protein, first described in 2000. This protein is found on epithelial and endothelial cells of the upper and lower respiratory tract, heart and vasculature, kidneys, and portions of the gastrointestinal tract. It is an ectoenzyme, meaning its actions occur outside of cells. The ubiquitous nature of this receptor explains, in part, why so many different organs can be affected by SARS-CoV-2.

The gene for ACE2 is found on the X chromosome, and it maps to a quantitative trait loci (QTL) associated with hypertension.

ACE2: Its functions

The primary role of ACE2 relates to the renin-angiotensin system (RAS), where it counterbalances the effects of the first angiotensin-converting enzyme to be described, commonly referred to as ACE. The RAS system is known for its role in controlling blood pressure, primarily through the action of angiotensin II. In brief:

• ACE cleaves peptides off of angiotensin I to increase levels of angiotensin II. Angiotensin II causes increases in blood pressure through vasoconstriction and changes in the kidneys that increase blood volume.
• If levels of angiotensin II are not kept in check, it can lead to inflammation of the heart and increased fluid retention, particularly in the kidneys. Because of vasoconstriction, local tissues can become hypoxic, receiving lower levels of oxygenated blood.
• ACE2 regulates angiotensin II by further cleaving it to produce Ang 1-7. This action is vasoprotective, reducing the effects of angiotensin II on the vascular system and the kidneys.

Watch more about RAS in this video, offered by the SENS Foundation.

ACE2 also acts on a series of other proteins and peptides, including apelin-13, neurotensin, kinestensin, dynorphin, and a couple of bradykinin fragments.

ACE2 and COVID-19

A previously known human coronavirus that is a cause of the “common cold,” called NL63 (which is one of four human coronavirus strains that circulate every year in the United States), as well as both SARS-CoV and SARS-CoV-2 attach to cells via the ACE2 receptor. While each binds to ACE2, their spike proteins have genetic differences that can result in different binding affinities. Indeed, a comparison of SARS-CoV and NL63 showed the former had greater binding capacity than the latter. However, a second difference may also be important to the infection-related differences among these viruses. SARS-CoV-2 has a cleavage site on the spike protein that has not been detected for SARS-CoV, but which may allow for infection of a wider array of cell types.

These differences can result in a divergence of clinical manifestations. For example:

• The increased ability of SARS-CoV-2 to infect cells in the upper respiratory tract, like ciliated nasal and bronchial epithelial cells, compared with SARS-CoV, means an infected person can more easily transmit the virus prior to developing symptoms, which tend to occur once the infection reaches the lower respiratory tract.
• The loss of smell is also theorized to be the result of the increased array of cells that are susceptible to SARS-CoV-2. Sustentacular cells associated with the olfactory epithelium have both ACE2 and a protease associated with viral and cellular membrane fusion, known as transmembrane protease serine 2 or TMPRSS2.

As a viral infection progresses, part of the immune response often includes down-regulation of cell surface receptors involved in the infection. In this case, a down-regulation of ACE2 receptors can negatively impact the balance of RAS, leading to increased levels of angiotensin II and its effects on the vascular system, including rises in blood pressure, increases in blood and fluid volumes, and upregulation of inflammatory responses, including related cytokines and complement pathways. These effects can contribute to subsequent tissue damage, such as lung damage caused by the breakdown of epithelial-endothelial barriers. The timing of some of the symptoms associated with these effects aligns with the later, or second, more severe phase of infection experienced by some patients.

Related to the gastrointestinal tract, the presence of ACE2 receptors is also likely to account for symptoms, such as nausea and diarrhea; however, despite about 30% of patients having detectable viral RNA, transmission via the fecal-oral route appears to be minimal.

As we continue learning more about the clinical outcomes and experiences associated with COVID-19 infection, we are likely to also continue learning more about ACE2, which will be important, given that it appears to be a popular destination for coronaviruses looking to survive by infecting humans.