The interest in our webinar, “An evidence-based approach to oncology patients during the COVID-19” was so tremendous that we have decided to post a series of related articles to help further the discussion. We at NantHealth will try to provide as much clarity about COVID-19 as possible, and this ongoing blog gives us a unique opportunity to delve into more in-depth answers to questions we received as a follow-up to the webinar.
Today, I will provide more background about the basic science of the virus – to provide everyone with a foundation to build on as we discuss prevention and treatment strategies in future blogs. Let’s get started with the official name of the virus: SARS-COV2, or Severe Acute Respiratory Syndrome Coronavirus 2, and is believed to have originated as a bat coronavirus that has crossed over into humans. It is a single-stranded RNA virus (as opposed to double-stranded DNA). Other single-stranded RNA (ssRNA) viruses that are well known include hepatitis virus C, West Nile virus, dengue virus, SARS and MERS coronaviruses, and rhinovirus (the virus that causes the common cold).
Unlike bacteria, these viruses are technically not alive. They instead hijack the host cell, and their genetic material can function both as a genome and as messenger RNA (it can be directly translated into protein). The coronavirus genome encodes four major structural proteins: the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein. The virus then replicates itself many times and can be released to infect new cells and new hosts. One particular protein is the spike protein, or S-protein, which sticks out and forms the crown that is seen on electron microscopy, which gives it the name coronavirus (corona = crown).
The entry receptor utilized by SARS-CoV is Angiotensin-Converting Enzyme 2 (ACE2), which means that the virus must bind to this protein on the host cell in order to gain entry and cause infection. ACE2 is similar to ACE, an enzyme long-known to be a key player in the Renin-Angiotensin system (RAS) and a target for the treatment of hypertension. It is mainly expressed in the lung, heart, and kidney, where ACE-2 has also been shown to exhibit a protective function in the cardiovascular system and other organs.
Typically, in response to low blood pressure, the kidney will secrete renin into the blood circulation. Renin then converts angiotensinogen (produced by the liver) into angiotensin 1. ACE (mostly in the lung) converts Angiotensin 1 into Angiotensin 2. ACE2 receptors bind the ACE2, which then stimulates blood vessels to constrict, causing the blood pressure to increase. Angiotensin 2 also stimulates the release of aldosterone from the adrenal gland. Aldosterone stimulates the kidneys to increase sodium retention, water retention, and potassium loss. This increases blood pressure as well. This is why these are good targets for drugs to decrease blood pressure.
In SARS-CoV2 infection, the ACE2 is grabbed by the virus spike protein, and clinical cases have been associated with low potassium. It is unknown whether ACE inhibitors (drugs like captopril, benazepril, enalapril, lisinopril, etc.) might increase the risk or severity of SARS-CoV2. Still, the theoretical mechanism is that ACE inhibitors decrease the amount of Angiotensin 2 in the circulation and so the body compensates by increasing the amount of ACE2 receptors. In the lung, this could create a good environment for the virus with high amounts of the receptor for the spike protein and low amounts of the angiotensin to compete with the spike protein for receptor binding.
Another class of drugs, Angiotensin Receptor Blockers (ARBs) may theoretically be beneficial through tissue-protective effects of these drugs and lower ACE2 expression. A joint statement from the American College of Cardiology (ACC), American Heart Association and Heart Failure Society of America was posted online on March 17 and basically states that patients should consult their physician regarding these medications given the lack of trial data and experience with the virus.
The take-home point is that if another drug is available to treat hypertension, then probably during the current pandemic, it would be best to stay away from the ACE inhibitor category. The ARB category is likely safe and may even be helpful, but we just don’t know enough yet. In our next blog post, we will look more closely at viral replication and treatment strategies aimed at this mechanism.