The Physiology of COVID-19

The Physiology of COVID-19

Physiologists are at the forefront of research that advances understanding of how COVID-19 attacks the body and the ways to prevent the damage it causes.

By Lauren Arcuri

The world has been in the grip of the novel coronavirus pandemic most of the year. The effects from the SARS-CoV-2 crisis on human health, health care systems and the global economy have been profound.

As U.S. states opened back up this summer, COVID-19 cases continued to rise, while researchers were working furiously to understand the virus better. Scientists need to learn more about the mechanisms of infection and the specific ways the disease exerts its deleterious effects on the physiology of the body, in hopes that they can thwart its damage and save more lives.

The major cause of mortality from COVID-19 is acute respiratory failure from acute respiratory distress syndrome (ARDS), but according to Mark Chappell, PhD, a number of patients with the disease are showing cardiovascular issues such as congestive heart failure, cardiac arrhythmias and vascular thrombosis, as well as brain dysfunction. Chappell is professor in the Cardiovascular Sciences Center at Wake Forest School of Medicine in Winston-Salem, North Carolina. He and his coauthors wrote on this subject in a May article in American Journal of Physiology-Heart and Circulatory Physiology. Research is mounting that the consequences of COVID-19 are more complex than they may have seemed at first blush, with wide-ranging effects on multiple physiological systems.

Enter SARS-CoV-2

Viruses must enter the cells of their hosts—which can be humans—in order to make copies of themselves. The copies are then released by the host cells and enter into circulation in the body, infecting still more cells. Then they travel into the world again via host emissions such as respiratory droplets, infecting new people. Researchers have learned that coronaviruses in the SARS family, including SARS-CoV-2, essentially “hijack” the protein angiotensin-converting enzyme-2 (ACE2) to allow them to gain entry into the cells in the lungs, heart, vasculature, brain and other tissues.

The viral coat of SARS-CoV-2 expresses a protein called SPIKE or S protein that contains a region that binds to the extracellular domain of ACE2. The virus uses this SPIKE protein to gain entry into the cell by binding to the ACE2 receptor. “That becomes really important,” Chappell says, “because if you could somehow block or downregulate the ACE2 receptor completely, then SARS-CoV-2 would not be infectious anymore.”

Several investigators have postulated that blocking ACE2 could be one way to prevent SARS-CoV-2 virus infection. However, the issue is that ACE2 is not merely a receptor for the SARS family of viruses, Chappell says. It’s an important enzyme found in most tissues in the human body. ACE2 belongs to an endocrine system called the renin-angiotensin-aldosterone system, or RAAS. This system has been the focus of Chappell’s research for 30 years.

Therapies used clinically to treat hypertension act directly on two components of the RAAS: angiotensin-converting enzyme (ACE), which generates angiotensin II (ANG II), and the angiotensin type 1 receptor (AT1 receptor). “The production of ANG II and the subsequent binding of ANG II to its receptor are thought to promote all the deleterious effects of the RAAS,” Chappell says. Those include increases in blood pressure, inflammatory events and fibrosis. “So you can target the RAAS with an ACE inhibitor which prevents production of ANG II, or you can block the AT1 receptor with various antagonists which attenuates the actions of ANG II. Those are the two main clinical therapies we have to reduce blood pressure, although recently AT1 receptor antagonists are combined with other antihypertensive drugs.”

When ACE2 was first discovered, researchers thought it would be similar to ACE and generate ANG II. They were surprised to discover that despite their similar structure, it has the opposite effect and metabolizes or destroys ANG II. “ACE2 is actually beneficial for our cardiovascular system,” Chappell explains. It degrades ANG II so it can’t activate the pathways associated with cardiovascular disease. What’s more, in the process of degrading ANG II, it forms angiotensin 1–7, or Ang-(1–7), which is also beneficial for the cardiovascular system. Ang-(1–7) is antifibrotic, lowers blood pressure and is anti-inflammatory.

As the SARS-CoV-2 complex is internalized by our cells, this removes ACE2 from the outside of cells, allowing ANG II to build up and lowering the levels of Ang-(1–7). “If there’s a high ratio of ANG II to Ang-(1–7) we think that’s actually bad for the cardiovascular system and likely bad for pulmonary function, heart function, kidney function and particularly for COVID-19 patients,” Chappell says. “The reduction of ACE2 may be contributing to the deleterious effects of viral infection.”

On the flip side, if a therapy could be found that would create a higher ratio of Ang-(1–7) to ANG II, that could be beneficial, according to Chappell. “That has been shown to have beneficial actions in some pulmonary diseases like ARDS, which has affected many COVID-19 patients,” he says. “And Ang-(1–7) has also been shown to have protective or beneficial actions in terms of the heart and the kidney, vascular system and brain.”

But this means, he cautions, that blocking ACE2 to try to prevent SARS-CoV-2 infection runs the risk of increasing ANG II and lowering Ang-(1–7), which would have negative effects on the cardiovascular system.

Another problem that has been revealed with COVID-19 infection is that older people who have cardiovascular disease and hypertension appear to have greater incidence of mortality from COVID-19. Some physicians have raised concern that being on an ACE inhibitor or angiotensin receptor blocker (ARB) could make this population more susceptible to SARS-CoV-2 infection.

Chappell thinks that patients should stay on their medications. “It is important for COVID-19 patients to remain on these antihypertensive medications because it may actually reduce the extent of inflammation and cell damage in these patients in addition to, obviously, controlling their hypertension,” he says. He also emphasizes that so far there is no clinical data showing that people on an ACE inhibitor or an ARB show a greater incidence of COVID-19 infection and there is some evidence that COVID-19 patients on ACE inhibitors or ARBs may exhibit less severe effects of the infection.

There is a lot that researchers still don’t know, but they do know that ACE2 is widely expressed in the brain and that the blood-borne SARS-CoV-2 virus may target brain ACE2 receptors to cause central nervous system infections. Chappell says it could also travel along afferent nerves from peripheral sites in the body into the brain. As more clinicians are reporting neurological symptoms in patients with COVID-19, learning more about ACE2 and how SARS-CoV-2 affects the central nervous system is an emerging focus.

Clues to Therapy

Many patients with severe COVID-19 complications are diagnosed with ARDS, a condition in which fluid collects in the distal air spaces (alveoli) of the lungs, depriving organs of oxygen. Viral pneumonia has been a well-recognized cause of ARDS, but the type of ARDS that COVID-19 causes has some features that seem to be unique.

Michael Matthay, MD, FAPS, is a pulmonologist and critical care physician at the University of California, San Francisco (UCSF), who studies acute respiratory failure from ARDS and from sepsis. He has turned his attention to ARDS in COVID-19. “There’s a lot to learn about the mechanisms of injury that might be specific to SARS-CoV-2, but it should be emphasized first that many of the features of SARS-CoV-2 ARDS are really very similar to ARDS from other causes,” he says. “The patients have severe hypoxemia, reduced lung compliance, elevated pulmonary dead space and associated non-pulmonary organ failure.”

In May, a New England Journal of Medicine study compared postmortem, gross and microscopic pathology reports of deceased patients who had COVID-19 ARDS to similar histology and pathology reports from patients who had died from influenza-related pneumonia. It piqued Matthay’s interest. “One of the features that seemed to be more characteristic of COVID-19 lung injury is that it is perhaps related more to pulmonary vascular injury” than lung injury from influenza or other viruses, he says. “And there is more evidence of alveolar capillary microthrombi as well as thrombi in other vessels.”

This feature is reflected in the complications seen in other body systems with COVID-19—there appears to be a greater incidence of events related to blood clots (prothrombotic), ranging from clotting of dialysis lines to venous thrombosis to strokes. “There seems to be a procoagulant feature of this illness that may be related to endothelial injury,” Matthay says. “It certainly seems to be occurring more frequently in patients who have elevated plasma D-dimers,” which are fragments produced when clots degrade.

Thus, one potential treatment strategy that has been of interest to researchers is the possibility of giving full-dose anticoagulants. Matthay says most patients are on a prophylactic dose. However, there is a concern that this could lead to an increase in bleeding events. “My view is that this may not be sufficient because it may not attack or manage adequately the primary mechanisms for vascular injury,” he says. “We may need more novel therapies that actually work at the level of trying to attenuate the lung vascular injury.”

In a March 2020 article in Physiological Reviews, Matthay and colleagues explored the elevated plasminogen and plasmin seen in COVID-19 patients that they think may be associated with the comorbidities that patients have, such as diabetes and possibly hypertension. Plasminogen is a precursor of plasmin, a critical enzyme found in the blood that degrades blood plasma proteins, including fibrin clots, in a process called fibrinolysis. “It’s possible that this ties into the hyperfibrinolysis associated with plasmin levels that lead to elevated D-dimers,” he says. “Theoretically, the plasminogen system could be a target for therapy.” Plasmin may cleave the spike proteins of SARS-CoV-2, increasing its ability to hijack the ACE2 receptor and invade cells. This may be why patients with these comorbidities have worse outcomes with COVID-19.

Another target could be the mechanisms that are activated and cause endothelial injury, such as angiopoetin-2 (Angpt2). “One area of particular interest to us and other investigators is the angiopoetin-2 system,” Matthay says. “It was reported by our research group in 2006 and in follow-up studies from us and others to be a very good plasma biomarker of poor prognosis in sepsis and ARDS and also a mediator of lung and systemic injury.” Therapies that inhibit the effects of Angpt2 might then decrease the injury to the vascular epithelium.

Other approaches to mitigate ARDS-induced lung damage and help lungs heal from the ravages of COVID-19 are also being investigated. Matthay and colleagues are currently enrolling a Phase 2b clinical trial at UCSF and other locations around the U.S. to test whether intravenous doses of mesenchymal stromal cells (MSCs)—a type of cell from bone marrow, adipose tissue or umbilical cord—can help heal the lungs of COVID-19 patients suffering from ARDS. MSCs reduce injury to the lung and seem to enhance recovery time. Results from a phase 2b efficacy trial should be available in 12 to 18 months.

Targeting the Plasmin(ogen) System

Matthay’s article about plasmin enhancing the virulence of SARS-CoV-2 and increasing fibrinolysis inspired Brant Wagener, MD, PhD, an anesthesiologist and critical care physician at the University of Alabama at Birmingham (UAB), and coauthor Andrew Barker, MD, an anesthesiologist and intensivist at UAB, to brainstorm ideas for therapies that may target this system.

“A senior investigator in our department, Timothy Ness, came to me with an idea that we’re working on together,” Wagener says. “We use a drug in the operating room all the time to stop bleeding, called tranexamic acid, or TXA. It prevents the conversion of plasminogen to plasmin.” Since it’s thought that plasmin is one of the proteases that may cleave various sites of the virus—making it more likely to infect patient cells and become more virulent—theoretically, with less plasmin, the infectivity of the virus may be reduced. “That would give the patient’s own immunity time to catch up and kill off the virus before it can get too far,” Wagener says. The trial will use TXA in the early stages of COVID-19 and in patients who have comorbidities such as diabetes and hypertension that put them at higher risk of serious complications from the virus.

Currently, Wagener, Ness and Sonya Heath, MD, an infectious disease specialist also at UAB, are recruiting patients for a TXA clinical trial. They’re specifically looking for patients shortly after diagnosis to administer five days of TXA and hopefully prevent hospitalization. Because TXA could potentially promote clotting, patients in the trial will concurrently have anticoagulation therapy. “We also use TXA in orthopedic surgeries, which are some of the highest-risk surgeries in terms of forming clots. When we use it in those patients, it doesn’t increase the amount of clots we see, but because this is COVID-19, and there’s a lot we still don’t know about this infection, we’re playing it safe,” Wagener says.

As of July, the first cases had been enrolled. The trial is ongoing, with results expected later this year, according to Wagener.

SARS-CoV-2 and the Blood-brain Barrier

The novel coronavirus can travel to the brain, too. More studies are being published that document neurological and neuropsychiatric symptoms in COVID-19 patients. These include dizziness, loss of equilibrium, problems with motor function, delirium and confusion, as well as vascular issues such as strokes and autoimmune responses such as Guillain-Barré syndrome. Researchers are scrambling to determine exactly how SARS-CoV-2 gets to the brain and what happens once it is there.

Dao Ho, PhD, a biomedical research physiologist at Tripler Army Medical Center in Honolulu, studies how SARS-CoV-2 affects the blood-brain barrier, which helps protect the brain from harmful substances. She is modeling the blood-brain barrier using a technology called electric cell-substrate impedance sensing (ECIS), in which brain microvascular endothelial cells are cultured on a plate outfitted with electrodes. These endothelial cells form the barrier by linking together with junction proteins that function much like bridges, holding the cells tightly to each other. The ECIS system uses the plate containing electrodes to detect the resistance of an electrical current through the layer of cells. Lower resistance means a leakier barrier, while higher resistance means tighter junctions, or spaces, between cells and fewer leaks. Applying a toxicant, drug or the spike proteins from SARS-CoV-2, Ho can test how the substance affects the function of this barrier layer.

Her research is not yet published, but what she and her team are finding suggests that the interaction of the spike proteins from SARS-CoV-2 with the endothelial cells in the blood-brain barrier may be initiating an inflammatory response. Once the response is underway, cytokines and other inflammatory markers that are elevated in COVID-19, such as interleukins and tumor necrosis factor alpha (TNFα), may induce leakiness in the blood-brain barrier.

“It becomes a feedback loop because once the inflammatory response is initiated in these cells, the cytokines work to reduce the expression of the junction proteins,” Ho says. Thus, a leaky blood-brain barrier becomes even leakier and inflammation continues to increase as proteins and other substances not meant to cross into the brain find their way there, damaging neurons in the brain. Damaged neurons could contribute further to the leakiness, as neurons play a role in keeping the blood-brain barrier functional.

Looking Forward

Research on SARS-CoV-2 and COVID-19 is moving rapidly, but there is still much that needs to be studied. Work continues on all fronts to understand how the virus affects so many systems and organs of the body and how to prevent and treat the damage it does.

“We know a little bit more about COVID-19 today than we did three months ago,” Matthay says, “but there is a lot more to learn.”