What did we know about how the virus attacked the body?
(Scientific understanding as of March 2021)
You may wish to read the following pages first in order to better understand this page:
What we knew
What we knew about the origin of COVID-19
What we knew about the structure of the SARS-CoV-2 virus
What we knew about the virus spreading in a population
Click on dark blue words or terms to see their meaning in the glossary.
Research during the first year of the pandemic has shown that SARS-CoV-2—the virus responsible for COVID-19—can enter the body through the eyes, nose, or mouth. Public health guidelines recommended avoiding touching one’s face (since virus particles may be present on the hands), keeping a safe distance from others, and wearing a mask indoors or when around people to help reduce the risk of infection.
Scientists have proposed that there might be a threshold level of virus exposure below which the immune system can effectively prevent infection, although the exact number of viral particles required is not yet known. Preliminary evidence also suggests that being exposed to a larger number of viral particles—referred to as the initial viral load—could be associated with more severe disease. This concern has been particularly noted among healthcare workers, who may face higher exposures in their work environments.
It is important to note that our understanding of SARS-CoV-2 and COVID-19 is still evolving, and ongoing research continues to shed light on how the virus causes disease.
Initiating Infection and Early Spread in the Respiratory Tract
Once the spike protein of a SARS-CoV-2 particle binds to an ACE2 receptor on a cell’s surface, the virus fuses with the cell membrane and releases its RNA into the cell. This genetic material instructs the cell to produce new viral components, beginning the process of viral replication and infection.
It is important to note that viral particles do not actively move on their own; rather, they are carried passively—such as in the flow of air when we breathe or by the movement of cilia in the respiratory tract.
The nasal cavity, one of the primary entry points, contains many cells rich in ACE2 receptors. Early evidence during the first year of the pandemic suggested that cells located higher up in the respiratory tract have a greater density of these receptors, making them more susceptible to infection compared to cells further down. This characteristic enables the virus to replicate sequentially from one cell to the next.
In many individuals with a robust immune system, the infection at this early stage might cause no symptoms or only mild ones. However, even when symptoms are absent, a high viral load—meaning a large number of viral particles—can be present in the mucus and exhaled breath, contributing to the individual’s contagiousness. (It is also worth noting that viruses can replicate within host cells without necessarily causing immediate cell death.)
At this stage, some infected individuals may experience a loss of smell. This phenomenon is thought to occur because certain cells in the olfactory epithelium—located near the neurons that send smell signals to the brain—express ACE2 receptors. When these supporting cells become infected, the normal function of the nearby olfactory neurons can be disrupted, leading to the anosmia (loss of smell) observed in many cases.
Transmission and Spread Beyond the Nasal Cavity
As of March 2021, studies have indicated that individuals with COVID-19 can be contagious as early as two days before symptoms appear. In some cases, a robust immune response may control the virus while it remains largely confined to the nasal passages. However, if the virus is not eliminated early, it may progress to other parts of the body, such as the lungs or the digestive system.
The virus may infect the throat—leading to symptoms like a sore throat—or it might bypass the throat entirely. Early evidence also suggests that the virus could be carried to the lungs via aspiration, which is supported by observations that lung infections often occur in isolated patches.
Severe Lung Infections that Affect Gas Exchange
Once SARS-CoV-2 reaches the lungs, the situation can become much more serious. In the lungs, cells called type II pneumocytes line the tiny air sacs known as alveoli that are like leaves on a tree of airways. The primary role of the lungs is to allow oxygen to enter the bloodstream and for carbon dioxide to be expelled. This gas exchange occurs across a thin membrane between the alveoli and the capillaries, the small blood vessels that wrap around them.
These type II pneumocytes produce surfactant, a substance that helps prevent the alveoli from sticking together. When these cells become infected, their impaired function can lead to the collapse of alveoli, a condition that may require mechanical ventilation in an intensive care unit to help maintain proper oxygenation. Infection of these cells disrupts the vital process of oxygen exchange, contributing significantly to the severity of the disease.
Research early in the pandemic also suggested that SARS-CoV-2 can interfere with the immune system. In some individuals, the virus appears to block the activation of genes responsible for producing interferon—a signaling protein that alerts neighboring cells to the presence of the virus, helping to slow its replication. At the same time, the virus can trigger the production of chemokines, including cytokines, which are signaling proteins that recruit immune cells to the site of infection. This prolonged and excessive immune response, often referred to as a “”cytokine storm,” may cause the body to attack its own tissues. The resulting inflammation and accumulation of white blood cells further impair oxygen transfer, leading to a condition known as acute respiratory distress syndrome (ARDS). ARDS is generally more severe than the pneumonia typically seen with seasonal flu and can result in death or long-term lung damage.
Silent Hypoxia and the Role of Pulse Oximetry
Reduced oxygen exchange in the lungs can lead to a condition called hypoxia, where not enough oxygen reaches the body’s tissues. In many COVID-19 cases observed during the early months of the pandemic, there was silent hypoxia—meaning individuals did not experience the expected shortness of breath despite having dangerously low oxygen levels. This occurs because the exchange of carbon dioxide, which normally helps signal the brain to adjust breathing, is not as severely affected as the oxygen exchange. As a result, patients may not notice respiratory distress until their condition has become critical, sometimes delaying medical care.
This silent hypoxia has contributed to severe outcomes, with some patients deteriorating rapidly—occasionally even before emergency services can intervene. To help monitor this condition, healthcare providers increasingly relied on pulse oximeters. These small devices, which clip onto a finger, measure both the pulse rate and the level of oxygen in the blood. Early in the pandemic, pulse oximetry became a valuable tool for alerting individuals and caregivers to the need for prompt medical attention.
Hospital-Based Care and Oxygen Support
In hospital settings during the early stages of the pandemic, providing oxygen was a critical component of patient care. Oxygen was often delivered non-invasively using devices like CPAP (Continuous Positive Airway Pressure) respirators, which supply oxygen through the nostrils. However, if a patient’s condition deteriorated to the point where they could no longer breathe adequately on their own, intubation became necessary. This procedure involves inserting a tube into the patient’s airway and connecting it to a ventilator—a machine that pumps oxygen into the lungs while simultaneously removing carbon dioxide.
Unfortunately, a significant number of patients on ventilators did not survive. For example, during the peak of the outbreak in New York City in April 2020, doctors learned how critical it was to determine the precise moment to switch patients from other oxygen delivery methods to mechanical ventilation. As treatment strategies evolved, clinicians also began using temporary artificial lung devices in the ICU to help patients who could not be saved by mechanical ventilation alone. Additionally, early observations revealed that severe COVID-19 could affect more than just the lungs, contributing to the high mortality seen in some patients.
Systemic Infections Beyond the Lungs
Although most serious cases of COVID-19 begin with lung infections, early observations have shown that the virus can also spread to other parts of the body. For example, patients have experienced complications such as strokes, heart attacks, kidney failure, and encephalitis (inflammation of the brain).
From the lung’s alveoli the virus can enter the bloodstream when the membranes separating the alveoli from the capillaries break down. The inner walls of these capillaries are composed of endothelial cells, which express ACE2 receptors. These cells can therefore become infected, leading to the formation of blood clots. In fact, X-rays from many of the first COVID-19 patients in Wuhan, China, revealed clots in their lung capillaries.
Once in the bloodstream, the virus may spread to other organs, including the heart, kidneys, and intestines. This systemic dissemination can result in severe complications, such as heart attacks, blood clots, and strokes—even in young, apparently healthy individuals, as well as older patients without a history of heart disease.
The endothelium—this inner lining of the blood vessels—was discovered to play a critical role in severe COVID-19. This helps explain why younger individuals are generally spared from severe outcomes while the risk of death is significantly higher in the elderly. As people age, the health and function of endothelial cells decline, and comorbidities such as hypertension, heart disease, and diabetes—conditions that already compromise endothelial function—greatly increase the risk.
One important role of the ACE2 enzyme is to break down a molecule produced by the ACE enzyme, allowing these two receptors to collaborate in regulating blood pressure by controlling the concentration of that molecule, which acts as a signaling agent throughout the bloodstream. Because of this mechanism, there was concern that high blood pressure or medications used to treat it might increase the likelihood of developing severe COVID-19. However, by mid to late 2020 it appeared that this was not a major issue.
It remained unclear, however, how much of the endothelial dysfunction in COVID-19 is caused by the direct attack of the virus versus indirect damage from inflammation and other effects of an overactive immune response. Studies had shown that endothelial cells cultured in the laboratory are resistant to SARS-CoV-2, suggesting that indirect damage is more likely to be the primary mechanism.
Endothelial Cell Dysfunction and Blood Clots
Endothelial cells are believed to play a key role in the formation of blood clots observed in severe COVID-19 cases. Damage to these cells—whether directly by SARS-CoV-2 or indirectly through the body’s immune response—can disrupt their normal function in regulating blood clotting. This dysfunction may lead to clot formation even in the smallest blood vessels, such as capillaries, potentially contributing to hypoxia by limiting blood flow.
Many patients, including young individuals, have experienced strokes when blood clots block the flow of blood to parts of the brain. In addition, although it is rare, some children with COVID-19 have developed a severe inflammatory condition affecting blood vessels throughout the body. In 2020, this condition was termed Multisystem Inflammatory Syndrome in Children (MIS-C).
Long-Term Effects
Early research indicated that many survivors of severe COVID-19 might not recover completely. In one study before March 2021, about 78% of patients continued to experience heart-related issues two months after their initial illness. Beyond heart complications, a wide range of persistent health problems has been reported in individuals who, despite recovering from the acute phase of the disease, have not regained their overall pre-infection level of health. Given these findings, further research was deemed necessary to fully understand the long-term effects of COVID-19.
Digestive System Involvement
Early evidence indicated that two types of cells in the body exhibit particularly high densities of ACE2 receptors: the cells in the alveoli of the lungs and certain cells lining the small intestine. By March 2021, it had become well established that SARS-CoV-2 can travel through the digestive tract and is detectable in the feces of many infected individuals.
This discovery has been practically applied around the world through wastewater surveillance. By testing the wastewater at treatment plants, public health officials have been able to detect increases in infection rates within communities at an early stage.
Consequently, proper hand washing after using restroom facilities has been emphasized as an important measure to reduce the risk of spreading the virus through this additional route. Additionally, masks may help protect against aerosolized droplets that can be generated by toilet flushes and potentially carry the virus.
It is important to note that while the virus can infect the intestines, the severity of COVID-19 in the digestive system does not appear to be as pronounced as the disease manifestations observed in the lungs or blood vessels.
Bloodstream and Potential Nerve Transmission
It was discovered that SARS-CoV-2 can spread through the bloodstream, which theoretically allows the virus to infect various parts of the body. This systemic spread helps explain how the virus can attack organs such as the heart, brain, and others.
Early on, scientists also theorized that SARS-CoV-2 might infect nerve cells and travel along nerves, potentially providing a route to reach the brain—for example, from the nasal passages. However, by mid‑2020, the idea of direct nerve transmission was largely set aside. Instead, researchers began favoring mechanisms involving systemic inflammation and vascular effects as the primary causes of the neurological symptoms seen in some COVID-19 patients. This shift was supported by observations that neurons do not significantly express the ACE2 receptor and that widespread neuronal infection was not found.
Medications Demonstrating Effectiveness
COVID-19 patient treatment has advanced considerably since the first two drugs—remdesivir (reported on April 29, 2020) and dexamethasone (reported on June 16, 2020)—demonstrated their effectiveness in clinical trials,. These treatments have significantly reduced the mortality rate of COVID-19. Because no one-size-fits-all “wonder drug” has been discovered or invented to prevent or cure COVID-19, appropriate treatments must be administered at the right time during the disease’s progression. This progress has been made possible since early 2020 through substantial advances in our understanding of how the virus attacks the body.
If you started reading from the What we knew page, you have now completed this series of pages summarizing early insights into COVID-19 science. For additional information on managing the disease during the first year of the pandemic, please explore the “Treatment Research” and “Vaccine development” sections on the COVID-19 menu.
©2020 Dr. Michael Herrera
