The Biology and Immunology of COVID-19 Susceptibility

June 5, 2020

Why do some people infected with SARS-CoV-2 carry a fever for weeks on end before going into acute respiratory distress syndrome (ARDS), while others don’t even know they’re infected? It turns out the answer has at least 2 angles: there’s the virus, and then there’s us. 

SARS-CoV-2 Infection and ACE2

The coronavirus family is named for the crown-like appearance of surface proteins called spike (S) proteins. Like its cousin SARS-CoV, SARS-CoV-2 uses these spike proteins to gain entry into epithelial cells (and other cell types) via a receptor on their surface known as Angiotensin Converting Enzyme-II (ACE2).This has 2 immediate outcomes: 
  1. The virus binds ACE2 with its spike protein and tricks the cell into swallowing it through endocytosis. Infection ensues.
  2. ACE2 is effectively occupied and unable to perform its regular function.
Overview of the SARS-CoV lifecycle. Glycoprotein S, located in the virus envelope, interacts with the cellular receptor ACE2 and the virus enters the host cell by endocytosis.
Overview of the SARS-CoV lifecycle. Glycoprotein S, located in the virus envelope, interacts with the cellular receptor ACE2 and the virus enters the host cell by endocytosis.
ACE2 is a critical negative regulator of the renin-angiotensin system (RAS), which modulates systemic fluid-salt-balance and blood pressure. Its expression promotes dilation of blood vessels by converting hypertensive angiotensin II into angiotensin 1-7, which reduces blood pressure. But it doesn’t stop there. ACE2 is expressed on multiple organs throughout the body, where it performs critical local regulatory tasks, such as promoting mitochondrial function. We know that ACE2 is expressed in the lungs, making them the primary site of COVID-19 infection through inhaled respiratory droplets. But it’s also highly enriched in the heart, kidney and intestine, and can be found in the liver, testes, brain and adipose tissue. ACE2 expression in these respective niches is necessary for healthy cardiac function, prevents acute lung failure from infection and promotes optimal beta-cell function (the cells in the pancreas that generate insulin) and insulin sensitivity. Thus, when ACE2 function is blocked by SARS-CoV-2, it is no longer available to perform its regulatory roles in the heart, pancreas, liver or other cell types, nor is it readily available to reduce blood pressure. When ACE2-expressing cells are infected and destroyed by the virus, the tissues as a whole suffer.

The expression and importance of ACE2 in certain body systems echoes the populations most vulnerable to COVID-19. Its expression is higher in men than women, which is a potential reason why men are more likely to suffer severe outcomes of COVID-19 than women. Its key contributions to the stability of beta-cell function and blood pressure underlie the higher susceptibility of diabetic and hypertensive patients to severe complications from COVID-19.  Although the majority of morbidity that we know of is associated with respiratory distress, there have been reports of  meningitis, pancreatic injurygastrointestinal outcomes and cardiac injury associated with COVID-19 as well. While most people are not at risk for severe outcomes, the pervasiveness and importance of ACE2 is a liability for tissues already weakened by comorbid conditions, assuming the virus can get there. 
The diversity of ACE2 expression also reflects the diversity of COVID-19 symptoms. The initial reports suggested that predominant symptoms included fever, cough, shortness of breath and muscle pain. Yet a variety of other symptoms have also been reported, including headache, diarrhea, abdominal pain, hepatic dysfunction and even stroke. It’s important to note that current modes of acute testing for COVID-19 emphasize respiratory infections, even though it’s possible that active virus exists elsewhere in the body. This is the equivalent of only looking for your keys in the circle of light offered by a street lamp, because that’s where you can see. If COVID-19 is capable of establishing an infection outside the respiratory tract (and studies suggest that it may be), a nasopharyngeal swab would not necessarily detect it. Since upper and lower respiratory specimens are the gold standard of acute diagnostic testing, we might be missing active infections elsewhere in the body, or continuing infections that have moved on from the respiratory tract. It’s simply too soon to know how often this is occurring.

SARS-CoV-2 and the Immune System

Once the virus has broken into our cells, it has to contend with the immune system. While our understanding of the immune response to SARS-CoV-2 is incomplete, we do know that those who go on to develop severe complications of COVID-19 have a few foreshadowing indicators, including high levels of pro-inflammatory molecules, like interleukin-6 (IL-6), and high neutrophil to lymphocyte ratios (NLR). ‘Lymphocyte’ refers to a variety of immune cells, many of which respond to a specific antigen. In that sense, they behave a bit like snipers, in which they seek and destroy a single, specific target. A study investigating the closely-related virus SARS-CoV found that T cells, a subset of lymphocytes, were an important aspect of viral clearance. Neutrophils, on the other hand, respond to conserved danger signals common to many pathogens. En masse, neutrophils are the immunological equivalent of a blunt force weapon, capable of causing significant collateral damage. 
When SARS-CoV-2 enters airway epithelial cells via ACE2, it avoids triggering certain antiviral interferon pathways, which are the front line antiviral response in epithelial cells. The assaulted airway epithelia produce IL-6 and other pro-inflammatory mediators instead, which recruit neutrophils (among other cells) to the site of infection. Importantly, the specific category of type III interferons provide early antiviral response that is not inflammatory in nature. Animals for which type III interferon receptors have been genetically knocked out suffer neutrophilia, lung injury and death following viral challenge, not unlike the most severe cases among COVID-19 patients. 
During a healthy response, a type of lymphocyte called a cytotoxic T cell arriving on the scene might recognize and destroy the infected cell, after which it would be cleaned up by phagocytic cells also summoned to the site. However,  IL-6 and interleukin 8 (IL-8), which are both elevated in severe cases of COVID-19, can promote exhaustion in cytotoxic T cells, which then have less power to perform their normal function or to counteract neutrophil action. IL-6 also inhibits the development of lymphocytes known as peacekeeper, or regulatory, T cells, which might otherwise dampen a spiraling immune response. It’s been proposed that what kills at least a subset of COVID-19 patients is actually a blitzkrieg of pro-inflammatory signals referred to as ‘cytokine storm syndrome.’ Consequences of this condition include cell-specific immunodeficiency, dramatic neutrophil influx, acute respiratory distress and organ failure. 
Cytokine storm and Acute Respiratory Distress Syndrome (ARDS) and are a cause of death in a subset of severe COVID-19 cases, in which infiltrates of neutrophils and other inflammatory cells and cytokines overwhelm the alveoli of the lung, causing downstream organ failure.
Cytokine storm and Acute Respiratory Distress Syndrome (ARDS) and are a cause of death in a subset of severe COVID-19 cases, in which infiltrates of neutrophils and other inflammatory cells and cytokines overwhelm the alveoli of the lung, causing downstream organ failure.

Bloodwork in severe COVID-19 cases also shows a drop-off in lymphocytes, with simultaneous enrichment in neutrophils, shifting the neutrophil to lymphocyte ratio. Evidence suggests that SARS-CoV-2 may be able to infect T cell lymphocytes directly via their spike proteins, which fuse to low levels of ACE2 expressed on the T cell membrane. Although the virus cannot replicate within the T cells, it does kill them. If accurate, this data suggests that not only are certain subsets of T cells being neutralized by intrinsic signals from other immune cell players, they may also be destroyed by the virus itself, resulting in the lymphopenia we observe in the most severe cases. Of those lymphocytes that remain during SARS-CoV-2 infection, many display an exhaustion marker called NKG2A, demonstrating that they are effectively unable to mount a response. Notably, a high neutrophil to lymphocyte ratio is independently observed in many susceptible populations, including those of advanced age, or with diabetes, hypertension and morbid obesity. SARS-CoV-2 could be exacerbating immunological trends that are already imbalanced in these populations. 

Bringing the Picture Together

In summary:
  • SARS-CoV-2 is expelled in respiratory droplets from an infected individual and subsequently inhaled. 
  • Entering the respiratory tract, the virus begins to infect airway epithelial cells by gaining entry through surface protein ACE2. (It’s also feasible that SARS-CoV-2 could bypass the lungs, for example, via a gastrointestinal route.) 
  • Once inside, the virus silently evades critical early antiviral response mechanisms (type III interferons), while triggering expression of IL-6 and other proinflammatory signals, which begin to recruit neutrophilic activity to the lung. 
  • IL-6 and IL-8 may also work to inactivate cytotoxic lymphocytes via exhaustion signaling. Meanwhile, it’s also possible that the virus itself infects local T lymphocytes and kills them, resulting in lymphopenia and a regulatory gap in exerting control of the innate immune response. 
 If the infection is not quickly controlled by the immune system, or spreads to extra-pulmonary tissues, ACE2 may also permit viral infection of other body sites.  In these locations, the effect of ACE2 co-option is felt more acutely by individuals with existing co-morbidities in those organ systems. It’s possible that the elevated rate of all-cause mortality observed this season may not only reflect undetected SARS-CoV-2 infection, but the diverse array in which its effects on ACE2 manifest outside of the viral pneumonia we recognize as COVID-19. 
It’s important to state that our understanding of the virus is still very young. New findings in COVID-19 are emerging daily. As with all science, we will continue to refine and revise our hypotheses as we add data to the story. In the meantime, we should continue to be mindful of vulnerable populations, support continued basic and translational research and doggedly keep on the trail of vaccine and treatment development.

Author: Christy Clutter, Ph.D.

Christy Clutter, Ph.D.
Christy Clutter, Ph.D., is a scientist, microbiome aficionado and writer whose research work focused on gut immunity and the microbiota, along with public health disparities in nutrition.