SARS-CoV-2 and the Human Body: New Evidence of How Our Immune System Fights Back

BY Kyrstin Lulow
September 8, 2020

Coronaviruses and SARS-CoV-2

Coronaviruses are a group of enveloped, positive-sense strand RNA viruses that are characterized by their “corona,” or crown, of spike-like structures. Some coronaviruses, like 229E and HKU1, are common among humans and can cause mild upper respiratory illness. Otherwise known as the common cold, the illness caused by these viruses tends to plague us during the darker, colder months of the year and typically have a mild impact, other than potentially interfering with holiday festivities. And every year, we trust that our immune system will fight off the pesky cold.

Yet there are other coronaviruses that have emerged in the last 20 years that are far more dangerous and potentially life-threatening. The latest emerging human coronavirus, SARS-CoV-2, is not to be mistaken with its common cold cousins. It is capable of causing severe illness, damaging a wide range of bodily systems, and its wake has left the world in disarray. 

But armed with an understanding of the human immune response to other coronaviruses, researchers are shedding new light on just how SARS-CoV-2 interacts with the human body and how the immune system fights back.

The Human Immune System: An Overview

The Innate Immune System

Just like with the common cold, our bodies attempt to fight off viruses through a coordinated immune response that starts with the innate immune system and later engages the adaptive immune system. The innate immune system is made up of two lines of defense: protective barriers like our skin and mucous membranes, and a host of defensive cells that are quickly deployed when pathogens breach those protective barriers. Some of these cells include granulocytes (leukocytes), NK cells, and monocytes. These cells perform various defenses, from engulfing and destroying pathogens, to activating the adaptive immune response, to killing infected cells. NK cells, or Natural Killer cells, are the innate immune system component that is responsible for knocking out infections, specifically killing virally-infected or cancerous cells.

The Adaptive Immune System

While the innate immune system leads a quick and general response to pathogens, the adaptive immune system response is targeted, specific to each pathogen, and based on a pathogen’s antigens, or specific molecular constructs that indicate the pathogen’s identity. When fighting off a virus like the common cold, the body deploys B lymphocytes (B-cells) to produce specific antibodies to bind to the invading virus and trigger events that will destroy it. This process is known as humoral immunity. Once antibodies attach to a virus or a virus-infected cell, they can either neutralize it, signal for phagocytes, or trigger additional proteins to cause lysis. 

The other branch of the adaptive immune system is cell-mediated immunity, which consists of T lymphocytes, or T-cells. There are several types of T-cells and they are involved in signaling the presence of a virus (helper T-cells), directly destroying a virus (cytotoxic T-cells), and storing information about a viral infection to support future immune responses to that virus (memory T-cells).

SARS-CoV-2 and the Immune System

Though the human body’s immune system is often capable of neutralizing infections when they arise, some novel infections present a greater challenge. As we have seen in these past several months, the novel coronavirus, SARS-CoV-2, is a dangerous and in many cases lethal virus. As companies and institutions race to develop vaccines, researchers are uncovering more and more about SARS-CoV-2 and the correlating human immune response. 

Anatomy of SARS-CoV-2

SARS-CoV-2 is an RNA virus that consists of four major structural protein types: nucleocapsid (N), membrane (M), envelope (E), and structural spike (S), along with 16-17 non-structural proteins, ns1-ns17. SARS-CoV-2 infects target cells by attaching to receptors with the S protein via the receptor-binding domain (RBD). Once attached, the virus subsequently fuses the host and viral membranes. The host receptor that SARS-CoV-2 attaches to is still being researched, though early studies on SARS-CoV-2 and on the homologous SARS virus indicate that the receptor might be an enzyme called ACE2, which plays a role in the cardiovascular system.

Immune Response to SARS-CoV-2

As we learn more about the way SARS-CoV-2 infects the body, we are also discovering the ways in which our immune system responds to these infections – and there have been some surprising developments.

Figure 1.

SARS-CoV-2 and the Human Immune Response

Gaining Entry
Coronaviruses are sometimes able to make contact with a host cell via the structural spike protein, or S protein. Recent research on SARS-CoV-2 indicates that this virus may enter host cells via the receptor binding domain (RBD), a subunit of the S protein. Research also suggests that SARS-CoV-2 binds to the host membranous protein ACE2 which is found predominantly in the lungs and heart.
Our Immune System’s Defense Against Entry
(1) IgG (immunoglobulin G) monoclonal antibodies are found circulating in the blood and extracellular body fluids. They are produced by B-cells as part of the humoral immune response, and they help protect bodily tissues from infection. (2) T-cells, a type of white blood cell, respond to infectious pathogens and have surface receptors that recognize the pathogenic antigens. CD8+ T-cells (also known as cytotoxic T-cells) directly attack pathogens, as well as cells that are virus-infected, cancerous or damaged. CD4+ T-cells (or helper T-cells) on the other hand, coordinate immune response by signaling other agents of the immune system to respond to an infection. (3) Sometimes, the immune system is able to respond to new infections with guiding information from previous infections by other pathogens. Usually, a given antibody or T-cell receptor will only recognize one type of antigen. But sometimes they can recognize multiple antigens if they are structurally similar. This is called cross-reactive immunity.

 

Antibodies

As discussed earlier, the body deploys several methods for neutralizing viral infections. Humoral immunity is responsible for generating antibodies that trigger cascading events to knock out viruses. In the case of SARS-CoV-2, Spike protein is thought to be an immune system target, one in which B-cells generate antibodies to attack and disrupt infection. Current and on-going research reveals that IgG mAbs (immunoglobulin G monoclonal antibodies) interrupt viral infection by attaching to either the S1 subunit of the Spike protein or the RBD that directly fuses to the host receptor. 

In a study by the Center for Biologics Evaluation and Research (FDA) published in Science Translational Medicine   researchers searched for effective vaccine constituents and looked at the different subunits of the Spike protein and the comparative generation rates of neutralizing antibodies. This study found that, of the Spike protein subunits, the RBD yielded the highest affinity antibodies.Generally, once the body develops antibodies to fight off an infection, we can count on those antibodies protecting us from re-infection for some time. 

However, a letter published in Nature Medicine by Quan-Xin Long et al. provided evidence that these IgG antibodies decline in convalescent patients within two to three months. This discovery has led to concern over the possibility of long-term immunity to SARS-CoV-2 and the potential for re-infection in recovered patients. 

Despite this potentially short life span of SARS-CoV-2-specific antibodies, there is burgeoning evidence that there is some cross-reactive immunity at play. Researchers out of the University of Arizona suspect that there may be an existing, though variable, antibody response that targets the Nucleocapsid (N) protein, a more highly conserved domain across coronaviruses. This suggests that some people may have some level of potential humoral immunity, thanks to the body’s ability to fight off previous, similar infections.

T-Cells

Despite the ominous learnings about antibody declines post-infection, there is new evidence that patients, and potentially even members of the general population, have more protection against SARS-CoV-2 than we previously realized. 

As we discussed earlier, the second branch of the adaptive immune response is cell-mediated immunity, wherein T-cells hunt down and eliminate viral invaders, and even store information for future immune responses to the same type of infection. In a SARS-CoV-2 infection, two types of T-cells attack the virus: CD4+ and CD8+. CD4+ T-cells predominantly attack at the Membrane (M) and Nucleocapsid (N) proteins, along with some non-structural proteins, in order to mediate viral death with the help of B-cells. CD8+ T-cells also primarily attack at the M protein, as well as at nsp6, ORF3a, and N proteins. This mechanism is unique, considering that T-cell responses to SARS and MERS (biologically similar coronaviruses) more exclusively targeted the S proteins of these viruses.

These discoveries give us deeper insight into the components of a potentially effective vaccine. Yet what is most surprising about the emerging research on T-cell responses to SARS-CoV-2 is the potential latent cross-reactive immunity that would develop after exposure to not just SARS-CoV-2 but similar viruses as well. A study published in Cell by Grifoni et al. showed that members of the population who have not been exposed to SARS-CoV-2, or even SARS or MERS, had a T-cell response to introduced SARS-CoV-2 antigens. 

Yet another study, this time by a research team from Duke-NUS Medical School and published in Nature showed that recovered COVID-19 patients, recovered SARS patients, and uninfected control subjects showed an adaptive immune response when CD4+ T-cells targeted various introduced epitopes of SARS-CoV-2 antigens, including the N protein. One finding from this study was that recovered SARS patients had an activated T-cell response to SARS antigens, 17 years after they were first infected in 2003. These subjects also had a cross-reactive immune response to the SARS-CoV-2 N protein.  

And then there are the unexposed control subjects. This same study from Duke-NUS found that these subjects, though never exposed to either SARS virus, still had a T-cell response to antigens of the novel coronavirus. While the recovered SARS and SARS-CoV-2 patients strongly reacted to N protein antigens, unexposed subjects had a distinct reaction to nsp7 and nsp13, as well as the N protein.  This finding suggests that these unexposed control subjects were exposed to a virus similar to SARS-CoV-2 such that they could develop a cross-reactive immunity. Uniquely, the study suggests that these viruses that could confer immunity could potentially have been various zoonotic coronaviruses, or coronaviruses that are transmissible from animals to humans. This would mean that animal coronaviruses were transmitted to humans, but caused mild to no symptoms. And why does this kind of T-cell response matter? Because T-cells must present viral antigens to B-cells, which in turn become memory cells and allows the body to generate virus-specific immune responses long term.

Finally, another study speculated that the people who were previously exposed to various HCoVs, or “common cold” coronaviruses, had a significant memory T-cell response and specifically CD4+ cells when exposed to SARS-CoV-2 epitopes. If the immune system were fighting off a truly novel attack, you would expect to see a high level of naive T-cells. But because this study found a strong presence of memory T-cells, this suggests that the body stores information from the minor “common cold” coronavirus infections that results in varying levels of cross-reactive immunity to SARS-CoV-2. 

All of this indicates that both humoral and cell-mediated immunity play important and distinct roles in fighting off SARS-CoV-2, and that though herd immunity is quite a ways off, there might be more latent immunity than we previously thought.

More Work to Be Done

Researchers around the world are working to understand SARS-CoV-2, how it interacts with the human body, and how we can engineer solutions to combat it. Every day we learn more about how SARS-CoV-2 attacks the body and in turn how the human immune system defends against the virus. There is growing evidence that the human body’s response to SARS-CoV-2 is vastly more complex, coordinated, and rigorous than we previously thought. 

Life science is mission critical now more than ever. Our industry is at the forefront of the fight against SARS-CoV-2, and in the past several months we have collectively made incredible progress. Though we are still in search of a breakthrough solution, we have made groundbreaking strides in our understanding of the virus to empower the development of diagnostics, treatments, and vaccines. But there is more work to be done. By continuing to study the mechanisms of SARS-CoV-2 and the immune response it provokes, life scientists, engineers, and clinicians are coming together to solve this crisis. 


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Published by Kyrstin Lulow
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