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  • Writer's pictureP.K. Peterson

The Immunology of COVID-19: the Big Picture

“There’s never been a better time to be an immunologist. The entire world is acutely aware of the expertise and value we bring to help solve some of the world’s most pressing health problems.”

- Faith Osier, African immunologist, pediatrician, and educator

“There’s no question this virus has humbled us. We have many mysteries still out there.” - Eric Topol, M.D., American scientist, author, and director of the Scripps Research Translational Institute

I spent most of my professional career studying various aspects of host defenses, that is, the ways our immune system defends us against foreign invaders, aka pathogens. As regular readers of my blog know, I have been closely tracking the literature on the immunology of COVID-19. The sheer volume of new information available every day/week is mindboggling. And it can be incredibly confusing—even for scientists.

In this week’s Germ Gems post, my goal is to step back and paint what I believe is the “big picture of the immunology of COVID-19.” I will, however, focus on only two aspects of immunity: antibodies (products of B lymphocytes), something the general public may know a lot about; and macrophages, cells that I believe the public should learn more about.

The broadening view of the immune system. In the early 1990s, immunologists divided the immune system into two modes, innate immunity (comprised of granulocytes, macrophages, and NK lymphocytes—battle-ready cells that kill pathogens directly) and adaptive immunity (B and T lymphocytes—cells endowed with the power to remember and respond to pathogens they’d seen before). This was a gross oversimplification. Modern-day studies have revealed that many other cell types in the body, and even microbes harbored in the gut microbiome, participate in defense against foreign invaders. As Carl Nathan, one of the foremost leaders in the field of immunology, wrote in his July 16, 2021 article in Science, “Rethinking Immunology,” “The boundary between what is and is not part of the immune system has recently sprung more holes with the recognition that besides the liver, the nervous system, epithelia, erythrocytes, and microbiota are key contributors to mammalian immunity.”

The big picture of antibodies in COVID-19. Of all the many types of mediators produced by cells of the immune system when they are activated during COVID-19 infection, antibodies are by far the most extensively studied. Their production is monitored before and after SARS-CoV-2 infection and following vaccination. They are used as a marker of herd immunity. We hear the most about what are called “neutralizing antibodies,” IgG immunoglobulins directed against the spike protein of SARS-CoV-2, and only a little about IgA immunoglobulins that neutralize viruses on mucosal linings, like those in the nose and throat.

Major attention is focused on the role of neutralizing antibodies because they are a source of identifying new treatments. To date, most treatments are aimed at neutralizing SARS-CoV-2’s spike protein. This is the knobby structure you’ve seen in photos of the virus. It binds to ACE2 receptors on human cells to gain entry. Therefore, much is made in the news about recombinant monoclonal antibodies (mAbs)-antibody cocktails that are made in the laboratory that target SARS-CoV2’s spike protein. The U.S. government recently ponied up nearly $3 billion for a large order of the COVID-19 monoclonal antibody cocktail, REGEN-COV, made by Regeneron Pharmaceuticals Inc.

At the same time, around the world other companies in partnership with academic institutions are developing next generation mAbs (so called “superantibodies”) that have broader neutralization capacity in the face of emerging viral variants. Several research groups and companies are even carrying out clinical studies of antibodies obtained from llamas! Why? Because llamas have antibodies that are unusually small and have the capacity to bind to specific parts of SARS-CoV-2’s spike protein giving them stronger neutralization activity against the Delta variant.

One of the most fascinating aspects of COVID-19 is the high incidence of people who develop no symptoms upon infection by SARS-CoV-2 (such “asymptomatic infections” occur in up to 50% of people). Certain types of antibodies, called “cross-reactive,” may play a role in this phenomenon that is sometimes referred to as pre-existing immunity. These cross-reactive antibodies appear to have been produced in response to other closely related coronaviruses, for example during infections by other coronaviruses that cause the common cold. But it is also possible that cells of another major component of the adaptive immune system, namely, T lymphocytes, are involved.

The big picture of macrophages in COVID-19 immunity. Macrophages are members of the innate immune system. As such, they respond immediately to foreign invaders like SARS-CoV-2 without the need of memory of this enemy. They are an important generator of another group of immune mediators called cytokines. Cytokines are proteins that serve as messenger molecules that activate other cells. There are many kinds of cytokines but interleukins have received most attention. (Antagonists of one of them, interleukin-6, are approved as treatment of COVID-19.)

When macrophages themselves are activated for example by the cytokine interferon-gamma, they produce reactive oxygen and nitrogen species that play a role in killing microbes. But when a so-called “cytokine storm” occurs, an unregulated release of multiple cytokines can inflict tissue damage, leading in some cases to death.

What is the endgame of the battle between the immune system and SARS-CoV-2? At this point in the SARS-CoV-2 pandemic we have a fairly good idea of the big picture of the immunology of COVID-19. While SARS-CoV-2 is a very wily adversary, scientific resourcefulness has been on our side in fighting this pathogen. As an example, consider the weapons (vaccines) scientists developed in record time. One of the big questions now is how long will immunity to SARS-CoV-2 last following natural infection or vaccination? Although it is far too early to know for sure, there are numerous studies that indicate both B lymphocytes and T lymphocytes retain memory of SARS-CoV-2 for longer than might be suspected. Consequently, some experts suggest that immunity may last longer than expected.

Our relationship with all pathogens has always been a battle for survival—survival of the fittest. But viruses were on our planet long before Homo sapiens and, in all likelihood, will be here long after. SARS-CoV-2 is no different. I am confident, however, that as more is learned about the immune system’s responses to SARS-CoV-2, more weapons are going to come along for the prevention and treatment of COVID-19. Therefore, the endgame of this pandemic may look more-or-less like a draw with SARS-CoV-2 settling down to a lifestyle similar to the coronaviruses that cause seasonal colds and man settling for coexistence with this virus.

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Main Page images courtesy of Shuxian Hu, MD. Dr. Hu is a scientist in the Neuroimmunology Research Laboratory at the University of Minnesota.

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