COVID-19: Coronavirus versus the Immune System Orchestra
“You can think of the human immune system as an orchestra playing together and needing a coordinated performance from all the musicians and their instruments.” Tom Evans, chief scientist, Vaccitech
"Certain people – men, of course – discouraged me, saying [science] was not a good career for women. That pushed me even more to persevere." Francoise Barre-Sinoussi, virologist, awarded the Nobel Prize in Physiology and Medicine in 2008 for the discovery of human immunodeficiency virus
The focus of this week’s Germ Gem is on the most critical determinant of the future of the COVID-19 pandemic—the outcome of the battle between the coronavirus that causes the disease, SARS-CoV-2, and the human immune system. So far, the virus is winning. But a large cadre of remarkable scientists, clinical researchers, and leaders of governmental organizations and pharmaceutical companies around the world are working overtime on the development of ways to bolster the immune system, through vaccines, use of antibodies, and immunomodulatory drugs.
Learning about the function of immune cells. The late Dr. Robert Good, a University of Minnesota pediatrician and a founder of the field of modern-day immunology, is often credited with the idea that we have learned most about the functions of the different cells of the immune system by “experiments of nature.” By this he meant that if you wanted to know what a specific cell type contributed to immune defense, all you needed to do was to determine what kinds of infections and diseases patients who lacked those cells were prone to develop.
The most recent example of this type of “experiment” is HIV/AIDS. The HIV virus selectively targets and kills CD4 T lymphocytes putting patients at risk of developing specific kinds of bacterial, fungal, and viral infections and malignancies that are ordinarily kept at bay by these lymphocytes.
Similarly, I believe SARS-CoV-2 infection is providing new insights into the operations of the immune system. This includes a potential answer to one of the most mysterious questions of all, “Why do some patients remain well when infected (about 40% of patients are asymptomatic), whereas others with COVID-19 develop illness of varying degrees of severity?”
Brief review of the immune system. When I taught medical students about the elegance of the immune system, I used a simple military analogy. Like the different branches of the military, I suggested, cells of the immune system are specialists in defense against different kinds of enemies (bacteria, fungi, viruses, and parasites). But as I’ve thought more about it, I think Tom Evans’ analogy, quoted above, of the immune system as an orchestra is more germane. A successful immune response against SARS-CoV-2 depends on a harmonious collaboration between all members of the orchestra: the string section (B lymphocytes—producers of antibodies), the woodwinds (T lymphocytes—defenders against an array of microbes, including viruses), brass section (macrophages—major generators of cytokines), and percussion instruments (natural killer cells and neutrophils—the cells earliest to arrive on the scene of microbial invasion).
The strings (B lymphocytes). A major goal of most of the vaccines against SARS-CoV-2 that are under development is to elicit neutralizing antibodies targeting the spike protein (S) of the virus, which prevent it from binding to ACE2 receptors on human cells, thereby blocking its entrance. This is the job of B lymphocytes. But just as the violins are joined by cellos and bass fiddles in the string section of an orchestra, other cells (including antigen presenting cells and T cells) work in concert to accomplish this goal. Once achieved—immunity! That is to say, if SARS-CoV-2 is encountered, these B cells remember it and produce antibodies before the infection takes off.
On-going multicenter clinical trials, coordinated by Johns Hopkins University, Mayo Clinic, and others, are providing evidence that neutralizing antibodies against SARS-CoV-2 works. In these trials, COVID-19 patients are being treated with plasma containing antibodies from patients who have recovered from COVID-19. This therapeutic approach is called passive immunization. So far, the results of these trials are encouraging. But, passive immunization is cumbersome and it has a downside: it doesn’t provide patients with the long-term protection against subsequent SARS-CoV-2 infections that a vaccine would (called active immunization).
The use of strongly neutralizing monoclonal antibodies against SARS-CoV-2 has the same downside. Nonetheless, two monoclonal antibody trials were recently launched under the “Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)” program of the National Institutes of Health (NIH) in collaboration with Eli Lilly and Company (thought by some to be an ‘Apollo 11 Moment’).
I’m sure we will be revisiting the string section of the Immune System Orchestra in future Germ Gem posts to hear the status of answers to questions about what types of antibodies are most important in defense against SARS-CoV-2, whether they can be used as an indication of protection (a “passport”), how many people in a population need to be antibody-positive before “herd” (community) immunity is established, how worried should you be if these antibodies fade over time, and the most worrisome question, can you be infected more than once, that is, re-infected?
The woodwinds (T lymphocytes). Analogous to the woodwind section of an orchestra, comprised of oboes, clarinets, and bassoons, there are several kinds of T cells: CD4 (helper) cells, CD8 (cytotoxic), and memory T cells. As their names suggest, helper T cells help other cells of the immune system, cytotoxic T cells kill virally infected cells, and memory T cells play a key role in immunity, that is, they remember and respond to pathogens that have been previously encountered.
While the precise role of each of these different types of T lymphocytes in COVID-19 infection, as well as their contribution to development of immunity, are being worked out, one of the most intriguing observations to emerge so far was reported in a publication in Nature on July 22, “SARS-COV-2-reactive T cells in healthy donors and patients with COVID-19.” This multicenter study looked at the SARS-CoV-2 spike protein (S)-reactive CD4 T cells in the blood of patients with COVID-19 and also in the blood of SARS-CoV-2 unexposed healthy donors. The researchers found that 83% of patients with COVID-19 had S-protein reactive CD4 T cells in their blood (no surprise). But, surprise, surprise, 35% of healthy donors who had never encountered the virus also had these S-reactive CD4 T cells.
One potential explanation for the presence of S-reactive CD4 T cells in a sizable fraction of the general population is that that their CD4 T cells were “cross-reactive,” meaning these healthy donors had been infected in the past with one or more of the four other coronaviruses that cause the common cold. This raises the possibility that such people are protected against developing symptomatic infection when they do confront SARS-CoV-2. If this is the case, it could be an “experiment of nature” that explains the 40% asymptomatic infection rate. (And it could be applicable to other infections with high percentages of asymptomatic infection—a not uncommon phenomenon.)
Brass section (macrophages). Macrophages line every cell membrane of the body. In our lab we studied those found in the lungs (alveolar macrophages) and abdomen (peritoneal macrophages), as well as those found in the brain (which were our research group’s favorite cell type, called microglia—key defenders of brain tissue).
While activated macrophages aren’t alone in their capacity to produce cytokines, they are a major source of these proteins that serve as activating signals of other immune cells as well as other cell types throughout the body that have cytokine receptors. Several research groups postulate that an overabundant or dysregulated release of cytokines (called a “cytokine storm”) plays an important role in organ damage in patients with severe or fatal COVID-19. This hypothesis underlies the use of potent anti-inflammatory drugs, such as, dexamethasone in the treatment of severe COVID-19. (The results of a clinical trial recently published in the New England Journal of Medicine has confirmed its therapeutic benefit.)
This finding serves to remind us that the immune system is a “double-edged sword.” While the immune system is crucial in defense against invading pathogens, through production of cytokines and other mediators, it also is responsible for the development of symptoms of illness, for example, fever, loss of appetite, and fatigue, and it can even kill us. (In our orchestra analogy, it’s akin to the effect of suddenly adding four tubas to the brass section. In other words, like an imbalanced orchestra, the product of a dysregulated immune response is cacophony.)
In addition to dexamethasone, which is a broad spectrum inhibitor of inflammation, a number of more selective therapies that are aimed at tamping down the putative cytokine storm triggered by SARS-CoV-2 are under investigation. The results of trials of two such anti-inflammatory drugs, anakinra and tocilizumab, that block the cytokine, interleukin-6, are just now emerging. It’s too early to know, however, what these promising drugs will add to the therapeutic armamentarium.
Percussion section (natural killer cells and neutrophils). Natural killer (NK) cells, a type of lymphocyte, and neutrophils (also referred to as polymorphonuclear leukocytes or PMNs) are the main contributors to what is called innate immunity. The purpose of the innate-immune response is to immediately prevent the spread and movement of pathogens throughout the body. These cells are ready to go from the very outset of microbial infection—no need for priming as in adaptive immunity provided by T and B lymphocytes. PMNs, however, generally aren’t involved in host defense against viruses. And, little, or nothing is known about their role in defense against SARS-CoV-2.
But, NK cells are known to provide defense against certain kinds of viruses, and potentially this could include SARS-CoV-2. Based on this hypothesis, some of my colleagues at the University of Minnesota recently embarked on a clinical trial using an experimental therapy containing NK cells called FT516.
Will the ‘Immune System Orchestra’ ultimately prevail? In the early years of my infectious diseases career, HIV/AIDS was terrorizing the world. That pandemic led to major advances in the fields of virology and immunology. Moreover, although development of a vaccine against HIV hasn’t panned out (yet), treatments were found that can provide lifelong wellbeing.
I predict we will also get a hold on COVID-19. I’m optimistic about the development of an effective vaccine, which will have a major impact. And treatments, many of which are aimed at the immune system, are becoming available at lightning speed, such as the use of monoclonal antibodies and inhibitors of IL-6 discussed above. The arrival of one or more effective vaccines and new immunomodulatory drugs will be music to everyone’s ears!
In the meantime, I suggest listening to Mozart. Although my research colleagues were dubious, I’m personally convinced that in addition to lifting one’s spirits, Mozart does something very special for my favorite immune cell, the microglia.
EXCELLENT ANALOGY