Viruses, Pandemics, and Immunity

by Arup K. Chakraborty

  We now turn to describing our modern understanding of the immune system, which will make clear that both antibodies and cells are critically important for our eternal battle against infectious viruses. Both blood and cells matter.

  Current Understanding of Immunity

  Our immune system is comprised of two inextricably linked parts called the innate and adaptive immune systems. The adaptive immune system generates a response that is tailored for the specific invading virus. This custom-designed response takes time to develop. If we relied only on adaptive immunity, by the time it was armed and ready for battle the invading virus would have multiplied many times and spread throughout the body, which would overwhelm us. The innate immune system prevents this from happening and keeps us alive until the adaptive immune system can kick in. It is an early warning system that alerts the body to a viral invasion. Sometime after infection you feel terrible because you have some combination of fever, body aches, inflammation, and loss of appetite. These symptoms are side effects of the actions that the innate immune system takes to fence in viruses near the site of infection and slow the growth and spread of virus particles. The adaptive immune system becomes fully active about a week after infection, and this is usually when you start feeling better. This is because your adaptive system has generated a response specifically tailored to the infecting virus, and, working together, innate and adaptive immunity are vanquishing the virus and eliminating it from your body. A memory of this victory is also established. Our story describing how all this works begins with how the immune system first encounters the infecting virus.

  How the Infecting Virus Meets the Immune System

  As we saw in chapter 3, to get into a cell, the proteins on a virus’s surface bind to receptors on human cells. For example, the spike protein of SARS-CoV-2 binds to ACE2, its receptor on cells in the lung and other tissues. The virus then hijacks our own cell’s machinery to assemble many new virus particles that are released from the host cell. These virus particles spread through the spaces in between the cells that make up tissues, looking for new cells to infect. A type of Metchnikoff’s phagocytic cells, called a dendritic cell, lives in all tissues. Dendritic cells are like sentinels that constantly sample and ingest things in the environment in between the tissue cells. Most of the time, they ingest some waste product of a cell. But, if due to an infection, there are virus particles present, a dendritic cell will ingest them. When this happens, a dendritic cell pulls up its stakes and leaves the tissue. The fluid in the spaces in between cells in tissues is called lymph. Just as arteries and veins carry blood to and from our tissues, lymphatic vessels drain the lymph from tissues. Among other substances, the lymph fluid contains virus particles and the dendritic cells that are ready to leave the tissue because they have eaten viruses. At regular intervals, the system of lymphatic vessels is interspersed with organs called lymph nodes. They act as filters that retain viruses and dendritic cells in lymph nodes near the infected tissue. Cells of the adaptive immune system circulate in blood, and enter lymph nodes by squeezing through the walls of blood vessels that pass through them. This is how the adaptive immune system meets the virus in a lymph node.

  Interactions between cells of the adaptive immune system, virus particles, and dendritic cells in a lymph node result in the generation of cells and their products that are like warriors equipped with specialized weapons designed to neutralize the effects of the specific infecting virus. These immune products migrate out of lymph nodes through lymphatic vessels that connect to the blood stream. They can then pass through blood vessel walls to enter tissues, where they prevent the virus from infecting new cells and kill the cells that are already infected. Antibodies are just one type of such specialized products that wage war with the virus. How antibodies specific for the invading virus are produced is the topic of the next section.

  Antibodies: An Important Arm of Adaptive Immunity

  After the discovery of antibodies to diphtheria toxin and other microbes, the obvious question was how humans could produce antibodies that were specifically tailored for neutralizing so many different disease-causing agents. Paul Ehrlich in Germany suggested that antibodies bind to their specific targets in the same way that a key fits a lock. The shapes of the antibody and the specific target that it binds to are complementary, just like the shapes of a key and a lock are matched. He then proposed that our cells’ surfaces have all the antibodies necessary for specifically recognizing all the disease-causing microbes and toxins that commonly attack humans.

  But this idea quickly ran into trouble because immunologists discovered that antibodies specific for chemical compounds were produced when these chemicals were injected into animals. As these compounds were not microbes or their toxins, this suggested that antibodies specific to almost anything could be generated. One idea proposed to explain this was that antibodies were flexible objects that could be actively molded into different shapes to bind to specific invading agents, including viruses and bacteria. But then how could memory for a previously encountered virus be retained? Why would the antibody maintain its shape after the virus was no longer present in the body?

  In the 1950s, Niels Kaj Jerne in Denmark and Macfarlane Burnet in Australia proposed a possible solution to the puzzles noted above. In the short story “The Library of Babel,” the Argentine writer Jorge Luis Borges describes a library in which there are books that contain every possible combination of letters. This library therefore contains every book that has been or could ever be written. Burnet proposed that the set of cells that comprised the immune system was like this library. Analogous to the sequence of letters in one book, each immune cell was equipped with an antibody that could bind to something different. So, we could mount immune responses specific to anything that we encountered in the past, present, or future. When a particular microbe or chemical invades us, the immune cell with the right antibody specificity binds to the invader. Binding causes this particular cell to multiply. The resulting progeny can then neutralize the infecting agent. Burnet also reasoned that memory of each past infection is imprinted in us because now the body would have many copies of the cell type with antibodies specific for the corresponding microbe. So, upon reinfection, the response would be rapid and robust because now, instead of only one cell specific to the microbe, many would be ready and waiting.

  This model implied that every human is born with a huge diversity of immune cells, each with a different antibody. To be able to recognize almost anything specifically, each of us must have millions of different antibodies. But humans have only about 20,000 genes that encode information about all the proteins our cells can make. How could we have many more different types of antibodies than genes?

  This puzzle was solved in 1976 by Susumu Tonegawa, a Japanese scientist then working in Basel, Switzerland. It had long been known that antibodies are produced by a type of cells called B lymphocytes, or B cells. B cells display a protein on their surface called the B cell receptor (BCR). Tonegawa discovered that the gene encoding information about the BCR is different in each B cell. This is because the BCR gene is comprised of different bits of DNA that have to be joined together to make a complete gene. Our DNA contains many flavors of each of these bits. One flavor of each bit is randomly picked and joined to assemble the BCR gene of a B cell. A different combination of bits is picked for each B cell, and so an enormous diversity of B cells with different BCRs can be generated. Indeed, each of us has about 100 billion B cells, and there are at least as many as 10 million types of B cells, each with a distinct BCR. So, most B cells have a BCR that is distinct from that of other B cells. Tonegawa’s finding was very surprising because until then it was believed that every cell in a person’s body had an identical copy of DNA. Tonegawa discovered that this was not so for B cells, and he was awarded a Nobel Prize in 1987 for this important discovery.

  What does Tonegawa’s discovery about B cells with different BCRs have to do with antibodies? When a B cell meets a virus particle i
n a lymph node, if its BCR can bind sufficiently strongly to a part of this virus’s spike, then chemical reactions occur inside the B cell that cause it to start multiplying. The progeny secrete a soluble form of their BCR, and this is what we call an antibody. So, BCRs are basically antibodies displayed on the surface of B cells, just as Burnet and Jerne had proposed. It is remarkable that the insights of Burnet and Jerne based just on their imagination turned out to be largely correct. Burnet was awarded a Nobel Prize in 1960, and Jerne won his in 1984.

  The secreted antibodies circulate through the blood and all tissues of the body, searching for the infecting virus that led to their production. An antibody binding to the spike protein on the virus can mask the spike, thus preventing the virus from attaching to receptors on human cells. Since this process neutralizes the virus’s ability to infect healthy cells, such antibodies are called neutralizing antibodies. Antibody-bound viruses are destroyed, either because they are eaten by phagocytic cells or because chemicals in our blood can bind to the antibodies and punch holes in the virus surface.

  A puzzling thing happens as the infection progresses that was first demonstrated by the late American physician and scientist Herman Eisen. Eisen spent part of World War II serving as a doctor on a navy ship. He did not have much to do sometimes, and so he read books on immunology. He found the topic fascinating, and after the war, he increasingly became interested in immunological research, and less so in practicing medicine. In experiments carried out with rabbits, Eisen and colleagues showed that the antibodies became more potent as time ensued after infection. Indeed, they found that antibodies could increase their potency over 1,000-fold in 1–2 weeks. Burnet’s ideas could not explain this increase in antibody potency.

  The answer ultimately came from Darwin’s ideas on evolution. Darwin’s landmark studies described how species continuously evolve to become fitter, or better suited to their environment. This process occurs because mistakes are made when our genetic material is copied, leading to mutations. Darwin’s theory of evolution says that, over time, individuals with mutations that confer traits that enhance fitness take over the population. B cells undergo such a Darwinian evolutionary process during the first 1–3 weeks after infection. B cells that bind sufficiently strongly to a virus get activated and multiply in lymph nodes. During this process, mutations arise in the BCRs of the progeny of the activated B cells at an unusually high rate. The new B cells with mutated BCRs compete with each other to bind to the virus that caused the parent B cells to get activated. B cells that bind better survive, while the others die. Some of the B cells that survive leave the lymph node and secrete antibodies. However, the vast majority of the B cells that survive remain in the lymph node for further rounds of mutation and selection. The repeated rounds of mutation and selection result in B cells with BCRs that bind increasingly more avidly to the virus’s spike. The corresponding antibodies that they secrete are thus more potent in masking the virus’s spike and neutralizing its ability to infect human cells.

  The antibody molecule has a Y shape with two identical binding sites for the virus spike. The stem of the Y-shaped antibody can be of different types, each of which can enable different antibody functions. During an infection, the first antibodies that are produced have stems of a type called IgM. As the infection progresses, the antibody response often changes to another type of antibody called IgG. There are other types of antibodies with different functions. For example, an antibody type called IgA specializes in protecting the surfaces of the body and is secreted into the gastrointestinal tract and the airway surfaces of the lung, mouth, and nose. Here they bind to and block viruses from attaching to and entering cells.

  Antibody Tests and Their Significance

  As described above, potent antibodies specific for the virus emerge 1–2 weeks after infection. Even after the infection is cleared from the body, these antibodies usually continue to circulate in the blood and tissues for a period of time (see more on the duration below). This is why a common way to screen individuals for a viral infection is to test whether they have antibodies specific to that virus in their blood. For example, the HIV screening test determines whether antibodies specific to the HIV virus are present. These so-called serological tests can be highly sensitive and specific, relatively simple, and inexpensive. The basic procedure is to mix a blood sample with the virus’s proteins. If antibodies specific to the virus are present, they bind to the viral proteins. The bound antibodies can be detected by using a second antibody that binds to all human antibodies. There are many ways to perform this test. In one method, the virus’s proteins are attached to a gold bead. If anti-viral antibodies are present in the blood, they bind to the bead. The mixture of blood and gold beads flows past a surface on which the second anti-human antibody is attached. If the anti-viral antibody is present, the gold beads are captured as the anti-human antibodies bind to the antibodies on them. The captured gold beads are easily visualized. Commercially made tests are available to test for antibodies specific for many microbes. Examples include measles, HIV, hepatitis C, tetanus, diphtheria, and SARS-CoV-2.

  During the COVID-19 pandemic, it was critical to diagnose potentially infected people quickly to determine how widespread the disease was and to identify whether an acutely ill or hospitalized patient was infected with the virus. At early stages of infection, specific antibodies are not likely to be detectable. That is why during the COVID-19 pandemic, direct detection of the virus using the method described in chapter 3 was at first the preferred way to test for infection.

  Later, as the pandemic progressed, antibody tests were deployed to identify those who were infected in the past but may not have been tested for the virus. As we will see in the next chapter, after the initial phase of a pandemic it is important for public health officials, employers, and the public to know how many have recovered from the disease and thus may be immune to reinfection. The accuracy required for a test to be useful for this purpose depends on circumstances. Antibody tests have to be specific. A test that produces false positives would mislead individuals, the public, and public health officials into believing that an individual or a large proportion of the population has recovered from the disease and is likely immune. The required accuracy of a test depends on the proportion of the population that is infected. Suppose that a particular vendor’s antibody test has a 5 percent error rate. If 90 percent of the population is antibody positive, this test may be adequate for estimating the fraction of infected people and for guiding public health policy. However, if only 10 percent of the population is antibody positive, a more accurate test is likely required.

  Recall that IgM antibodies arise early in the infection, followed by the more potent IgG antibodies. Thus, IgM type antibodies by themselves are usually an indicator of early infection. The presence of sufficient numbers of IgG antibodies usually signals that the person is likely to be protected from reinfection. COVID-19 is a disease of the respiratory tract, and so it may also be important to test for the presence of IgA antibodies because they protect surfaces in our lungs, mouth, and nose. Indeed, some of the antibody tests being developed now for SARS-CoV-2 infection status look for IgM, IgG, and IgA antibodies.

  For reasons that are not properly understood, depending on the infecting virus, antibodies circulate in our blood and tissues for varying periods of time after recovery. For some viral infections, protection is conferred for the lifetime of an individual who has recovered. Available data suggest that antibodies generated upon infection with the virus that causes the disease SARS, which afflicted East Asia in 2003, circulate in recovered persons for up to two years after recovery from infection, but not much longer. While the SARS-CoV-2 virus that causes COVID-19 is closely related to the virus that causes SARS, it is not yet known for certain how long protective antibody levels circulate in persons who have recovered from COVID-19. For any viral infection, issues like this are clarified as more patient data become available.

  Circulating Antibodies Are
Not the Only Way to Retain Memory of Past Infections

  The absence of circulating antibodies does not mean, however, that a person who has recovered from an infection cannot rapidly ramp up production of protective antibodies shortly after reinfection. After a person clears an infection, most of the B cells that were produced by the rapid multiplication of B cells in response to the particular virus die. This feature ensures that your immune system is not strongly biased to combat the virus that you just vanquished, and this is important because the next infectious microbe that assaults you is likely to be different. Also, given that we constantly battle infections, if the B cells that grow to large numbers during every infection did not die, we would soon become one large B cell! However, some of the B cells that were produced in response to the infection that was just cleared remain as so-called memory cells, which can rapidly produce antibodies and mount a robust response upon reinfection with the same virus. Memory B cells are not detected by antibody tests. So, the persistence of circulating antibodies specific to the virus in the blood is not the only way that memory of past infections is imprinted in our immune system.

  T Cells: The Other Important Arm of Adaptive Immunity

  As we described, antibodies principally attack free virus particles in blood or in the spaces in between cells in tissues. But this means that infected cells and the virus particles that they harbor are protected from antibody attack. To clear the infection, we also need to destroy the infected cells. T lymphocytes, or T cells, kill infected cells. Because of the intense focus on antibodies in the first half of the twentieth century, how T cells function was understood only more recently.