Influenza is an RNA virus that, unlike coronaviruses, does not have a proofreader. So, its proteins, including HA and NA, mutate continuously. For reasons that will become clear in the next chapter, humans often mount strong immune responses against influenza that target HA and prevent it from binding to its receptor. This prevents the virus from infecting new cells, and the infection is controlled. Vaccines also elicit immune responses designed to target HA and thus prevent infection. As the winter progresses, many people develop immune responses to the HA proteins in the circulating strains of the influenza virus, due either to natural infection or to vaccination. Thus, they become immune to these viruses. The virus mutates, and the mutant strains that are both functional and able to evade this shield of immunity established in past years then prevail among the circulating strains the following year. Thus, the war between influenza and our immune systems continues every year.
The World Health Organization has a network of people and countries who surveil the world, sequencing RNA from influenza viruses. Based on this data, and which viruses have circulated among humans in past years, a group of experts make educated guesses about which strains of influenza are likely to be prevalent in the next year. Next year’s vaccine is then designed. It usually takes several months to manufacture millions of doses of next year’s flu shot, and so this decision is made well before the flu season begins. Even if the educated guess that leads to the design of the vaccine is not correct in some years, since the prevailing mutant strains of influenza that circulate in a given year are usually not too different from ones in past years, most people have partial immunity to them. So, illnesses and deaths are mostly confined to vulnerable groups, such as the elderly and the immunocompromised. But influenza nevertheless kills anywhere between 15,000 and 60,000 people every year in the United States.
The number of deaths and hospitalized patients changes dramatically when influenza pandemics arise. There have been four such pandemics in the last century, in 1918, 1957, 1968, and 2009. Twenty to fifty million people died during the 1918 pandemic, when the world population is estimated to be almost four times smaller than today. How do influenza pandemics arise?
The RNA genome of the influenza virus is made up of eight discrete segments, each of which encodes information about one or two of its proteins. Influenza viruses can also infect animals, such as birds and pigs. Of course, these viruses are different because they have adapted to live in their host animals. However, each of the eight segments of the influenza genome is like a cassette that can be taken out and replaced by another variant of the same gene segment. For example, one of the eight segments encodes information about HA, which is the spike protein. A particular variant of this segment could be swapped for another variant. If the new spike protein is compatible with the proteins encoded by the other gene segments, you have a viable virus. But now the virus has a completely new HA spike to which humans have no immunity, and such a novel influenza virus could cause a pandemic. Indeed, influenza pandemics occur when gene segments of the virus circulating in humans are swapped with those of a bird or a pig.
The 1957 pandemic occurred when three gene segments in the influenza virus that was circulating in humans at the time were swapped with those from a bird influenza virus. The swapped segments included the one corresponding to HA. The 1968 pandemic arose when two gene segments of the strain then circulating in humans, including the one for HA, were swapped for those from birds. The bird viruses are not well adapted to thrive in humans, but since the majority of gene segments in the pandemic causing viruses that emerged in 1957 and 1968 were from viruses that were already circulating in humans, they thrived in the human population. Swaps of gene segments from different influenza viruses usually occur during coinfections. A person who works closely with birds that harbor influenza viruses could be infected by a bird virus and a human virus at the same time, and the viruses might swap their gene segments by a process called gene reassortment. These swaps likely do not produce viable viruses most of the time, but sometimes, as in 1957 and 1968, they do so with devastating consequences.
The 2009 pandemic, however, was caused by a virus that emerged in pigs and directly infected humans. This was likely because multiple viruses derived from humans, pigs, and birds were circulating in pigs at that time. It is thought that a number of reassortments occurred within pigs until the pandemic-causing virus that thrived in humans emerged. We are much more similar to pigs than to birds, which may have helped the direct jump of the virus from pigs to humans in 2009.
Human Immunodeficiency Virus (HIV)
In Africa, a relative of the HIV retrovirus circulates in many species of primates like monkeys and apes. It is believed that HIV, the form of this virus that can infect humans, jumped from a certain kind of chimpanzee to us. Hunters who captured chimpanzees for meat (bush meat) came in contact with blood from these animals and ate the meat. This sort of contact with a large amount of the animal virus likely allowed a few mutant forms of the virus that could multiply in humans to emerge in a few individuals. Using computational approaches based on viral sequences and rates of mutation, scientists now believe that HIV started circulating in humans perhaps as far back as the 1920s, primarily around the Republic of Congo in Africa. It was only in the early 1980s, however, that a number of unusual cases of lung and mouth infections and cancer, all among young men in California and New York, raised the alarm that a new type of disease might be spreading. This is because these conditions usually arise in people whose immune systems are compromised, and young healthy people are not normally immunocompromised. In 1981, Dr. Michael Gottlieb, an immunologist at the University of California Los Angeles Medical Center, published a report of the cases in California among young gay men in the CDC’s Morbidity and Mortality Weekly Report. This marked the beginning of the pandemic disease that we call acquired immunodeficiency syndrome (AIDS).
In 1983, Françoise Barré-Sinoussi and Luc Montagnier at the Pasteur Institute in Paris announced that they had identified the virus that is the causative agent of AIDS. In 1984, Dr. Robert Gallo at the National Institute of Health in the United States, who had previously discovered the first human retrovirus, reported that his laboratory had also identified the retrovirus that caused the disease. Soon it was realized that the two viruses were identical. A test was then developed, which is used to this day. There was a bitter patent rights dispute between the United States and France, which was ultimately resolved in 1987 when Presidents Reagan and Chirac agreed to share the profits, and donate the bulk of it for AIDS-related research and treatments. Barré-Sinoussi and Montagnier shared the Nobel Prize in 2008 for their discovery of HIV.
HIV is transmitted to others by exchange of bodily fluids, such as blood, semen, and milk from lactating mothers. Before tests were available, tainted supplies in blood banks infected hemophiliacs. Initially, it was thought that the disease infects only gay men or intravenous drug users, but this is not true. Heterosexual sex is the principal cause of HIV infections in sub-Saharan Africa, the epicenter of the disease today. To date, HIV has infected almost 75 million people, and as many as 40 million people have likely died from complications associated with AIDS. In South Africa, there are still approximately 1,000 new infections every day.
Upon initial infection, HIV causes flu-like symptoms that then go away. The virus infects a cell that plays a key role in coordinating our immune responses, resulting in a decline in the number of these cells. This is why patients have a compromised immune system, which results in vulnerability to infections that our immune system normally controls with ease. Without treatment, ultimately, the numbers of the immune cells decline to very low levels, resulting in death. Today, innovations in HIV drug treatment (described in chapter 6) keep the virus under control in treated individuals. But the virus is not eradicated in these people, and it comes right back if treatment is interrupted. The search for a cure for HIV is an active area of research, as is the search for a vaccine. After over 30 years of effo
rt and enormous expense, we still do not have a vaccine that can protect against HIV infection. As we will see in chapter 7, this is because HIV mutates at a very high rate. Fortunately, this is not the case for the virus that caused the COVID-19 pandemic.
Why Do RNA Viruses Cause So Many Pandemics?
As we have described, most RNA viruses mutate quite a bit. Also, their genomes are relatively malleable, which makes possible reassortment of genes as occurred during influenza pandemics, or recombination of genes as that which might have resulted in COVID-19. This malleability and the circulation of related forms of RNA viruses in animals make the emergence of new RNA viruses a perpetual existential threat to humanity. For example, an influenza pandemic is always waiting to happen. Various forms of influenza viruses circulate among birds and pigs. Humans interacting closely with pigs and poultry in farms and markets can facilitate exchanges of the influenza virus between them and these animals. The global population will have no immunity to the new virus, and if, like SARS-CoV-2, it is easily transmitted by casual human contact and is quite lethal, a pandemic will result. As the COVID-19 pandemic has made vivid, this threat is not localized to particular nations or peoples.
Examples of DNA Viruses
DNA viruses are a different beast. Most have a double-stranded helical DNA genome, just like us. As we described earlier, double-stranded DNA can be copied with very high fidelity. So, mutations are rare, which allows DNA viruses to have much longer genomes than RNA viruses. For example, the herpesvirus genome has around 80–100 genes, and smallpox has around 200. Most RNA viruses contain about 10 genes or fewer. With many more genes, DNA viruses are more complex machines and do not change guise as rapidly as RNA viruses.
DNA viruses are very familiar to us, especially those that belong to the herpes family. The herpesvirus family includes the viruses that cause chicken pox and shingles (varicella zoster), cold sores and contagious genital rashes, and mononucleosis (Epstein–Barr virus). Another herpesvirus known as cytomegalovirus (CMV) is also prevalent. Most people are infected by one or more herpesviruses by the teenage years. These viruses are passed from human to human in different ways, but close human contact is usually necessary.
Herpes is an ancient virus, which inserts its genome into the nucleus of the host cell. So, after infection, the cell is permanently infected. For most of us, the virus stays silent after one recovers from the initial infection, and never bothers us again. But in some cases, the virus can reawaken and make new virus particles. This is what happens during a shingles outbreak. After exposure to chicken pox in childhood, the virus hibernates in cells of the nervous system. Usually in older adults, the virus can reawaken and cause a reddened, painful, skin condition, which we call shingles. We really do not understand why the virus gets activated again. It is likely that the immune system normally keeps the virus under control. But in stressful circumstances, or when the immune system is suppressed, herpesviruses are reactivated. Reactivation can occur with all herpesviruses, not just the one that causes chicken pox.
With this understanding of the enemy, viruses, let us turn to our immune system, which combats these scourges on the planet.
4 Immunity
The immune system is our department of defense. It serves as a shield that protects us from invasion by infectious, disease-causing microbes, and combats them if they succeed in infecting us. Our immune system also interacts with other physiological systems to influence health and disease in myriad important ways. In this book, we will focus on how the immune system functions to combat, and usually vanquish, viruses. The concepts that we describe are also generally applicable to how our immune system battles other microbial pathogens.
A remarkable feature of our immune system is that upon infection with a virus, we can mount an immune response that is specifically tailored for it. Think about how amazing that is: the SARS-CoV-2 virus, which causes the illness COVID-19, did not exist when most people living today were born, yet the immune system of infected people responded in a way that was specifically designed to combat this virus. Equally remarkably, our immune system remembers past infections. It responds rapidly if the same virus reinfects us and swats it away before it can cause disease. Assuming SARS-CoV-2 is like most viruses that we encounter, people who have recovered from COVID-19 are likely to be protected from reinfection for at least some time. For some viruses, immune memory can protect us for many years, even for life. This virus-specific memory is the basis for vaccination. An effective vaccine elicits memory immune responses that are specific to a virus against which we wish to protect the population.
In this chapter, we will explain how our immune system mounts responses that are tailored to a particular virus, and how memories of past infections are formed to protect us from reinfection. Our narrative roughly follows the historical order in which various aspects of how our immune system functions were discovered. In the last section, we provide a brief summary of how the immune system works.
The Dawn of the Modern Era of Immunology
Blood or Cells
Wounds and microbial infections often lead to inflammation—that is, swelling, redness, heat, pain, and the accumulation of pus. In the nineteenth century, it was known that plants and animals were composed of cells. It was also known that a strong inflammatory response was often a harbinger of a bad outcome for the patient and that pus was composed of dead cells. Therefore, inflammation was considered to be harmful, and the participating cells were considered to promote illness. It was even thought that these cells could spread disease-causing microbes throughout the body. In spite of these prevailing beliefs, in the late nineteenth century Ilya Metchnikov made the heretical proposition that the cells involved in inflammation were the good guys, the body’s first responders to infection and injury.
Metchnikov was born in Russia in 1845, but later emigrated to France where he became known as Élie Metchnikoff. He was a zoologist by training, and had a long-standing interest in the digestive processes of animals. This interest may have influenced his thinking when he made an important discovery about how our immune system works.
One day in 1882, when Metchnikoff was working in Messina, a city in Sicily, he was observing starfish larvae. The starfish were transparent, and so he could watch their cells moving around. A sudden thought occurred to him. What if our cells that moved around could travel to the site of a wound or infection, and surround it to isolate and eliminate the problem? Metchnikoff decided to test his idea that night by inserting a splinter into a starfish. To his great satisfaction, he woke up in the morning to find that cells of the starfish had surrounded the splinter. He then thought that these cells might be trying to eliminate the invader by eating it. Thus began Metchnikoff’s lifelong work on trying to establish that cells of the immune system homed in on an area of microbial infection and then destroyed the microbe by ingesting and digesting it. The word phagein in ancient Greek means “to eat,” and so he labeled these cells phagocytes, and the process by which they ingest invading microbes, phagocytosis. Metchnikoff published a paper describing his observations in starfish, and proposed that inflammation was a beneficial response to infection or injury.
Ideas developed over millennia had led to the belief that inflammation was bad and that an imbalance of the humors, like blood, led to disease. Correcting this imbalance was thought to be critical for restoring health. This was why blood-letting was considered a therapy for many diseases. Given this background, Metchnikoff’s proposal was met with strong objections. Two camps emerged: the cellularists, who supported Metchnikoff, and the humoralists, who believed that healing was mediated by blood components. Akin to the Koch–Pasteur rivalry, the cellularists were mostly French, from Metchnikoff’s adopted country, and the humoralists were mostly German. The humoralists tried to show that blood products could neutralize the effects of various microbes and toxins. The cellularists believed that phagocytic cells were critical for responding to and getting rid of infectious, disease-causing microbes.
In 1890, Emil von Behring and Shibasaburo Kitasato reported important findings that supported the humoralists. The bacterium that causes diphtheria infects the mouth and throat and results in severe damage to these tissues, often causing suffocation and death. It was known that a toxin produced by the bacteria made it so lethal. Von Behring and Kitasato reasoned that if they vaccinated individuals with just the diphtheria toxin instead of the bacteria, they might generate an immune response that would block the toxin. Their experiment worked and they found that after immunization, there was something in the blood that specifically bound to the diphtheria toxin. It was then shown that transferring blood containing this antitoxin could protect the recipient from diphtheria’s effects. As tens of thousands of children died in Germany every year from diphtheria, von Behring worked with the Hoechst chemical and pharmaceutical company to develop these discoveries into a working therapy. Interestingly, well over a century after von Behring and Kitasato’s discovery, injecting people with blood products from people who have recovered from COVID-19 is being pursued as a therapy. Von Behring was rewarded for the discovery of this form of therapy, called serum therapy, with a Nobel Prize in 1901. Notably, Kitasato did not share this recognition.
Von Behring and Kitasato’s discovery was a great victory for the humoralists since a substance contained in blood was shown to be curative. So, although evidence kept trickling in that phagocytic cells played a role in the immune response, the cellularists had lost. Metchnikoff shared the 1908 Nobel Prize for his work on immunology, but it was generally believed by then that his observations, and those of his supporters, were unimportant for understanding immunity. For the next 50 years, most scientists working on immunology focused on understanding the origin and character of the blood products that confer immunity. These blood components came to be called antibodies. The protective role of cells was ignored until the second half of the twentieth century.
Viruses, Pandemics, and Immunity Page 6
