Why We Get Sick

by Randolph M. Nesse

  We have mentioned several times that evolutionary hypotheses need to be and can be tested. Beverly Strassmann has mounted a challenge to the hypothesis that menstruation protects against infection. She maintains that the pathogen load in the reproductive tract is the same before and after menstruation, that menstruation does not increase when there is infection, and that there is no consistent relationship between the amount of sperm females in a particular species are exposed to and the amount of menstrual flow. As an alternative explanation, Strassmann proposes that the degree of shedding or reabsorption of the uterine lining depends on the metabolic costs of maintaining it or shedding it, a hypothesis that she supports with comparisons between species and the relationship between menstruation and the body weight of the female and her neonate. Obviously, we have not heard the last word on this issue.

  MECHANISMS TO ATTACK INVADERS

  Vertebrates in general, and mammals in particular, have amazingly effective immunological defenses that are in essence a system of carefully targeted chemical warfare. Cells called macrophages constantly wander the body searching for any foreign protein, whether from a bacterium, a bit of dirt in the skin, or a cancer cell. When they find such an intruder, the macrophages transfer it to a helper T cell, which then finds and stimulates whichever white blood cells can make a protein (called an antibody) that binds specifically to that particular foreign protein (an antigen). Antibodies bind to antigens on the surfaces of bacteria, thereby impairing the bacteria and also labeling them for attack by specialized larger cells. If the antigens persist, say during a continuing bacterial infection, they stimulate the production of ever more of the cells that make that specific antibody, so that the bacteria are destroyed at an ever-increasing rate. Whatever is recognized as a properly functioning part of the body is permitted to remain. All else—disease organisms, cancerous tissue, organs transplanted from other individuals—is attacked.

  How does the body recognize cells as its own? Each cell has a molecular pattern on its surface, called the major histocompatibility complex (MHC), which is like a photo ID card. Cells that have a valid MHC are left alone, but those that have a foreign or missing MHC are attacked. Interestingly, when cells are infected, they transport protein from the invader to the MHC, where it is bound. Like individuals with obviously fake ID cards, such cells are priority targets for the killer cells of the immune system. The adenovirus, a common cause of sore throats, has found a way to get around this defense. It makes a protein that blocks the ability of the cell to move foreign proteins to the MHC. In essence, it prevents the infected cell from signaling that it has been invaded.

  The operation of the MHC system is a vivid example of altruism in its biological sense. An infected cell “volunteers” for destruction for the good of the rest of the body. This is like a soldier with plague asking his comrades to destroy him before he infects them. The analogy, however, is false in one crucial respect. The cell’s comrades are genetically identical, and its only chance for passing on its genes lies in the success of the whole organism. Soldiers, however, seldom share foxholes with identical twins and are understandably less likely to volunteer for elimination.

  The weapons of the immune system are truly fearsome. They include general inflammation, several kinds of antibodies—each specialized for a different group of opponents—and a series of chemicals (the complement system), five of which attack the targeted cells, boring holes in their membranes and digesting them. Despite these weapons, some invaders can nonetheless persist. When a clump of bacteria can be neither expelled nor destroyed, it may be walled off by a membrane that keeps it away from vulnerable tissues. The tubercles from which tuberculosis gets its name are the best-known example, but analogous imprisonment of roundworms and other multicellular parasites has also been important throughout most of human evolution.

  DAMAGE AND REPAIR

  In the contest with their host, pathogens must rob the host to secure their own nourishment. Various bacteria and the protozoa that causes amoebic dysentery secrete enzymes that digest nearby host tissues and then absorb the products of digestion. Others literally eat through host tissues, for example, filaria worms, which live in the anterior part of the eye, or the larvae of another species of worm, Angiostrongylus cantonensis, which burrow through the brain. Both of these defend themselves with secretions that inhibit inflammation. Still others, such as the trypanosomes, a group of protozoans that cause diseases such as African sleeping sickness, live in the bloodstream and absorb nutrients directly from the plasma. Whatever the means, parasites secure their resources from the host and then use them for their own maintenance, growth, and reproduction.

  These activities of pathogens incidentally damage the host, but this damage is not a pathogen adaptation. It does not do a tapeworm any good to have its host malnourished. It does not do the malarial parasite any good to destroy its host’s blood cells (unless, perhaps, this frees up iron for use by the parasite). Most often, the opposite must be true. The survival and well-being of the parasite depend on the host’s continued survival and ability to provide it with nourishment and shelter. Such incidental damage must therefore be considered a cost to both host and pathogen.

  The cost may be a general reduction in host resources or an obviously localized destruction. Bacteria that attack bone where a tooth is rooted cause structural damage and perhaps the loss of the tooth. The bacteria that cause gonorrhea may erode the connective tissue and cartilage of joints, causing functional impairment. Hepatitis viruses may destroy substantial portions of the liver, so that all liver functions, such as the clearing of toxins from the blood, become less effective. Such functional impairments are simply incidental consequences of pathogen adaptations. It does not do bacteria any good to make the host’s chewing less effective or its running less rapid.

  It’s important to keep damage conceptually separate from any resulting functional impairment. The damage causes the impairment, which can then itself be a cause for another host adaptation, which we call compensatory adjustment. There are many examples, some much more subtle than chewing on the left side of your mouth if it hurts to chew on the right. For instance, when disease-damaged lungs become less effective at oxygenating the blood, this may be partly compensated for by an increase in blood hemoglobin concentration. The body has a mechanism that monitors the oxygen level in the blood. If there is too little, whether from living at a high altitude or from lung damage, the body makes more erythropoietin, a hormone that stimulates the production of more red blood cells.

  Another obvious host adaptation is repair of damage. Natural selection has adjusted the ability to regenerate various tissues according to how useful it would normally be to do so. The skin, which is often damaged, is a first line of defense against pathogens and injuries. As might be expected, it quickly regenerates and rapidly recovers its protective capabilities. Other structures that regenerate quickly are the lining of the gut and organs such as the liver, which are in open communication with the gut and therefore with the outside world and its infectious agents. By contrast, the heart and especially the brain are less accessible to most pathogens. If pathogens do gain access and cause serious damage, it is ordinarily fatal, so regenerative capabilities would rarely be of benefit.

  PATHOGEN EVASION OF HOST DEFENSES

  So far we have mentioned only one kind of pathogen adaptation, the ability to nourish itself in the body of the host. We can also expect it to have evolved ways of shielding itself from the host’s efforts to destroy, expel, or sequester it. We will now turn to one such mechanism, evasion of host defenses.

  The first trick for many parasites, once inside the body, is to gain entrance to cells. Invaders may accomplish this just as door-to-door peddlers do, by appearing to offer something else. The rabies virus binds to acetylcholine receptors as if it were a useful neurotransmitter; the cowpox virus to epidermal growth-factor receptors as if it were a hormone; and the Epstein-Barr virus (which causes mononucleosis) to a C4 receptor. Rhin
ovirus, a common cause of colds, binds to the intercellular adhesion molecule (ICAM) on the surface of the lymphocytes that line the respiratory tract. This is extremely clever, since attacking lymphocytes releases chemicals that greatly increase the number of ICAM binding sites, thus providing many more openings by which the virus can enter cells.

  Another trick is to evade the immune system. The trypanosome that causes African sleeping sickness does this by rapidly changing its disguises. It takes the body about ten days to make enough antibodies to control the trypanosome, but on about the ninth day, the trypanosome changes its disguise by exposing an entirely new surface layer of proteins, thus escaping attack by the antibodies. The trypanosome has genes for more than a thousand different antigenic coats and so can live on for years in the human host, always one step ahead of the immune system. Two other common bacteria use similar strategies. Hemophilus influenza, a common cause of meningitis and ear infections, and Neisseria gonorrhoeae, the cause of gonorrhea, both have what seem to be flaws in the genetic mechanisms that make their surface proteins. The seeming errors are useful, however, because the resulting variation makes it hard for our immune systems to keep up with the random changes.

  Malarial parasites have special surface proteins that allow them to bind to the walls of blood vessels so that they are not swept to the spleen, where they would be filtered out and killed. The genes that code for these binding proteins in malarial parasites mutate at a rate of 2 percent per generation, just enough so that the immune system cannot lock in on the organism. The pneumococcal bacteria that cause pneumonia use a different trick to circumvent the immune system. They have “slippery” polysaccharides on their surface that white blood cells can’t get a grip on. The body copes with this by making chemicals called opsonins, which bind to the microbe like handles that the antibodies can grab.

  Another common evasion is a chemical analog of a disguise a spy might use behind enemy lines. The external chemistry of some bacteria and some worms is so similar to that of human cells that the host may have difficulty in recognizing them as foreign. (Thus antibodies sometimes attack both invader and host cells.) The streptococcus bacterium, a longtime associate of humans, is especially adept at this trick. The antibodies to some strains cause rheumatic fever, in which a person’s antibodies attack his or her own joints and heart. Similar antibody attack on nerve cells in the basal ganglia of the brain can cause Sydenham’s chorea, with its characteristic uncontrollable muscle twitches. Interestingly, many patients who have obsessive-compulsive disorder, a psychiatric illness characterized by excessive hand washing and fear of accidentally harming others, had Sydenham’s chorea in childhood. There is now growing evidence that the brain areas involved in obsessive-compulsive disorder are very close to those damaged by Sydenham’s chorea. Thus, some cases of obsessive-compulsive disorder may result from the arms race between the streptococcus and the immune system.

  Chlamydia, today’s most common cause of venereal disease, does the equivalent of hiding in the police station. It enters white blood cells and then builds a wall to prevent itself from being digested. Schistosomes of the mansoni type go a step further and essentially steal police uniforms. These parasites, a serious cause of liver disease in Asia, pick up blood-group antigens so that they may look to the immune system like our own normal blood cells.

  ATTACK ON HOST DEFENSES

  Pathogens not only attempt to shield themselves from the weaponry of the host, they also have destructive weaponry of their own. The bacterium that causes most simple skin infections, Staphylococcus aureus, secretes a neuropeptide that blocks the action of Hageman’s factor, a crucial first step in useful inflammation. Bacteria that cannot secrete this peptide do not cause infection. Even the common streptococcal bacteria that cause so many sore throats make streptolysin-O, which kills white blood cells. Vaccinia, the virus that causes cowpox, makes a protein that inhibits the complement system, an important host defense, as noted previously. Why doesn’t the complement system attack our own cells? In part because our cells have a layer of sialic acid, a chemical that protects them from attack by the complement system. Sure enough, certain bacteria, in this case the K1 strain of the common E. coli that live in our guts, are able to cover themselves in sialic acid and thus gain protection from the complement system.

  One of the great dangers of serious infection with certain kinds of bacteria is shock, a decrease in blood pressure that can be rapidly fatal. Shock is caused by chemical lipopolysaccharide (LPS) formed by the bacteria. Superficially, it would seem that LPS is a toxin made by bacteria to harm us, but, as researcher Edmund LeGrand has noted, this is unlikely, because LPS is a necessary component of the cell wall of this whole group of bacteria. Hosts recognize this reliable cue to the presence of dangerous infection and react strongly—sometimes too strongly. Here is an example of a defensive weapon that can turn on its bearer.

  The human immunodeficiency virus (HIV), the virus that causes AIDS, hides in the helper T cells that bring antigens to the attention of the immune system. These cells have a protein in their outer membrane called CD-4, to which the HIV binds to gain entrance to cells. This protein on HIV would make it vulnerable to the immune system, except that it is hidden in deep crevices in the viral wall. As HIV kills helper T cells, it incidentally causes the victim to be ever more vulnerable to other infections and cancer, the problems that eventually kill a person who has AIDS.

  OTHER PATHOGEN ADAPTATIONS

  There remain two related categories of parasite adaptation. No matter how well a pathogen survives and proliferates in a host, it must have a dispersal mechanism so that it can get itself or its descendants into other hosts. For external parasites this can be rather easy. Lice and the fungus that causes ringworm, for example, are readily spread by personal contact. Internal parasites face greater problems. Those that can regularly get onto the skin have the possibility of contact with other susceptible individuals. Cold viruses and intestinal bacteria may get onto hands or other surfaces and be spread by handshakes or more intimate contact.

  Microorganisms in the bloodstream are not likely to be spread in this way. Many can be transmitted only with the help of biting insects or other transport agents (vectors). Malaria is a well-known example. If there are about ten malarial parasites in the dispersal stage (called gametocytes) in each milligram of blood and a mosquito sucks up three milligrams, it will be taking in about thirty gametocytes. The next item on the mosquito’s agenda is to convert this rich blood meal into eggs and get them fertilized and laid in an environment suitable for development. Meanwhile, the sexually produced offspring of the malarial plasmodia have migrated to the mosquito’s salivary glands, where they transform into an infectious stage in the fluid that will be used to inhibit clotting when the mosquito sucks up its next blood meal. The mosquito then unwittingly injects the plasmodia into the next victim. An enormous variety of insects and other organisms can serve as vectors of human diseases.

  Another kind of parasitic adaptation is technically termed host manipulation. By subtle chemical influence a parasite may gain some control over the machinery of the host’s body and cause that machinery to serve the interests of parasite rather than host. Many curious examples are known from many groups of organisms. The tobacco mosaic virus causes its host to enlarge the pores between adjacent tobacco cells enough to allow the virus particles to pass through and infect other cells. One kind of parasitic worm alternates its life stages between ants and sheep, just as malarial parasites must alternate between vertebrate hosts and mosquitoes. The worm is effectively transmitted from an ant to a sheep because it enters certain sites in the ant’s nervous system where it causes the ant to climb to the top of a blade of grass and hang on, unable to let go. This greatly increases the likelihood that the ant will be eaten by a sheep. Another kind of worm alternates between snails and gulls. It causes the snail, which is ordinarily hard to find in the tangled growths of shallow coastal waters, to crawl up to a high level of bare rock or
sand and stay there. It is then easily seen and eaten by a gull.

  The rabies virus offers a particularly remarkable and gruesome example of how a pathogen can manipulate a host’s behavior. After gaining entrance to the body, usually via the bite of an infected individual, the rabies virus moves along nerve fibers to the brain, where it concentrates in regions that regulate aggression. It can then make the host attack and bite, thereby infecting other individuals. It also paralyzes the victim’s swallowing muscles, thus causing virus-laden saliva to build up in the mouth, increasing the likelihood of transmission and incidentally causing the victim to have the terror of choking on fluids that originally gave the disease the name hydrophobia.

  Perhaps the most important human examples of manipulation by pathogens are the sneezing, coughing, vomiting, and diarrhea triggered by bacteria and viruses. At some stage in the history of an infection, this expulsion will serve the interests of both host and microbe. The host is benefited by having fewer pathogens attacking its tissues, the microbe by an increased chance of finding other hosts. The losers in this game are currently healthy but vulnerable individuals. A chemical released by cholera bacteria reduces absorption of liquid from the bowel, causing profuse diarrhea that, in a society without well-developed public hygiene, can effectively spread an epidemic.

  Sometimes we are successfully manipulated by our parasites, at other times we successfully resist manipulation, and in still other situations there is some intermediate resolution. Any given example of such a conflict is likely to be at an evolutionary equilibrium and have a consistent outcome. Conflicts are often decided in favor of the antagonist that has the most to gain from winning. If someone is sneezing twice as often as would be ideal for the control of a cold virus, that is not likely to be a great burden of lost time or energy, but it may nearly double the rate at which the virus reaches new hosts. This is just the sort of contest we would expect the virus to win. How frequently are expulsion mechanisms exaggerated by pathogens beyond what would be optimal to a human host? The paucity of evidence on this issue shows the habitual neglect of such evolutionary questions.