Why We Get Sick (8 page)

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.

S
o 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. Rhinovirus, 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.

P
athogens 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.

T
here 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.

W
e end this chapter by making three remarks about
Table 3-1
(
this page
), which classifies the signs and symptoms of infectious disease according to their functions. First, a functional classification of the signs and symptoms of disease is important and useful. In order to choose appropriate treatment, we need to know if the cough, or other symptom, benefits the patient or the pathogen. We also need to know if the pathogen is manipulating the host or attacking its defenses. Instead of just relieving symptoms and trying, perhaps ineffectively, to kill the pathogen, we can analyze its strategies, try to oppose each of them, and try to assist the host in its efforts to overcome the pathogen and repair the damage. The second point is that the classification is really rather simple and obvious.