Chapter 17 on disease

From a distance, meningococcus appears to be a ruthless and dangerous enemy of the entire human race.The epidemic has swept through military camps, campuses, and sometimes endangered the population of entire cities.That microbe invades the bloodstream, then invades the meningeal space, and the result is meningitis.In the days before effective chemotherapy, it was a terrible, highly fatal affliction.Meningococci seem to be particularly adapted to life inside the meninges of humans.In that sense, the encounter seemed targeted.You might even say that's how it makes a living.It is a predatory animal, and its prey is us.

But that's not the case.If you count the total number of meningococcal infections and compare the total number of meningitis victims, the arrangement takes on a different look.The actual cases of meningitis are always a very small minority.Yes, most people are infected with this bacterium, but in the carriers, it is only confined to the nasopharynx, and the carriers usually pass without knowing it.A few days after the infection, they produce antibodies against meningococcus in the blood of those people, and then the microbe either stays in the mucous membrane of the throat, or it doesn't, but that's the end of the matter.The central nervous system was not involved.

Meningitis cases are some exceptions.Meningococcal infection is usually a benign, transient upper respiratory infection, hardly an infection, but rather a peaceful association.It remains a mystery that some patients develop meningitis, but it is unlikely to imply that this is a particular penchant for that bacterium.It may be that something has gone wrong with the defense mechanisms of the infected patient, so that the meningococcus is granted access, invited in, so to speak.At any rate, the disease was some anomaly of nature, much like an accident. Viruses of lymphocytic choriomeningitis are ubiquitous in mouse populations.The typical disease it causes is a fatal meningitis in which an exudate from the surface of the brain is composed almost entirely of lymphocytes.At first glance, the disease seemed to represent an attack on the central nervous system by a virus specially adapted to this behavior.The reality, however, is that the disease is caused by the invasion of the surface of the brain by the host's own lymphocytes, not by any neurotoxicity of the virus.If the lymphatic response is prevented, e.g., by inducing infection in the embryo, a "tolerance" to that virus results, and the result is a persistent, ubiquitous viral infection including the CNS, but without any symptoms of encephalopathy .If the immune response was then restored by transplanting lymphoid tissue from normal, intolerant mice, meningitis developed within a few days.New arrivals of lymphocytes flood the surface of the brain in search of the virus, and that's what kills.Essentially, that disease is the result of the host's response to the virus.

Corticosterone has many properties.One of these, shutting down various defense responses to bacteria, also seems to shut down some of the most conspicuous clinical manifestations of infectious disease. In the early 1950s, when adrenal corticosterone was just available for clinical research, it was used to treat several cases of pneumococcal lobar pneumonia and several cases of atypical pneumonia.At first, what appeared to be miraculous clinical effects were observed.Within hours, the high fever, malaise, prostration, chest pain, and cough all subsided, and the patient himself felt as healthy as ever, was eating, and claimed to be up and about.But at the same time, X-rays revealed a surprisingly advanced course of pneumonia.Therefore, the test was immediately stopped.Later, other investigators observed a similar dramatic disappearance of the clinical picture in patients with typhoid fever and rickettsial infection, again with the unacceptable cost of accelerated infection spread.

The most striking example of host-dominated pathology is the cascade of responses induced in various animals by endotoxins of gram-negative bacterial lipopolysaccharides.In these cases, the bacterial toxin itself doesn't even appear to be toxic.Although that substance has a strong effect on various cells and tissues, including polymorphonuclear leukocytes, platelets, lymphocytes, macrophages, arteriolar smooth muscle, etc., and also has a strong effect on complement and coagulation mechanisms, but all These effects are completely normal reactions, everyday things in the normal course of life.What makes it catastrophic is that these mechanisms are turned on all at once by the host, as if in response to an alarm signal, and the result is widespread tissue destruction, as in a systemic Schwarzmann reaction; Failure, as in endotoxic shock.

Schwarzman reactions can be avoided by simply removing one of the participants in the reaction.Temporary removal of polymorphonuclear leukocytes can be done.The method is to treat with nitrogen mustard, or to prevent blood clotting with heparin.Animals thus treated were unable to develop either local or systemic Schwarzmann reactions.The phenomenon of fatal shock can be completely prevented by prior treatment with corticosterone. It is not yet known how endotoxins act to generate the signal, but the mechanism appears to be a very old one in nature.One of the most sensitive laboratory animals is the horseshoe crab (Limulus polyhemus).A microgram of lipopolysaccharide injected into their bloodstream can cause a violent reaction.Circulating blood cells become trapped in dense clots, bound together with clotted proteins secreted by these cells.As a result, blood flow stops and the animal dies.This response appears to represent a greatly exaggerated defense response designed to protect horseshoe crabs from Gram-negative pathogens.Fredrick Bang showed that blood cell particles contain a coagulable protein that is expelled when Gram-negative bacteria enter the tissue.It is conceivable that usually, a single microorganism is surrounded and swallowed in this way.Once the purified endotoxin is injected into the bloodstream, it becomes propaganda, sending the message that bacteria are everywhere and need to be surrounded.All blood cells then expel the protein at once.In fact, there is now evidence that the endotoxin signal is received directly by a receptor contained in blood cell extracts.Thus, there is an extremely sensitive and accurate method for detecting endotoxin using Limulus blood cell extract.In this test, as long as one nanogram of lipopolysaccharide is added to one milligram of blood extract, blood coagulation reaction will occur.

From the horseshoe crab's point of view, this is undoubtedly a useful and effective mechanism to prevent the invasion of pathogens.As long as it works well, against a single or a small group of microorganisms, the mechanism is not dangerous.But it becomes a costly defense when the defenses are breached and bacteria emerge in abundance, or when purified endotoxin is injected in experiments.The defense mechanism itself then becomes the cause of disease and death, while the germs play the role of bystanders, innocent from their point of view. Even where bacteria are indeed toxic and destructive to the cells of the host, as in the case of some exotoxin-producing microorganisms, the immediacy of the encounter cannot but be questioned.Diphtheria, if not for its toxin, would not be a pathogen in any sense.However, the toxin-bacteria relationship must be an extremely intimate two-way relationship, involving recognition, and an exact fit of the molecular machinery of the human cell, as if that toxin were mistaken for a normal participant in protein synthesis .Also, to be fair, the toxin was not deliberately produced by the diphtheria bacterium.It's made by bacteria, of course, but at the behest of a virus, the bacteriophage.Only microorganisms that are lysogenic to viruses can produce toxins.Diphtheria is not simply an infection of the diphtheria bacterium; it is an infection of a bacteriophage.That bacteriophage's life's work is to infect that bacterium.It is even conceivable that the genetic information that enables the phage to induce the bacterium to produce a certain toxin was acquired elsewhere, during a long-term close relationship with the animal host.This may explain why the composition of the toxin itself is so similar to that of the host cell itself.

It's a strange relationship indeed, without the straightforward predator-prey relationships we've imagined for infectious diseases.It is difficult to see what benefit the diphtheria bacterium could gain in life from its ability to produce this toxin.Corynebacteria live fairly well on the mucous membrane surfaces of the human respiratory tract, and creating necrotic pseudomembranes runs the risk of killing the host and ending the relationship.In short, it makes little sense and looks more like a biological mess that doesn't seem to help its evolution. For humans, the most malicious microbial exotoxin is botulinum toxin.Here, the irrelevance of toxins is beyond doubt.Tetanus and its toxin represent an accident in the same sense.However, these microbes, like Bacillus diphtheriae, and group A streptococci and their erythrotoxin, produce toxins because of infection with certain bacteriophages.This is rather interesting.If, by extension, bacteria make exotoxins only when given specific instructions by some virus, then this is an extraordinary mystery.

In preparation for the first trip to the moon, we were all assured that the utmost precautions would be taken to protect life on Earth, and especially human life, from whatever might live on the moon.Indeed, the first few moon landings, each completed, were followed by a meticulously thought-out ritual of lunar sterilization; the astronauts were masked behind glass panels and sent to a forty-day quarantine Quarantine and keep them off the ground until we're sure we won't get anything from them.The idea that germs are all around us, always trying to reach us, eat us, and destroy us, is deeply ingrained in the modern consciousness.Therefore, people naturally think that the strange bacteria brought from the moon will be more terrible and more difficult to deal with.

It is true that bacteria are literally all around us, they make up a modest part of the vast soils, and they are not insignificant in the air.But they are really not our natural enemies.In fact, we realize with astonishment that out of so many bacterial populations on Earth, so few are of any interest to us.The most common encounter between bacteria and higher life forms is after the latter has died, in the process of decomposing and reusing the elements of life.This is obviously the main business of microorganisms in general, and it has nothing to do with disease. Symbiotic relationships between bacteria and their metabiotic hosts are probably much more common in nature than infectious diseases, although I can't prove this.But if you count how many of the indispensable microbes that live in the various guts, supply vital nutrients, or provide the various enzymes that break down otherwise indigestible food, plus All those special bacteria -- which live in the tissues of many insects as if they were essential organs; plus all the bacterial symbionts that work with legume plants to fix nitrogen -- then the symbiotic relationship The whole huge group of will leave you jaw-dropping.On the other hand, the list of important bacterial infectious diseases of humans is really short.

I think things would be different if we knew less about hygiene, nutrition and crowding.Things are indeed different for newborns in places where these things are not done well.The greatest cause of infant mortality is undoubtedly intestinal infection, spread by environmental pollution.However, with the improvement of our civilization and the installation of sewers, in general, infection has become a relatively small threat to life.Now, after we have antibiotics, the threat is even less. But even before all this, in the years when things were equally dire everywhere, in the centuries of the Great Plague, the war between microbes and men was never a really large-scale event.Often, the viciousness of those diseases is first attributed to the ferocity of the host's defense mechanism.Leprosy, like tuberculosis, is a very destructive disease, but that destruction is largely immune and at the disposal of the host.The major lesions in syphilis, including arterial lesions and possibly tabes, are based, at least in part, on an immune response against spirochetes. Today, with so many infectious diseases under control, what remains is a series of critical illnesses, increasingly termed "degenerative diseases," including chronic diseases of the cerebrospinal cord, chronic nephritis, arteriosclerosis in arthritis, and Various disorders caused by disturbance of blood circulation.While the underlying mechanisms that govern these diseases remain largely a mystery, the increasingly popular idea is that many of them may be the result of environmental influences—what we eat, breathe, or come into contact with.As in so many ideas about cancer, we are looking externally for something that is wrong. However, once we know more about the pathology, it may turn out that most of the events behind tissue destruction in these diseases are host mechanisms and are controlled by the host.We are vulnerable because we are overly complex.We are different systems of various mechanisms, affected by all kinds of tiny disturbances.It was a small thing left in the machine by carelessness.They can finally break and pry apart the endless chain of otherwise coordinated, finely precisely timed interactions.