Microbes or men: who will win?

Photo Maxime Schwartz / Honorary General Director of Institut Pasteur / April 14th, 2010

Throughout history, changes in human behavior have caused the dissemination of infectious diseases, from smallpox to the flu. But thanks to scientific progress and plain old international cooperation and coordination, we’ve been able to ward off disaster, or at least the worst of it. However, an additional factor will up the stakes for scientists and policymakers worldwide in the fight against emergence or re-emergence: the remarkable adaptive capacities of microbes. The question is, microbes or men, who will win?

Infectious diseases have been making headlines for the past quarter century or so. The 1980s saw the emergence of Acquired Immune Deficiency Syndrome (AIDS), which was unknown before and has become the most deadly infectious disease in the world. During the 1990s, in Europe, and to some extent in the rest of the world, the mad cow crisis had devastating effects on the economy. Since the beginning of the new millennium, the pandemic potential of Severe Acute Respiratory Syndrome’s (SARS) has been checked, but a new major threat immediately took prominence: avian flu (H5N1 virus). Another serious disease, caused by the chikungunya virus, then appeared in the Indian Ocean islands. And now, we are confronted with a new flu pandemic, caused by an A (H1N1) virus. Is this emergence of infectious diseases a new phenomenon? Where do they come from? How can we control them? Will new ones emerge?

A new phenomenon?
The answer to this question is no and yes. No, because numerous examples of emergence have been observed since Antiquity. For instance, the black plague devastated Europe during the 14th century. Ships involved in the silk trade brought it from Asia and most European towns lost 30% to 50% of their population to the epidemic. One may also recall how American Indians were decimated by smallpox, brought by Europeans, and how, in return, the former delivered to the latter syphilis, unknown until then to Europeans. In all of these cases, emergence resulted from the transport of a disease from a region where it was endemic to a region where it was unknown.

Yes, because the cases of emergence have been much more frequent over the past few years, with an average of one per year according to the World Health Organization (WHO). And also because epidemics are not always onset by the transport of a disease from one region of the world to another; often, they are brought on by a disease never before seen among human populations. In addition, aside from the cases of true emergence, we have witnessed the re-emergence of diseases thought to be under control.

Where do these new diseases come from? The analysis of three case studies will give us a clue: legionellosis, AIDS and the (in)famous mad cow disease.

In July 1976, a few hundred World War II veterans gathered for a conference in four luxury hotels in Philadelphia. During the second night of this congress, two of the participants fell ill. They had fever, muscular pains, and a pulmonary infection. During the week that followed, the Department of Health of the state of Pennsylvania received an avalanche of reports of cases of acute pneumonia, sometimes followed by death, from people who had stayed at one of the above-mentioned hotels. A total of 182 cases were declared, with 29 deaths.

It took six months for epidemiologists of the US Centers for Disease Control (CDC), the institution in charge of infectious disease surveillance in the US, to discover the cause of this small epidemic. The culprit was a bacterium, usually found in rivers, ponds or lakes, which had found a new habitat in the residual water of the hotel air conditioning system. Rather difficult to grow in cultures—which explains why it took six months to find—it happens to grow very well in pulmonary cells, provided that it has the opportunity to come across them. And this is what happened when these bacteria were disseminated in the hotel by the air conditioning system.

In the US, World War II veterans are members of the American Legion. And so, the newly bacterium was christened Legionella. Never identified before 1976, legionellosis is a typical emerging disease. Outbreaks now regularly cause small epidemics resulting from the contamination of air conditioning systems and, sometimes, of collective shower installations. France, for example, witnesses about 1,500 cases each year.

The emergence of AIDS in the 1980s made the world realize that, contrary to popular belief, new infectious diseases could still appear, including deadly diseases that modern medicine and science are powerless against.

It’s perhaps common knowledge that AIDS was first detected among American homosexual men in 1982, and how Human Immunodeficiency Virus (HIV), the virus that causes this disease, was isolated at France’s Institut Pasteur in 1983. Although the epidemic was partially controlled in the western world thanks to strict prevention measures, AIDS is still spreading in a terrifying manner in numerous other regions, notably Africa and Asia. As of today, AIDS has become the most deadly infectious disease on earth, with about three million deaths each year and about 35 million persons currently infected. Despite antiviral treatments (that stabilize the infection but fail to stop it) and measures of self-protection, both of which turn out to be difficult to apply in developing countries, we are still unable to put an end to this epidemic. AIDS was totally unknown before 1981. How did it emerge? Here is the most likely scenario.

There is presently no doubt that the AIDS virus came from apes, because HIV is indistinguishable from an ape virus. Since inhabitants of villages in Central Africa often go into the wild to kill and eat apes, they run a high risk of contamination while carving the meat from these animals, which can be asymptomatic carriers of the virus. However, re-transmission of the virus from the contaminated individuals to other inhabitants of these villages remains very limited, probably thanks to local social traditions (no prostitution, no intravenous drug usage). Indeed, it was found that in a village of Zaire (now the Democratic Republic of the Congo) where 1% of the population was HIV-positive in 1976, this proportion was unchanged nine years later. Therefore, in all probability, the disease had existed for a long time at a very low level in such villages, and remained undetected. A first cause of its spread was probably the rural flight of a few HIV carriers to Kinshasa, where prostitution and intravenous drug use were rampant. There, the virus was given all opportunities to diffuse among the inhabitants of this city and then, because of the development of tourism and international travel, to the rest of the world. Finally, in the western world, especially in the U.S., the sexual habits that had developed in the gay community, involving (politically correct alternative: «involving unprotected sexual relations with various partners») extreme cases of promiscuity, gave a further boost to the epidemic.

Mad cow and Creutzfeldt-Jakob diseases
The first cases of Bovine Spongiform Encephalopathy (BSE), also known as mad cow disease, were described in an article published in October 1987. The article described the symptoms as well as the lesions in the brain, very similar to those found in sheep suffering from the disease called “scrapie.” The first cases described dated back to 1985. From that point on, the number of cases increased dramatically and was to reach close to 40,000 in 1990.

An epidemiological study published in December 1988 provided strong evidence that the infectious agent (a prion) was transmitted through the Meat and Bones Meal (MBM) provided to cattle as a food supplement. Since some of the MBM originated from sheep, it was believed that scrapie had thus been transmitted to cows. Although this latter point is disputed today, it remains that this study stopped the use of MBM as cattle feed, which, after a delay due to the long incubation time of the disease, led to a progressive disappearance of BSE in cattle.

In 1996, the number of cases was already four to five times lower than in 1990. At that time, the risk of transmission to people seemed very low, because BSE was assumed to be scrapie and there was ample evidence that scrapie could not be transmitted to man. It thus seemed mad cow disease would soon be forgotten. This proved wrong when, in March 1996, the British described 10 cases of patients with a new type of Creutzfeldt-Jakob Disease (CJD), a rare fatal neurological disease known to be scrapie’s human equivalent. Evidence then rapidly accumulated showing that, contrary to predictions, the same infectious agent that had caused BSE caused this new type of CJD too. A panic then started in the UK as well as several other countries, including France, where cattle had been fed UK-produced MBM and where a significant part of human-consumed meat also came from the UK. Newspapers at that point also started to mention the possibility of hundreds of thousands of victims. Fortunately, thanks to knowledge of spongiform encephalopathies (prion diseases), adequate measures were taken and human causalities were kept to a minimum—to date, around 200.

What exactly happened? First, since no infectious agent identical to that of BSE was ever found in sheep with scrapie, it is unclear if BSE is scrapie. Since this type of disease may occur spontaneously in the absence of infection, BSE might have come from a spontaneous case of encephalopathy that had occurred in a cow. MBM from this cow and fed to other animals may have started the epidemic. Then why did the epidemic start in the UK and nowhere else? The best explanation, given in an official but little-known report, is that the British breeders, unlike those in other countries, fed MBM to calves, and not just to cows. Since young animals—just like young humans—are more sensitive to prion infection, the disease spread much more easily.

What of human responsibility?
What conclusions can be drawn from these examples? In all three cases, the infectious agent, bacterium, virus, or prion, was hardly new. Each existed in its own habitat: Legionella in environmental water, HIV in apes, and prions in domesticated farm animals. If these agents infected human beings and started epidemics, this resulted from the human behavior and lifestyle changes. The invention and development of air conditioning created a new habitat for Legionella. Rural flight in Africa, the development of international travel, and “promiscuity” among homosexuals in the US presumably allowed AIDS to spread from small villages in Africa to the whole world. As for mad cow crisis, changes in cattle feeding practices were the cause.

However, an additional factor is also often at work in the emergence or re-emergence of infectious diseases. It is the remarkable adaptive capacities of microbes. Two examples follow.

A first and well-known example of adaptation is microbes’ ability to resist the actions of anti-infectious agents such as antibiotics. This is a major cause of re-emergence of infectious diseases that were thought to be under control.

What is an antibiotic? It is a molecule that blocks a chemical reaction essential for the growth and multiplication of a bacterium. Usually, it acts by inhibiting an enzyme catalyzing such a reaction. Many resistance mechanisms have been discovered that prevent the interaction of the antibiotic with its target by:
• altering membrane permeability
• modifying target enzymes
• short-circuiting target enzymes
• producing an enzyme that destroys or alters the antibiotic
• activating efflux pumps

These resistance mechanisms result either from mutations or from the acquisition of genes from other bacterial species. Bacteria endowed with such resistive capacity obviously have a selective advantage when confronted with the antibiotic.

Because antibiotics have been used extensively, and sometimes inappropriately, in human as well as veterinary medicine, antibiotic resistance is now observed in an increasingly worrying proportion of pathogenic bacteria. As a consequence, certain infectious diseases that were easily controlled a few years ago have become very difficult, if not impossible to cure. Tuberculosis, the second most deadly infectious disease after AIDS with about nine million cases and two million deaths each year, has thus had a new lease of life. According to the most recent statistics, about 5% of new tuberculosis cases are due to bacteria that resist most of the antibiotics used in the treatment of the disease.

Flu: adapting to immune defenses and leaping across species
Influenza (commonly referred to as the flu) viruses can be found both in human beings and in several animal species, including birds, swine, and horses. Viruses from the different species have the same general structure but are not identical.

At their surface, these viruses bear two types of molecules, haemaglutinin and neuraminidase (H and N), which allow them to bind to host cells. When an individual in good health is infected by such a virus, he or she becomes sick but fights back by developing an immune response; his or her body learns, in effect, learns to produce antibodies that attach to the H and N molecules, therefore preventing the virus from binding to host cells. The patient then recovers and, if re-infected by the same virus, immediately produces the antibodies that stop the infection. A similar bodily response can be obtained through vaccination, where the patient is injected with a vaccine consisting of killed viruses. However, this protection is only temporary. Indeed, viruses evolve constantly. Mutations occur that slightly alter the H and N molecules, enabling the virus to escape detection by the antibodies present in people who were either previously infected or vaccinated. This gives the altered strain a selective advantage. The virus thus shows its ability to overcome immune defences. Hence the need to be vaccinated on a year basis, as the new vaccine is adapted to changes in the virus.

In addition to the gradual evolution of viruses, sudden jerks occur from time to time, with sometimes dreadful consequences. Everyone may remember the awful “Spanish flu” epidemic in 1918-1919 that caused 20 million to 50 million deaths. About half the world’s population was infected and a quarter became sick. Two other epidemics of lower amplitude occurred in 1957 and 1968. These recurring epidemics, called pandemics because they span the whole world, were due either to avian influenza viral infections or to hybrids between avian and human viruses. These viruses had both H and N molecules never before experienced by human beings, who were thus totally devoid of protective antibodies. This lack of protective antibodies explains the very high death toll when influenza viral infections cross between species.

A major concern since 2003 involves the deadly H5N1 avian virus. This virus proved highly pathogenic for birds as well as for the odd 400 individuals that were infected through contact with infected birds. The fear is that it may adapt to human beings and become contagious. More recently, another influenza virus, A (H1N1), a hybrid between human, swine, and avian viruses, has been responsible for a new pandemic. Fortunately, this new virus, although highly contagious, is only moderately virulent. As we can see, the flu virus displays a double capacity of adaptation, allowing it to overcome immune defenses and to cross species barriers.

The future of infectious diseases
Since mankind is not likely to stop changing its lifestyle, and since micro-organisms will always retain their adaptive capacity, new infectious diseases will likely continue to emerge. What can we do to control them?

Fortunately, while infectious diseases remain a threat, science and technology continues to make remarkable progress in the development of new approaches to combating them. This includes the search for new therapies, the development of vaccines, the extension of immunotherapeutic treatments, and the exploitation of knowledge on natural resistance mechanisms in individuals endowed with particular genetic backgrounds. These various approaches will not be developed here. However, one cannot close such a chapter without mentioning the importance of monitoring, or epidemiological and microbiological surveillance.

A very efficient system for epidemiological surveillance is currently in various parts of the world, mainly under the auspices of international organizations such as the WHO. Its efficiency was greatly improved by the development of electronic communications; they make it possible to immediately share information on unusual occurrences in human or animal health with specialists worldwide, thus allowing early control of possible epidemics. The early check on SARS demonstrated the effectiveness of these procedures. Still, this surveillance can be improved, and it will be.

However, it would be even better to prevent the emergence of infectious diseases in the first place. Several steps have been taken in this direction, by putting into place a microbiological surveillance of the environments where microbes of possible future epidemics lurk. Hence, for instance, the monitoring of bird populations that may harbour dangerous influenza viruses. Hence, also, the monitoring of non-human primates among within which a high mortality rate may signify the emergence of Ebola hemorrhagic fevers. As for insect-borne infectious diseases, satellite monitoring can be used to detect changes in humidity, foreshadowing an increase in the population of insect vectors. This technique is currently being employed to anticipate Rift valley fever epidemics in certain regions of Africa.

Thus, while the microbes are making a great comeback, science has made such spectacular progress that a victorious counter strike by mankind is far from remote. However, the example of AIDS is here to remind us that we haven’t won yet. Therefore, we should remain on our guard and support research on infectious diseases and the training of experts in the many disciplines concerned, including those that were unfortunately neglected over the past 20 or 30 years, such as, for instance, ecology and medical entomology.


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