Who Speaks for the Microbes?

Special Issue

Stanley Falkow Stanford University School of Medicine, Stanford, California, USA

In discussing emerging infectious diseases, slowed and has been replaced by the encroach- the focus is often on the clinical effects of the host- ment of human populations into the domain of parasite relationship, i.e., the impact on the animal species all over the globe. It is little wonder health and survival of humans and animals, that our deliberate destruction of predators and the rather than the examination of the biology of the outgrowth of human populations into virgin land pathogen. It seems fitting to take a moment to with its attendant destruction of habitat led to the reflect on how pathogens “got that way in the first emergence of new diseases such as Lyme disease place.” Thus, while we discuss emerging and murine typhus (spread now by opossums and infections, it is worthwhile to consider that from cat fleas in our slums, instead of by the more classic the beginning of recorded history—in books or rat and rat flea vector—“sic transit gloria mundi”). the pictographs of ancient cultures—infectious diseases have been the leading cause of illness The Enemy Is Us and death. Even today, because of infectious The cartoon character Pogo, invented by Walt diseases most of the world’s population does not Kelly, once announced to his companions that have the luxury of living long enough to succumb “the enemy is us.” I believe that many of what to the chronic diseases of aging. we refer to as emerging diseases are What were and what remain the reasons that characterized better as “diseases of human infectious diseases are still the leading cause of progress.” Thus, many major public health death? I believe there are four answers. 1) The crises of the past 2 decades have been infectious presence of human populations was and is large in origin. Many, like the outbreaks of Lyme enough to sustain and amplify parasites. We have disease and murine typhus, are a natural lived in communities large enough to perpetuate consequence of human meddling. Similarly, the parasites for only about 10,000 years, barely a appearance of infections, like Legionnaires’ blink of the eye in the time frame of evolution, disease, can be traced to more subtle which means that most of the well-known differences in human behavior and social infectious diseases adapted to humans are very conventions that have an effect on the microbial recent in the evolutionary sense. The black death world. Thus, the aerosolization of water, now so of the 14th century, just 700 years ago, led to the prominent in the Western world from the death of approximately one quarter to one third of widespread use of showers instead of baths to the the human population of what was then the spraying of produce in large markets to air Western world. We may never understand the conditioning, likely has played an important role full implications of the plague outbreaks of the in the emergence of Legionnaires’ disease and also Middle Ages. The resistance of some caucasian of Mycobacterium avium infection in both healthy populations to the recent scourge of HIV actually and immunocompromised persons. may reflect the genetic consequences of plague Legionella pneumophila, the Legionnaires’ survival 20 generations ago. 2) Poverty, with its bacillus, is found in nature as an infectious agent of crowding, unsanitary conditions, and often predatory protozoa. Introduction of this organism, malnutrition, has led to an increased susceptibil- often as part of an aerosol of potable water into the ity to infection and disease. 3) War, famine, civil alveolus of the lung, results in the microorganism’s unrest, and, indeed, epidemic disease have led to finding a new niche in the macrophage instead of in a breakdown in public infrastructure and the its usual host Acanthamoeba or Hartmanella. More increased incidence of infectious diseases. 4) The absorbent tampons helped select for a new disease, domestication of animals, beginning about 12,000 toxic shock syndrome. years ago, was another important factor. The While pathogenic traits of the disease- actual large-scale domestication of animals has causing microbes are of consequence, humans

Vol. 4, No. 3, July–September 1998 495 Emerging Infectious Diseases Special Issue

and their technology and social behavior have The distinct difference between commensal, played a major role in providing pathogenic opportunistic, and pathogenic microbes is that microbes with new venues for their wares. Food pathogenic microbes have evolved the genetic poisoning by Escherichia coli O157, Campy- ability to breach cellular and anatomic barriers lobacter, and Salmonella emerged more from food that ordinarily restrict other microorganisms. technology and food distribution networks than Thus, pathogens can inherently cause damage to from any fundamental change in the virulence cells to forcefully gain access to a new, unique properties of the bacteria. In a sense, we have niche that provides them with less competition provided these bacteria with a moveable feast. from other microorganisms, as well as with a ready new source of nutrients. What Is a Pathogen, Anyway? For microorganisms that inhabit mammals Medicine views pathogens as microorgan- as an essential component of their survival tactic, isms capable of causing disease. The emphasis is success can be measured by their capacity to on disease, not the microorganism. However, multiply sufficiently to be maintained or be from the microbial standpoint, being pathogenic transmitted to a new susceptible host. This is true is a strategy for survival and simply one more for commensal and pathogenic organisms alike. remarkable example of the extraordinary However, if the pathogen gains a new niche free diversity of the microbial world. Humans are a of competition and rich in nutrients, it also faces home to a myriad of other living creatures. From a more hostile environment designed by mouth to anus, from head to toes, every evolution to restrict microbial entry and, indeed, millimeter of our cells exposed to the outside to destroy any intruders that enter these world is inhabited by a rich biology. From the protected regions. Thus, pathogens have not only mites that may inhabit the eyebrows to the acquired the capacity to breach cellular barriers seething cauldron of more than 600 species of but also, by necessity, have learned to bacteria that inhabit the large bowel, we are a circumvent, exploit, and subvert our normal veritable garden of microorganisms. Most of cellular mechanisms for their own selfish need to these microorganisms are not only innocuous but multiply at our expense. play a useful, yet unseen, role in our lives. They protect against the few harmful microorganisms How Did Pathogens Get That Way? that we encounter each day; they provide vitamins Recent advances in bacterial genetics, and nutrients and help digest food. We have molecular biology, and microbial genomics have harbored them so long in our evolution that they are led to a better understanding of the evolution of even a necessary part of the developmental bacterial pathogenicity. In genera that have both pathways required for the maturation of intestinal pathogenic and nonpathogenic organisms, the mucosa and the immune system. nonpathogenic bacteria frequently possess one Most microbes are commensal; that is, they (or more) large genetic insert that contains genes “eat from the same table.” Others are either exclusively associated with the pathogenic commensal or transient microbes that are phenotype. Indeed, in gram-negative enteric opportunistic; they can cause disease if one (or bacteria, pathogenic traits are commonly found more) usual defense mechanism, evolved to as large inserts of DNA in the chromosome, as are restrict microorganisms from normally sterile plasmids dedicated to the pathogenicity of the inner organs and tissue, is breached by accident, host microbe. Certain qualities of these DNA by intent (as in surgery and, increasingly, in inserts suggest that they were acquired by gunshot wounds), or by an underlying metabolic horizontal gene transfer from one microbe to or even infectious disorder. Nevertheless, a small another and that the ultimate origin of these group of microorganisms often causes infection virulence genes was a microbe very different from and overt disease in seemingly healthy persons. the organism in which these genes now reside. Many of the microorganisms, for example, These “pathogenicity islands” have been the the typhoid bacillus, gonococcus, tubercle subject of a number of recent articles. However, bacillus, and treponema of syphilis, are adapted the evolution of pathogenicity is not the product exclusively to humans; others, for example, of a slow, plodding process as much as it is the Salmonella Typhimurium, can regularly cause product of a large single genetic event that had a disease in humans, animals, birds, and reptiles. profound influence on the biology of the

Emerging Infectious Diseases 496 Vol. 4, No. 3, July–September 1998 Special Issue

microorganism. Thus, the divergence of Salmo- debate after 50 years. Is it because we could see nella from an ancestor that also gave rise to E. coli the effects of DDT in the pictures of fragile eagle resulted when the organism received a large eggs but not in the unseen microscopic world? As pathogenicity island that encoded a contact- Pasteur said, the microbe will endure. Perhaps dependent secretory system, which gave the host the fate of the last human is to be consumed by bacterium the ability to cross epithelial barriers. its own microorganisms. Later on in evolution, some Salmonellae received another pathogenicity island that provided the Suggested Bibliography host bacterium with the ability to survive within 1. Bäumler AJ. The record of horizontal gene transfer in phagocytic macrophages; finally, other Salmonel- Salmonella. Trends Microbiol 1997;5:318-22. lae that infect only warm-blooded animals 2. Falkow S. The evolution of pathogenicity in Escherichia, Shigella, and Salmonella. In: Neidhardt eventually inherited a plasmid that appears to F, editor. Escherichia coli and Salmonella: cellular permit systemic spread and, perhaps, some degree and molecular biology. Washington: American of host animal preference. These genetic events Society for Microbiology; 1995. p. 2723-9. occurred over millions of years of evolution and 3. Finlay BB, Cossart P. Exploitation of mammalian host were undoubtedly rare, perhaps occurring only cell functions by bacterial pathogens. Science 1997;276:718-25. once in evolution. 4. Galán JE, Bliska JB. Cross-talk between bacterial The success of these genetic changes also pathogens and their host cells. Ann Rev Cell Dev Biol depended on subsequent selective pressures and 1996;12:221-55. genetic fine-tuning by mutation and other 5. Groisman EA, Ochman H. How Salmonella became a genetic mechanisms. Nevertheless, the molecu- pathogen. Trends Microbiol 1997;5:343-9. 6. Hacker J, Blum-Oehler G, Muhildorfer I, Tachape H. lar fossil record in the DNA of contemporary Pathogenicity islands of virulent bacteria: structure, pathogens leads to the inevitable conclusion that function and impact on microbial evolution. Mol microbial evolution is still dynamic and that Microbiol 1997;23:1089-97. these periodic genetic upheavals in microbes affecting their pathogenicity can occur at any time. To underestimate the evolutionary poten- tial of microorganisms and their ability to survive, even in the face of enormous pressures to eradicate them and their effects on humankind, would be a mistake. Infectious agents will emerge so long as there are microorganisms. Humans help the evolutionary process sometimes unwittingly and sometimes by arrogance or ignorance. Antibiotic resistance on a global scale in what seems such a short time comes as no surprise. Does feeding animals antibiotics to promote growth have any effect on human microbes and the health of the human population as a whole? Rachel Carson’s book Silent Spring, which documents the devastating effects of insecticides (e.g., DDT) on the health of a number of living creatures far removed from the insects that were the target, was easily understood. Yet, applica- tion of a selective pressure on the microbes of the Stanley Falkow and Lucy Tompkins Stanford University School of Medicine, Stanford, planet with antibiotics, a pressure that dwarfs the California, USA use of DDT in its scope, as well in the number of species that are affected, still remains a subject of

Vol. 4, No. 3, July–September 1998 497 Emerging Infectious Diseases