3
The Ecology of Pathogenesis

OVERVIEW

Over the course of the last century, the identification of increasing numbers of microbial pathogens and the characterization of the diseases they cause has begun to reveal the extraordinary complexity and individuality of host-pathogen relationships. The vast majority of microbes does not produce overt illness in their hosts, but instead act as persistent colonists. Genetic changes in either host or microbe may disrupt this equilibrium and shift the relationship toward pathogenesis, resulting in illness and possibly death for the host. These considerations are reflected in the contributed papers collected in this chapter, which explore how pathogens coexist within host-microbial communities, placing infectious disease within an ecological and evolutionary context.

In this relatively recent, dynamic model of pathogenesis, it has become exceedingly difficult to identify what makes a microbe a pathogen. This challenge is taken up at the beginning of the chapter by Stanley Falkow, who describes the variety of circumstances that lead to pathogenesis. Recognizing that a considerable amount of infectious disease is caused by “accidents” of transmission, susceptibility, and host response to microbes, Falkow illustrates how primary pathogens pursue an adaptive strategy that produces disease in normal hosts. This perspective informs an ecological model of pathogenicity as a product of ongoing evolution between pathogen and host.

The chapter continues with a detailed exploration of a single human pathogen, the bacterium Helicobacter pylori, which is strongly associated with increased risk for peptic ulcer disease and gastric cancer. Martin Blaser considers this example of amphibiosis—a term coined decades ago by microbial ecologist



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary 3 The Ecology of Pathogenesis OVERVIEW Over the course of the last century, the identification of increasing numbers of microbial pathogens and the characterization of the diseases they cause has begun to reveal the extraordinary complexity and individuality of host-pathogen relationships. The vast majority of microbes does not produce overt illness in their hosts, but instead act as persistent colonists. Genetic changes in either host or microbe may disrupt this equilibrium and shift the relationship toward pathogenesis, resulting in illness and possibly death for the host. These considerations are reflected in the contributed papers collected in this chapter, which explore how pathogens coexist within host-microbial communities, placing infectious disease within an ecological and evolutionary context. In this relatively recent, dynamic model of pathogenesis, it has become exceedingly difficult to identify what makes a microbe a pathogen. This challenge is taken up at the beginning of the chapter by Stanley Falkow, who describes the variety of circumstances that lead to pathogenesis. Recognizing that a considerable amount of infectious disease is caused by “accidents” of transmission, susceptibility, and host response to microbes, Falkow illustrates how primary pathogens pursue an adaptive strategy that produces disease in normal hosts. This perspective informs an ecological model of pathogenicity as a product of ongoing evolution between pathogen and host. The chapter continues with a detailed exploration of a single human pathogen, the bacterium Helicobacter pylori, which is strongly associated with increased risk for peptic ulcer disease and gastric cancer. Martin Blaser considers this example of amphibiosis—a term coined decades ago by microbial ecologist

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Theodore Rosebury to describe a relationship between two life forms that is either symbiotic or parasitic, depending on the context—as representative of most relationships between humans and their indigenous organisms. The intricate signaling that occurs between humans and H. pylori has provided important insight on the effects of indigenous microbes on normal human physiology, as well as on disease. It also raises questions about the consequences of the disappearance of H. pylori (and other less-detectable indigenous bacteria) from the human gastrointestinal tract, a trend apparently underway in the industrialized world. In contrast to the sole human-microbe interaction known to produce peptic ulcers, a broad range of normal luminal bacteria can induce and perpetuate intestinal inflammation (and possibly extraintestinal inflammatory conditions such as arthritis) in genetically susceptible hosts. Balfour Sartor’s contribution to this chapter describes bacterial factors and genetically programmed host responses that influence whether the host’s response to commensal bacteria is one of coexistence or of aggressive defense via inflammation, as occurs in idiopathic inflammatory bowel disease (IBD), Crohn’s disease, and ulcerative colitis. Greater understanding of the mechanisms of induction and perpetuation of intestinal inflammation may indicate how these responses could be inhibited in order to restore mucosal homeostasis, and how therapies for these conditions might be tailored to individual patients. The chapter concludes with further reflections on the human microbiome by Maria Dominguez-Bello, who notes two promising areas for continued research on host-microbe ecology. The first is the rumen, which she portrays as a model system of host-microbe mutualism and the subject of seminal studies on digestive processes in humans and other animals. The second research area—which follows from Blaser’s aforementioned observation that modern life is changing the human microbiota—is the comparative study of indigenous microbes in human populations outside the industrialized world. To this end, Dominguez-Bello describes her own work among indigenous Venezuelan Amerindian tribes that examines the association between microbiome diversity and human health. THE ZEN OF PATHOGENICITY Stanley Falkow Stanford University The following remarks are meant to present a human’s idea of the microbe’s “point-of-view” and the various ways that a microorganism might cause disease. In so doing, I will offer a view of host-pathogen relationships that is in keeping with the goal of this workshop of replacing the war metaphor. As a first example of the intricacies of such relationships, consider a host macrophage engulfing the plague bacillus (Yersinia pestis), as shown in Figure 3-1. To many, this apparently defensive moment represents the essence of the host-parasite relationship.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary FIGURE 3-1 Host macrophage engulfing the plague bacillus (Yersinia pestis). SOURCE: Falkow (2005). In the end, the ingested bacteria are killed, but so is the host cell. There are more bacteria than host cells, and often the microbe has the last laugh. The impact of microbes on humans extends to our culture (Cockburn, 1971; McNeill, 1976). Figure 3-2 shows variations in the human population over several centuries and notes the factors driving these changes, which are dominated by disease and war. The graph reveals an interesting trend: peaks of human population, followed by die-offs due to infectious diseases, followed by renaissance periods of peak human productivity in the resulting population valleys. If this pattern continues to hold, then we are approaching a time of epidemics, of which HIV/AIDS may be considered a harbinger. Throughout most of our history, people have lived in small groups. Most known epidemic infections of humans require populations of 50,000 to 100,000 to spread; therefore, the diseases that are strictly adapted to our species are relatively recent in the evolutionary sense. The development of pathogens specific to humans was further encouraged by the crowding, defective hygiene, and poor nutrition associated with the transition to living in larger communities. In addition, the domestication of animals has permitted the evolution of infectious diseases such as measles (from canine distemper and rinderpest), diphtheria (from

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary FIGURE 3-2 Infectious diseases were, and still are, the most common cause of death worldwide. SOURCE: Falkow (2005). cows), and influenza (from birds). Humans over time have become the preferred hosts of several species of bacteria, viruses and, in many parts of the world, worms. We really are a fertile landscape of opportunity for microbes. What Is a Pathogen? Once it was understood that microbes caused disease, the term pathogen was coined to describe any disease-causing organism, and this is the term still employed in medicine. Although this definition is certainly practical, it may not be entirely accurate from a biological—that is, the microbe’s—standpoint. As I see it, humans play host to the following categories of microbes: Transients: Microbes that we ingest and with which we come in contact, but which do not persist on us. They are just “passing through.” Commensals: (to eat from the same table): The hundreds of microbial species growing within each of us. Many of them are with us from the moment of birth, when we are first colonized by microbes, and remain with us to the grave. Some commensal species play essential roles in the development of our gas-

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary trointestinal tract and immune system. Their last role is to participate in our decomposition (think of it as recycling) after we die. Pathogens: I use the term primary pathogen (which is not a universally accepted term) to describe microbes that cause disease in apparently normal human hosts. By contrast, opportunistic pathogens cause disease only in compromised human hosts. Commensals can be opportunists, and an opportunist in one host can be a primary pathogen in another host. Differentiating between pathogens and commensals is important to devising new ways to thwart off attacks by pathogens. However, this is not an easy distinction to make because of the considerable similarities between the colonization strategies used by both pathogens and commensals. Successful microbes of both classes must find ways to enter their hosts (us), locate a niche to colonize, interact intimately with the host, replicate, persist (although this may not be necessary for pathogens), disseminate to new hosts, and, ultimately, evolve. I believe that the major difference between pathogens and commensals is that pathogens have the inherent ability to cross anatomic and biochemical barriers in the host that serve to limit colonization by commensals. Most pathogens establish themselves in niches devoid of other microorganisms. For example, E. coli that cause diarrheal disease and urinary tract infections do not occupy the same niche as the commensal strains of E. coli in the colon. Instead, enterohemorrhagic E. coli specifically colonize a special niche within the colon near the lymphatic centers, while the urinary tract pathogens leave the colon altogether for another mucosal surface. Pathogens have the inherent ability to colonize these host-protected niches, and the invasive properties pathogens use to get there are essential to their survival in nature and are often host specific. This adaptive strategy, or lifestyle, is specific to primary microbial pathogens and absent from opportunists. A considerable amount of human infectious disease is not caused by primary pathogens. Some infectious diseases—such as Lyme disease, rabies, and botulism—occur in humans through accidents of transmissibility, when we are infected by microbes that are specific to other host species. Most potential bioterrorism agents fit this general description. In these cases, disease is a disadvantage to both the host and the microbe, because the host often dies before the microbe can be transmitted to another host. Other human infections are accidents of susceptibility, which result from noninherent defects in host immunity. These defects could be either mechanical or biochemical, but in either case allow commensals that were previously held in place by normal host defense mechanisms to cross the barriers that contain them. Finally, there are human diseases that represent accidents of host response, or heritable defects in host immunity like that seen in cystic fibrosis. Although we can get disease from a variety of microorganisms, I would argue that only some of them are primary pathogens. This subset of disease-causing

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary microorganisms has evolved specifically to cross host barriers in order to survive, and in crossing host barriers they often cause injury. The virulence factors that allow pathogens to pursue this strategy are equivalent to the fur, claws, and fangs of higher animals: adaptations to an organism’s environment that favor survival. Pathogenicity in this instance reflects the ongoing evolution between a parasite and host, and disease is the product of a microbial adaptive strategy for survival. Moreover, what we recognize clinically as disease is very often our human response to microbial invasion. In some cases, disease is a host-microbe experiment gone wrong, and when that happens, the host is as likely to be “at fault” in causing disease as the microbe. Host Defenses Animals have evolved both innate and adaptive immune mechanisms to avoid microbial intrusion or traumatic insult. The main function of the innate immune system is to keep commensal or transient organisms in their place—that is, to limit their ability to colonize host tissues beyond the mucosal surface. Immune signal cascades mediated by toll-like receptors (TLRs), which specifically recognize molecules characteristic of prokaryotes and other kinds of parasites, alert the host to microbial intrusion. The features recognized by TLRs are not unique to pathogens, but they set off an elaborate cascade that can summon cells with antibacterial characteristics, such as the macrophages that are recruited to ingest the Yersinia in Figure 3-1. Invading microbes without specific mechanisms to avoid the innate immune system are destroyed. Pathogens must possess inherent ways to avoid or subvert these innate host defense mechanisms. Adaptive immunity, or the ability to produce antibodies that can neutralize microbes, occurs in higher animals. The capacity of humans to make antibody is of course critical to the effectiveness of vaccines. If we know how to stimulate production of antibody against a particular antigen, it is relatively easy to develop a vaccine against an organism that invades the bloodstream. However, it is much more difficult to make vaccines directed against microbes that inhabit the mucosal surfaces (e.g., the gut). Thus, the development of mucosal vaccines has been a great challenge, particularly when one considers the huge differences in individual susceptibility to infection between, for example, a normal neonate and one that has a low birth weight, is preterm, or is otherwise physically compromised. Some pathogens have devised ways to get around the adaptive immune system by constantly changing their surface or by camouflaging their appearance. Steps to Successful Pathogenesis The following section describes the challenges faced by pathogens, and the various mechanisms they have evolved to address them.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Entry There are 9 natural portals of microbial entry in humans (10, if the umbilicus is included); along with injured tissues, these are the typical routes of entry for pathogens. The skin and the mucosal surfaces present formidable physical barriers to microbes: tight cell junctions; the mucus “stream” that flows through the gut, capturing organisms washing them out of the body; and antimicrobial substances. All of these obstacles, along with competition from commensals, stand in the way of the microbe. Colonization Following entry, the microbe must find a niche to inhabit. This process is often called colonization, and the microbe usually achieves it by attaching itself to a unique host cellular target, or by adapting to host physiology. Bacteria have hairlike structures called pili that have evolved to recognize and adhere to a specific receptor on the surface of the host cell. The various forms of pili have been studied extensively in the uropathogenic strains of E. coli. Genomic analysis of Salmonella reveals at least eight different kinds of pili that the bacterium uses to find targets for attachment in different contexts, both inside and outside the host’s body. Microbes are very simple creatures, but they can perform the tasks of recognition at their surfaces through either proteins or proteinaceous appendages. The bacterial strain that causes salmonellosis, for example, recognizes specific kinds of cells in the terminal ileum.1 Protein-based adherence mechanisms are also found in viruses; herpesviruses, for example, have proteins on their surfaces that recognize specific receptors on host cells. Persistence Many common pathogens are organisms such as Pneumococcus, group A Streptococcus, Meningococcus, and Hemophilus influenzae that all humans carry at some point in their lives. These microbes occasionally cause clinically apparent disease, because they have an adaptive strategy of persistence achieved through mechanisms that avoid, circumvent, or subvert host defense mechanisms. One of the common mechanisms bacteria use is encapsulation, as occurs in Streptococcus pneumoniae (the most common cause of bacterial pneumonia) and Ba- 1   Such specificity might seem to suggest that one could make a vaccine based on a single kind of pilus. This might work in some cases, but more often than not this strategy would be foiled by the redundant recognition and adherence mechanisms present in most species of bacteria. Moreover, bacterial adherence is often an interactive, multicellular phenomenon, as when the presence of a device such as a prosthetic valve or indwelling catheter supports communities of microorganisms as biofilms.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary cillus anthracis (anthrax). The capsule, made of carbohydrate or protein, surrounds the microorganism and interferes with phagocytosis, much as the slimy coating on a wet bar of soap makes it hard to grab. Without a capsule, S. pneumoniae is essentially avirulent; it can live in the human host, but it is very unlikely to cause disease. Another means to persistence is to breach the tight junctions between epithelial cells or to get inside the cells themselves. Salmonella and Shigella can stimulate human epithelial cells and cause them to extend cytoplasmic ruffles that act to trap the bacteria and literally pull them into the cell. Other bacteria harness the cytoskeleton; the organism that causes enterohemorrhagic E. coli reorganizes the cytoskeletal actin of its host cell in the colon epithelium into a sort of pedestal. The bacterium sticks avidly to this pedestal, where it is bathed with host cell nutrients that the microbe uses for growth. The attached bacteria replicate to form microcolonies on the surface of the host cell. Yet, other pathogens persist in their hosts by circumventing the intracellular trafficking that allows host phagocytes to take up commensal bacteria or other kinds of particles, put them into vacuoles, and digest them. In some cases, the digested products trigger the production of antibodies by the host’s immune system. Some pathogenic bacteria divert normal trafficking by phagocytes; others (e.g., Yersinia) kill the phagocyte quickly after they attach or have been ingested. Enzymes and toxins allow pathogenic bacteria to spread through local tissues and perturb host immune function. Group A Streptococci secrete substances that disintegrate the molecular “cement” between cells—hyaluronic acid—so that the bacteria slip easily along the tissue plane. Other secreted streptococcal toxins kill host cells. The released host cell contents form a viscous mass that might impair the ability of bacteria to spread through the tissues, but the bacteria make a DNase that dissolves this barrier. Thus, the microbe releases a series of substances exquisitely timed to permit the microbe to spread, replicate, and persist in an environment that is normally lethal for other microorganisms. Replication What do microbes gain from host-pathogen relationships? Replication. The successful microbe is one that can replicate sufficiently to be transmitted to a new susceptible host. What does the host gain from its associations with microbes? Usually immunity sufficient to clear the immediate threat and, in the best of circumstances, forevermore. Some pathogens persistently colonize their hosts and continuously transmit small numbers of their kind into the host’s environment. Under these conditions, disease represents an option, not a goal, for a pathogen. It is merely one means to the end of replication, not a necessary outcome of colonization. When an organism causes disease, it is but a byproduct of its survival strategy. And, disease is often as much a factor of the state of the host defenses as it is of the microbes’ need to breach host barriers.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary For example, while many people become ill in influenza outbreaks, even more people escape disease. In seeking to understand host-pathogen relationships, disease can distract us from understanding the actual mechanisms that underlie these associations. However, we must understand how pathogens operate in order to devise new ways to protect ourselves from their ill effects. Dissemination Bacteria need an exit strategy from their hosts. Microbes are conveyed between humans in a variety of ways: through respiratory droplets or saliva, fecaloral transmission, and even in our lovemaking. Zoonotic infections, which rarely spread person-to-person, are transmitted through animal bites, feces, and insect vectors (ticks, fleas, etc.). Even organisms such as Salmonella typhi, Mycobacterium tuberculosis, and Helicobacter pylori, which cause lifelong infections, must eventually find new hosts. The ease and the frequency with which a pathogen leaves its host may influence its virulence. The Roles and Origin of Bacterial Toxins A particularly fascinating aspect of bacterial evolution is the existence of toxins. Vibrio cholerae, for example, produces an extraordinarily powerful and well-known toxin that causes patients with cholera to pass copious amounts of watery stools. These patients survive only if the number of liters of fluid they lose can be balanced with the same volume of fluid going in. Humans do not carry the cholera bacterium; its reservoir is probably in marine estuaries. Toxins appear to perform a variety of functions for bacteria, including nutrient acquisition, the breakdown of anatomic barriers, facilitation of exit and transmission, and the modulation of immune function. It seems unlikely that the original purpose of toxins was to poison mammals. Thus, if we can put aside our desire to avoid cholera or botulism or other toxic bacterial infections, and instead consider what advantages toxins confer upon bacteria, we may come up with a better way to neutralize toxin-producing pathogens. I suspect that bacterial toxins first evolved in compost heaps when bacteria came in contact with predatory amoeba and especially with nematodes. Pound for pound, nematodes eat more bacteria than any other organism. To avoid becoming prey, bacteria harmed their predators. Thus, the toxins that bacteria initially evolved to avoid phagocytosis by amoebae became—after millions of years of evolution—the same molecules that stop the human phagocyte from engulfing bacteria. Finally, it has been said of bacterial toxins that we incriminate the microbe for the sins of the viruses (Hayes, 1968). Many toxins are encoded by accessory genetic elements, and the advantage they confer upon the organism that possesses

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary them is unknown. We might be able to get answers to such questions by comparing bacteria such as Bacillus anthracis, which carries a DNA insert known as a pathogenicity island (further discussed below), and its close relative Bacillus cereus, which does not carry a pathogenicity island. Such studies could also provide new insights on protecting ourselves from anthrax. Corollaries of Pathogenicity A better understanding of the previously described steps that pathogens must take in order to live successfully in their hosts could result in the search for new ways to protect humans from infectious diseases. Such efforts should also address the following “corollaries” of pathogen behavior, as revealed through microbiological research. Bacteria Have Keen Senses Pathogens and other bacterial specialists (almost all bacteria are specialists) use elaborate regulatory mechanisms based on environmental and biochemical cues. Bacteria have extremely sensitive chemical sensory systems that measure environmental variables such as oxygen and carbon dioxide concentration and pH. Significant changes in these measures signal the microbe to alter the products it makes to suit its environment. Such adjustments allow simple organisms to survive transitions. When a bacterium in a bit of feces on the ground moves into a human’s mouth, it undergoes an enormous change in pH and comes in contact with lysozyme and a variety of other antibacterial chemicals. Then the ingested bacterium is plunged into the acid vat of the stomach and quickly passes into the small bowel, where it is bathed in bile and an impressive array of digestive enzymes, all along being propelled by the forces of peristalsis. The bacterium takes all of this in stride and responds to each change in environment by rapid changes in its own structure and metabolism. These constantly changing environmental cues permit many microbes to anticipate when they will reach their optimal niche. Thus, Salmonella uses changes in pH, the viscosity of intestinal mucus, and the concentration of oxygen adjacent to host epithelial cells to determine when it will encounter its target cell in the terminal ileum. The bacterium quickly readies itself for infection during its transition through the gut. Clearly, it can respond far faster to us than we can to it. Pathogens Are Opportunists As Walt Kelly’s comic strip hero, Pogo, said, “We have met the enemy, and he is us.” Pathogens can respond to a host’s biological and social behavior (Falkow, 1998). Many pathogens that coexist uneventfully with other hosts cause

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary disease when they encounter humans; for example, the Lyme bacterium (Borrelia burgdorferi) persists in mice, deer, and ticks, and only causes disease when it colonizes humans or dogs. These hosts represent new “opportunities” for such microbes, and unfortunately may result in new diseases for hosts that (unlike mice, deer, and ticks) have not evolved a relationship with a given pathogen. Similar scenarios involving human behavior underlie several recent infectious crises, including Legionnaire’s disease and toxic shock syndrome. The increasing presence of aerosols in our environment—created by taking showers rather than sitting demurely in a bathtub, by air conditioning, by misting of produce in supermarkets—has provided new opportunities for organisms to spread in a “modern” world. The bacterium Legionella, for example, lives primarily in amoebae in an aquatic environment. When amoebae are dispersed in aerosols that are inhaled by humans, they—along with their bacterial hitchhikers—are taken up by macrophages in the lung. Once inside a human cell, the bacterium replicates and causes a clinical pneumonia we call Legionnaire’s disease. Likewise, the response of American industry to women’s demand for more absorbent tampons, which gave them greater freedom during menstruation, resulted in a product that unexpectedly encouraged growth of certain staphylococci that typically exist in small numbers in women’s genital tracts. The regrettable result was the emergence of a new disease entity: toxic shock syndrome. Bacteria Evolve Rapidly The previous 20 years of research on bacteria reveal that they become pathogenic through a horizontal exchange of genetic information. In some ways microbial genomes comprise a genetic information network, operating much like the Internet. Mobile genetic elements such as plasmids, phages, and transposons are constantly streaming among microorganisms as they contact each other or enter into new environments. This elementary form of gene transfer enables microbes—often quite diverse ones—to share information with one another (Dobrindt et al., 2004). For example, as described by Martin Blaser and colleagues (see paper in this chapter), there are two types of H. pylori: one that is associated with gastritis, and another that is associated with peptic ulcer and gastric cancer. The difference between the two types is that the more pathogenic type contains an insertion of DNA that is called a pathogenicity island. This extra DNA encodes a protein that leads to cancer and ulcers in some human hosts, although exactly how it does that remains to be determined. It is known that such islands of genes often allow bacteria to synthesize surface proteins that function much like a hypodermic needle (type III secretion). This structure makes contact with host cells and permits the bacteria to deliver other proteins, called effectors, directly into the host cell. The injected effector proteins have the ability to change or capture or manipulate normal host functions to the microbe’s favor. This apparently ancient and relatively common pathogenic mechanism is present in plant pathogens as

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary tion resistance, but when pathogens break the barrier, they can disturb the ecological equilibrium. Ecologic disturbances can lead to monopolization of the niche by a primary pathogen or by indigenous microbes that become opportunistic pathogens. As the host grows old, the impairment of the immune response leads to disturbance of this dynamic equilibrium and to disease. Adequate and complete identification of the indigenous human microbiome is the first step in elucidating its role in the physiology of our colonized organs and in the maintenance of health. REFERENCES Akopyants NS, Clifton SW, Kersulyte D, Crabtree JE, Youree BE, Reece CA, Bukanov NO, Drazek ES, Roe BA, Berg DE. 1998. Analyses of the cag pathogenicity island of Helicobacter pylori. Molecular Microbiology 28(1):37–53. Amieva MR, Vogelmann R, Covacci A, Tompkins LS, Nelson WJ, Falkow S. 2003. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300(5624):1430–1434. Araki A, Kanai T, Ishikura T, Makita S, Uraushihara K, Iiyama R, Totsuka T, Takeda K, Akira S, Watanabe M. 2005. MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. Journal of Gastroenterology 40(1):16–23. Aras RA, TakataT, Ando T, Van der Ende A, Blaser NJ. 2001. Regulation of the HpyII restriction-modification system of Helicobacter pylori by gene deletion and horizontal reconstitution. Molecular Microbiology 42(2):369–382. Aras RA, Small AJ, Ando T, Blaser MJ. 2002. Helicobacter pylori interstrain restriction-modification diversity prevents genome subversion by chromosomal DNA from competing strains. Nucleic Acids Research 30(24):5391–5397. Aras RA, Kang J, Tschumi A, Harasaki Y, Blaser MJ. 2003a. Extensive repetitive DNA facilitates prokaryotic genome plasticity. Proceedings of the National Academy of Science USA 100(23):13579–13584. Aras RA, Lee Y, Kim S-K, Israel D, Peek RM, Blaser MJ. 2003b. Natural variation in populations of persistently colonizing bacteria affect human host cell phenotype. Journal of Infectious Diseases 188(4):486–96. Axelsson LG, Midtvedt T, Bylund-Fellenius AC. 1996. The role of intestinal bacteria, bacterial translocation and endotoxin in dextran sodium sulphate-induced colitis in the mouse. Microbial Ecology in Health and Disease 9:225–37 Azuma T, Suto H, Ito Y, Ohtani M, Dojo M, Kuriyama M, Kato T. 2001. Gastric leptin and helicobacter pylori infection. Gut 49(3):324–329. Azuma T, Yamakawa A, Yamazaki S, Fukuta K, Ohtani M, Ito Y, Dojo M, Yamazaki Y, Kuriyama, M. 2002. Correlation between variation of the 3’ region of the cagA gene in Helicobacter pylori and disease outcome in Japan. Journal of Infectious Diseases 186(11):1621–1630. Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. 2005. Host-bacterial mutualism in the human intestine. Science 307(5717):1915–1920. Beard, AS, Blaser MJ. 2002. The ecology of height: The effect of microbial transmission on human height. Perspectives in Biology and Medicine 45(4):475–498. Berg, JA, Tom-Petersen A, Nybroe O. 2005. Copper amendment of agricultural soil selects for bacterial antibiotic resistance in the field. Letters in Applied Microbiology 40(2):146–151. Blaser MJ. 1990. Helicobacter pylori and the pathogenesis of gastroduodenal inflammation. Journal of Infectious Diseases 161(4):626–633.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Blaser MJ. 1992. Hypotheses on the pathogenesis and natural history of Helicobacter pylori-induced inflammation. Gastroenterology 102(2):720–727. Blaser MJ. 1997. Ecology of Helicobacter pylori in the human stomach. Journal of Clinical Investigation 100(4):759–762. Blaser MJ. 1998. Helicobacters are indigenous to the human stomach: Duodenal ulceration is due to changes in gastric microecology in the modern era. Gut 43(5):721–727. Blaser MJ. 1999. The changing relationships of Helicobacter pylori and humans: Implications for health and disease. Journal of Infectious Diseases 179(6):1523–1530. Blaser MJ. 2005 (March 16). Session I: Host-Pathogen Interactions: Defining the Concepts of Pathogenicity, Virulence, Colonization, Commensalism, and Symbiosis. Presentation at the Forum on Microbial Threats Workshop Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship, Washington, D.C., Institute of Medicine, Forum on Microbial Threats. Blaser MJ, Atherton JC. 2004. Helicobacter pylori persistence: Biology and disease. Journal of Clinical Investigation 113(3):321–333. Blaser MJ, Kirschner D. 1999. Dynamics of Helicobacter pylori colonization in relation to the host response. Proceedings of the National Academy of Sciences USA 96(15):8359–8364. Blaser MJ, Chyou PH, Nomura A. 1995a. Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer, and duodenal ulcer risk. Cancer Research 55(3):562–565. Blaser MJ, Pérez-Pérez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, Stemmermann GN, Nomura A. 1995b. Infection with Helicobacter pylori strains possessing cagA associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Research 55(10):2111–2115. Breitbart M, Rohwer F. 2005. Here a virus, there a virus, everywhere the same virus? Trends in Microbiology 13(6):278–284. Calam J. 1995. Helicobacter pylori, acid and gastrin. European Journal of Gastroenterology and Hepatology 7:310–317. Cash HL, Hooper LV. 2005. Commensal bacteria shape intestinal immune system development. American Society of Microbiology News 71(2):77–83. Censini S, Lange C, Xiang ZY, Crabtree JE, Ghiara P, Borodovsky M, Rappuoli R, Covacci A. 1996. Cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proceedings of the National Academy of Sciences USA 93(25):14648–14653. Chen LW, Egan L, Li ZW, Greten FR, Kagnoff MF, Karin M. 2003. The two faces of IKK and NF-kappaB inhibition: Prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nature Medicine 9(5):575–581. Chow WH, Blaser MJ, Blot WJ, Gammon MD, Vaughan TL, Risch HA, Pérez-Pérez GI, Schoenberg JB, Stanford JL, Rotterdam H, West AB, Fraumeni JF. 1998. An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Research 58(4):588–590. Cockburn TA. 1971. Infectious diseases in ancient populations. Current Anthropology 12:45–62. Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M. 1975. A model for gastric cancer epidemiology. Lancet 2(7924):58–60. Covacci A, Censini S, Bugnoli M, Petracca R, Burroni D, Macchia G, Massone A, Papini E, Xiang Z, Figura N, Rappuoli. 1993. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proceedings of the National Academy of Sciences USA 90(12):5791–5795. Cover TL, Dooley CP, Blaser MJ. 1990. Characterization and human serologic response to proteins in Helicobacter pylori broth culture supernatants with vacuolizing cytotoxin activity. Infection and Immunity 58(3):603–610.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Crabtree JE, Taylor JD, Wyatt JI, Heatley RV, Shallcross TM, Tompkins DS, Rathbone BJ. 1991. Mucosal IgA recognition of Helicobacter pylori 120 kDa protein, peptic ulceration, and gastric pathology. Lancet 338(8763):332–335. de Martel C, Llosa AE, Farr SM, Friedman GD, Vogelman JH, Orentreich N, Corley DA, Parsonnet J. 2005. Helicobacter pylori infection and the risk of development of esophageal adenocarcinoma. Journal of Infectious Diseases 191(5):761–767. Devesa SS, Blot WJ, Fraumeni JK Jr. 1998. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 83(10):2049–2053. Dieleman LA, Ridwan BU, Tennyson GS, Beagley KW, Bucy RP, Elson CO. 1994. Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology 107(6):1643–1652. Dieleman LA, Goerres M, Arends A, Sprengers D, Torrice C, Hoentjen F, Grenther WB, Sartor RB. 2003. Lactobacillus GG prevents recurrence of colitis in HLA-B27 transgenic rats after antibiotic treatment. Gut 52(3):370–376. Dobrindt U, Hochhut B, Hentschel U, Hacker J. 2004. Genomic islands in pathogenic and environmental microorganisms. National Review of Microbiology 2(5):414–424. Dobson, DE, Prager EM, Wilson AC. 1984. Stomach lysozymes of ruminants. I. Distribution and catalytic properties. Journal of Biological Chemistry 259(18):11607–11616. Dominguez-Bello MG, Blaser MJ. 2005. Are iron-scavenging parasites protective against malaria? Journal of Infectious Diseases 191(4):646. Dominguez-Bello MG, Ruiz MC, Michelangeli F. 1993. Evolutionary significance of foregut fermentation in the hoatzin (Opisthocomus hoazin; Aves, Opisthocomidae). Journal of Comparative Physiology B 163:594–601. Dominguez-Bello MG, Pacheco MA, Ruiz MC, Michelangeli F, Leippe M, de Pedro MA. 2004. Resistance of rumen bacteria murein to bovine gastric lysozyme. BioMed Central Ecology 4:7. Dominguez-Bello MG, Marini GE, Maldonado AL, Hidalgo G, Cabras S, Buffa R, Marini E, Floris G, Racugno W, Pericchi LR, Castellanos ME, Blaser MJ, Gröschl M. 2005. No Evidence of Detrimental Effect of Helicobacter pylori and Intestinal Parasites on the Nutritional Status of Amerindians in Venezuela. ASM Conference on Beneficial Microbes, Lake Tahoe, Nevada. Dreyfuss ML, Msamanga GI, Spiegelman D, Hunter DJ, Urassa EJ, Hertzmark E, Fawzi WW. 2001. Determinants of low birth weight among HIV-infected pregnant women in Tanzania. American Journal of Clinical Nutrition 74(6):814–826. Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. 2005. Diversity of the human intestinal microbial flora. Science 308(5728):1635–1638. Edwards RA, Rohwer F. 2005. Viral metagenomics. Nature Reviews Microbiology 3(6):504–510. Egan LJ, Eckmann L, Greten FR, Chae S, Li ZW, Myhre GM, Robine S, Karin M, Kagnoff MF. 2004. IkappaB-kinasebeta-dependent NF-kappaB activation provides radioprotection to the intestinal epithelium. Proceedings of the National Academy of Sciences USA 101(8):2452–2457. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni JF Jr, Rabkin CS. 2000. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 412(6842):99. Falkow S. 1998. Who speaks for the microbes? Emerging Infectious Diseases 4(3):495–497. Falkow S. 2005 (March 17). Session III:Understanding the Dynamic Relationships of Host-Microbe Interactions. Presentation at the Forum on Microbial Threats Workshop Ending the War Metaphor: The Changing for Unraveling the Host-Microbe Relationship, Washington, D.C., Institute of Medicine, Forum on Microbial Threats. Falush D, Kraft C, Taylor NS, Correa P, Fox JG, Achtman M, Suerbaum S. 2001. Recombination and mutation during long-term gastric colonization by Helicobacter pylori: Estimates of clock rates, recombination size, and minimal age. Proceedings of the National Academy of Sciences USA 98(26):15056–15061.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Falush D, Wirth T, Linz B, Pritchard JK, Stephens M, Kidd M, Blaser MJ, Graham DY, Vacher S, Perez-Perez GI, Yamaoka Y, Negraud F, Otto K, Reichard U, Katzowitsch E, Wang X, Achtman M, Suerbaum S. 2003. Traces of human migration in Helicobacter pylori populations. Science 299(5629):1582–1585. Forchielli ML, Walker WA. 2005. The role of gut-associated lymphoid tissues and mucosal defence. British Journal of Nutrition 93(Suppl 1):S41–S48. Ghose C, Perez-Perez GI, Dominguez-Bello MG, Pride DT, Bravi CM, Blaser MJ. 2002. East Asian genotypes of Helicobacter pylori: Strains in Amerindians provide evidence for its ancient human carriage. Proceedings of the National Academy of Sciences USA 99(23):15107–15111. Ghose C, Perez-Perez GI, van Doorn LJ, Dominguez-Bello MG, Blaser MJ. 2005. High frequency of gastric colonization with multiple Helicobacter pylori strains in Venezuelan subjects. Journal of Clinical Microbiology 43(6):2635–2641. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ. 2003. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. Journal of Biological Chemistry 278(11):8869–8872. Goodman KJ, Correa P. 2000. Transmission of Helicobacter pylori among siblings. Lancet 355(9201): 358–362. Goodman KJ, Correa P, Tengana Aux HJ, Ramirez H, DeLany JP, Guerrero Pepinosa O, Lopez Quinones M, Collazos Parra T. 1996. Helicobacter pylori infection in the Colombian Andes: A population-based study of transmission pathways. American Journal of Epidemiology 144(3): 290–299. Govoni G, Gros P. 1998. Macrophage NRAMP1 and its role in resistance to microbial infections. Inflammation Research 47(7):277–284. Grajal A, Strahl S, Parra R, Dominguez MG, Neher A. 1989. Foregut fermentation in the hoatzin, a Neotropical leaf-eating bird. Science 245(4923):1236–1238. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M. 2004. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118(3):285–296. Halfvarson J, Bodin L, Tysk C, Lindberg E, Jarnerot G. 2003. Inflammatory bowel disease in a Swedish twin cohort: A long-term follow-up of concordance and clinical characteristics. Gastroenterology 124(7):1767–1773. Harford WV, Barnett C, Lee E, Perez-Perez G, Blaser MJ, Peterson WL. 2000. Acute gastritis with hypochlorhydria: Report of 35 cases with long-term follow-up. Gut 47(4):467–472. Harmsen, HJ, Raangs GC, He T, Degener JE, Welling GW. 2002. Extensive set of 16S rRNA-based probes for detection of bacteria in human feces. Applied Environmental Microbiology 68(6): 2982–2990. Hatakeyama M. 2004. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nature Reviews Cancer 4(9):688–694. Hayes W. 1968. Genetics of Bacteria and Their Viruses: Studies in Basic Genetics and Molecular Biology. 2nd ed. New York: John Wiley & Sons, Inc. Hazell SL, Lee A, Brady L, Hennessy W. 1986. Campylobacter pyloridis and gastritis: Association with intercellular spaces and adaptation to an environment of mucus as important factors in colonization of the gastric epithelium. Journal of Infectious Diseases 153(4):658–663. Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, Mankertz J, Gitter AH, Burgel N, Fromm M, Zeitz M, Fuss I, Strober W, Schulzke JD. 2005. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129(2):550–64. Hentschel E, Brandstatter G, Dragosics B, Hirschl AM, Nemec H, Schutze K, Taufer M, Wurzer H. 1993. Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. New England Journal of Medicine 328(5):308–312.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, Hatakeyama M. 2001. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295(5555):683–686. Hisamatsu T, Suzuki M, Reinecker HC, Nadeau WJ, McCormick BA, Podolsky DK. 2003. CARD15/NOD2 functions as an anti-bacterial factor in human intestinal epithelial cells. Gastroenterology 124(4):993–1000. Hoentjen F, Harmsen HJ, Braat H, Torrice CD, Mann BA, Sartor RB, Dieleman LA. 2003. Antibiotics with a selective aerobic or anaerobic spectrum have different therapeutic activities in various regions of the colon in interleukin-10 gene deficient mice. Gut 52(12):1721–1727. Hooper, LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. 2001. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291(5505): 881–884. Hooper LV, Stappenbeck TS, Hong CV, Gordon JI. 2003. Angiogenins: A new class of microbicidal proteins involved in innate immunity. Nature Immunology 4(3):269–273. Horvath TL, Diano S, Sotonyi P, Heiman P, Tschöp M. 2001. Minireview: Ghrelin and the regulation of energy balance—a hypothalamic perspective. Endocrinology 142(10):4163–4169. Howson CP, Hiyama T, Wynder EL. 1986. The decline in gastric cancer: Epidemiology of an unplanned triumph. Epidemiology Review 8:1–27. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. 2001. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411(6837):599–603. Hungate RE. 1966. The rumen and its microbes. New York: Academic Press. Hungate RE. 1972. Relationships between protozoa and bacteria of the alimentary tract. American Journal of Clinical Nutrition 25(12):1480–1484. IARC (International Agency for Research on Cancer). 1994. Infection with Helicobacter pylori. IARC Monograph Evaluation of Carcinogenic Risks in Humans 61: 77–240. Isomoto H, Nakazato M, Ueno H, Date Y, Nishi Y, Mukae H, Mizuta Y, Ohtsuru A, Yamashita S, Kohno S. 2004. Low plasma ghrelin levels in patients with Helicobacter pylori-associated gastritis. American Journal of Medicine 117(6):429–432. Israel D, Lou A, Blaser MJ. 2000. Characteristics of Helicobacter pylori natural transformation. FEMS Microbiology Letters 186(2):275-280. Israel D, Salama N, Krishna U, Rieger UM, Atherton JC, Falkow S, Peek RM. 2001. Helicobacter pylori genetic diversity within the gastric niche of a single human host. Proceedings of the National Academy of Sciences USA 98(25):14625–14630. Karnes WE Jr, Samloff IM, Siurala M, Kekki M, Sipponen P, Kim SW, Walsh JH. 1991. Positive serum antibody and negative tissue staining for Helicobacter pylori in subjects with atrophic body gastritis. Gastroenterology 101(1):167–174. Kersulyte D, Chalkauskas H, Berg DE. 1999. Emergence of recombinant strains of Helicobacter pylori during human infection. Molecular Microbiology 31(1):31–43. Kim SC, Tonkonogy SL, Bower M, Sartor RB. 2004. Dual-association of gnotobiotic IL-10-/- mice with two nonpathogenic commensal bacterial species accelerates colitis [abstract]. Gastroenterology 126:A291. Kim SC, Tonkonogy SL, Albright CA, Sartor RB. 2005a. Different host genetic backgrounds determine disease phenotypes induced by selective bacterial colonization [abstract]. Gastroenterology 128:A512. Kim SC, Tonkonogy SL, Albright CA, Tsang J, Balish EJ, Braun J, Huycke MM, Sartor RB. 2005b. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology 128(4):891–906. Kirschner DE, Blaser MJ. 1995. The dynamics of Helicobacter pylori infection of the human stomach. Journal of Theoretical Biology 176(2):281–290.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Klein PD, Graham DY, Gaillour A, Opekun AR, Smith EO. 1991. Water source as risk factor for Helicobacter pylori infection in Peruvian children. Gastrointestinal Physiology Working Group. Lancet 337(8756):1503–1506. Klieve AV, Bauchop T. 1988. Morphological diversity of ruminal bacteriophages from sheep and cattle. Applied Environmental Microbiology 54(6):1637–1641. Klieve AV, Swain RA. 1993. Estimation of ruminal bacteriophage numbers by pulsed-field gel electrophoresis and laser densitometry. Applied Environmental Microbiology 59:2299–2303. Klieve AV, Hudman JF, Bauchop T. 1989. Inducible bacteriophages from ruminal bacteria. Applied Environmental Microbiology 55:1630–1634. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, Flavell RA. 2005. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307(5710): 731–734. Kucik CJ, Martin GL, Sortor BV. 2004. Common intestinal parasites. American Family Physician 69(5):1161–1168. Kuipers EJ, Uyterlinde AM, Peña AS, Roosendaal R, Pals G, Nelis GF, Festen HP, Meuwissen SG. 1995a. Long-term sequelae of Helicobacter pylori gastritis. Lancet 345(8964):1525–1528. Kuipers EJ, Pérez-Pérez GI, Meuwissen SGM, Blaser MJ. 1995b. Helicobacter pylori and atrophic gastritis: Importance of the cagA status. Journal of the National Cancer Institute 87(23):1777–1780. Kuipers EJ, Israel DA, Kusters JG, Gerrits MM, Weel J, van der Ende A, van der Hulst RWM, Wirth H-P, Hôôk-Nikanne J, Thompson SA, Blaser MJ. 2000. Quasispecies development of Helicobacter pylori observed in paired isolates obtained years apart in the same host. Journal of Infectious Diseases 181(1):273–282. Lagergren J, Bergström R, Lindgren A, Nyrén O. 1999. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. New England Journal of Medicine 340(11): 825–831. Lala S, Ogura Y, Osborne C, Hor SY, Bromfield A, Davies S, Ogunbiyi O, Nunez G, Keshav S. 2003. Crohn’s disease and the NOD2 gene: A role for Paneth cells. Gastroenterology 125(1):47–57. Lederberg J. 2000. Infectious history. Science 288(5464):287–293. Lee HM, Wang G, Englander EW, Kojima M, Greeley Jr. GH. 2002. Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: Enteric distribution, ontogeny, influence of endocrine, and dietary manipulations. Endocrinology 143(1):185–190. Loffeld RJLF, Werdmuller BFM, Kusters JG, Blaser MJ, Pérez-Pérez GI, Kuipers EJ. 2000. Colonization with cagA-positive H. pylori strains inversely associated with reflux oesophagitis and Barrett’s oesophagitis. Digestion 62(2-3):95–99. Lu X, Francois F, Yang L, Zhou M, Bini E, Blaser MJ, Pei Z. 2005 (June). Alteration of the bacterial biota in reflux esophagitis. Paper presented at: 105th General Meeting of the American Society of Microbiology; Atlanta, GA. MacDonald TT, Gordon JN. 2005. Bacterial regulation of intestinal immune responses. Gastroenterology Clinic of North America 34(3):401-412. Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S, Castro Alves C, Campos ML, Van Doorn LJ, Caldas C, Seruca R, Carneiro F, Sobrinho-Simoes M. 2003. A pro-inflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology 125(2):364–371. Mackowiak PA. 1982. The normal microbial flora. New England Journal of Medicine 307(2):83–93. Mann BA, Kim SC, Sartor RB. 2003. Selective induction of experimental colitis by monoassociation of HLA-B27 transgenic rats with various enteric Bacteroides species [abstract]. Gastroenterology 124:A322. Matson CA, Reid DF, Cannon TA, Ritter RC. 2000. Cholecystokinin and leptin act synergistically to reduce body weight. American Journal of Physiology, Regulatory, Integrative and Comparative Physiology 278(4):R882–R890.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary McNeill WH. 1976. Plagues and Peoples. Garden City, NY: Anchor Books. Moss SF, Calam J. 1993. Acid secretion and sensitivity to gastrin in patients with duodenal ulcer: Effect of eradication of Helicobacter pylori. Gut 34(7):888–892. Moss SF, Legon S, Bishop AE, Polak JM, Calam J. 1992. Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease. Lancet 340(8825):930–932. Murray J, Murray A, Murray M, Murray C. 1978. The biologicalsuppression of malaria: An ecological and nutritional interrelationship of a host and two parasites. American Journal of Clinical Nutrition 31(8):1363–1366. Nacher M, McGready R, Stepniewska K, Cho T. Looareesuwan S, White NJ, Nosten F. 2003. Haematinic treatment of anaemia increases the risk of Plasmodium vivax malaria in pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene 97(3):273–276. Naumann M, Wessler S, Bartsch C, Wieland B, Covacci A, Haas R, Meyer TF. 1999. Activation of activator protein 1 and stress response kinases in epithelial cells colonized by Helicobacter pylori encoding the cag pathogenicity island. Journal of Biological Chemistry 274(4):31655–31662. Nelson KE, Zinder SH, Hance I, Burr P, Odongo D, Wasawo D, Odenyo A, Bishop R. 2003. Phylogenetic analysis of the microbial populations in the wild herbivore gastrointestinal tract: Insights into an unexplored niche. Environmental Microbiology 5(11):1212–1220. Nemcova R, Styriak I, Stachova M, Kmet V. 1993. Isolation and partial characterization of three rumen Lactobacillus plantarum bacteriophages. New Microbiology 16(2):177–180. Newman B, Siminovitch KA. 2005. Recent advances in the genetics of inflammatory bowel disease. Current Opinions in Gastroenterology 21(4):401–407. Nomura AM, Stemmermann GN, Chyou P-H, Pérez-Pérez GI, Blaser MJ. 1994. Helicobacter pylori infection and the risk for duodenal and gastric ulceration. Annals of Internal Medicine 120(12): 977–981. Nomura AM, Perez-Perez GI, Lee J, Stemmermann G, Blaser MJ. 2002a. Relationship between H. pylori cagA status and risk of peptic ulcer disease. American Journal of Epidemiology 155(11): 1054–1059. Nomura AM, Lee J, Stemmermann G, Nomura RY, Perez-Perez GI, Blaser MJ. 2002b. Helicobacter pylori cagA seropositivity and gastric carcinoma risk in a Japanese American population. Journal of Infectious Diseases 186(8):1138–1144. Nwokolo CU, Freshwater DA, O’Hare P, Randeva HS. 2003. Plasma ghrelin following cure of Helicobacter pylori. Gut 52(5):637–640. Occhialini A, Marais A, Urdaci M, Sierra R, Munoz N, Covacci A, Megraud F. 2001. Composition and gene expression of the cag pathogenicity island in Helicobacter pylori strains isolated from gastric carcinoma and gastritis patients in Coast Rica. Infection and Immunity 69(3):1902–1908. Odenbreit S, Püls J, Sedlmaier B, Gerland E, Fischer W, Haas R. 2000. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287(5457):1497–1500. Ogimoto K, Imai S. 1981. Atlas of Rumen Microbiology. Tokyo, Japan: Scientific Society Press. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH. 2001. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411(6837):603–606. Oliveira AM, Queiroz DM, Rocha GA, Mendes EN. 1994. Seroprevalence of Helicobacter pylori infection of children of low socioeconomic level in Belo Horizonte, Brazil. American Journal of Gastroenterology 89(12):2201–2204. Oppenheimer SJ. 2001. Iron and its relation to immunity and infectious disease. Journal of Nutrition 131(2S-2):616S-633S. Pantoja, I, Mojica M, Vargas-Pinto G, Scott K, Patterson A, Flint H, Blaser M, Dominguez-Bello MG. 2005. Tetracycline Resistance Genes in Bolivian Amerindians with Low Antibiotic Exposure. San Francisco, CA: Infectious Diseases Society of America.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Parsonnet J. 1995. The incidence of Helicobacter pylori infection. Alimentary Pharmacology and Therapeutics 9(Suppl 2):45–51. Parsonnet J, Friedman GD, Orentreich N, Vogelman H. 1997. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut 40(3):297–301. Peek RM, Blaser MJ. 2002. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nature Reviews Cancer 2(1):28–37. Peek RM Jr, Peek RM, Vaezi MF, Falkow S, Goldblum JR, Pérez-Pérez GI, Richter JE, Blaser MJ. 1999. The role of Helicobacter pylori cagA+ strains and specific host immune responses on the development of premalignant and malignant lesions of the gastric cardia. International Journal of Cancer 82:520–524. Pei Z, Bini EJ, Yang L, Zhou M, Francois F, Blaser MJ. 2004. Bacterial biota in the human distal esophagus. Proceedings of the National Academy of Sciences USA 101(12):4250–4255. Pei Z, Yang L, Peek RM, Levine SM, Pride DT, Blaser MJ. 2005. Bacterial biota in reflux esophagitis and Barrett’s esophagus. World Journal of Gastroenterology In press. Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X, Newman B, Van Oene M, Cescon D, Greenberg G, Griffiths AM, St George-Hyslop PH, Siminovitch KA. 2004. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nature Genetics 36(5):471–475. Perez-Perez GI, Salomaa A, Kosunen TU, Daverman B, Rautelin H, Aromaa A, Knekt P, Blaser MJ. 2002. Evidence that cagA+Helicobacter pylori strains are disappearing more rapidly than cagA-strains. Gut 50(3):295–298. Perez-Perez GI, Sack RB, Reid R, Santosham M, Croll J, Blaser MJ. 2003. Transient and persistent Helicobacter pylori colonization in Native American children. Journal of Clinical Microbiology 41(6):2401–2407. Pohl H, Gilbert H. 2005. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. Journal of the National Cancer Institute 97(2):142–146. Queiroz DM, Guerra JB, Rocha GA, Rocha AM, Santos A, De Oliveira AG, Cabral MM, Nogueira AM, De Oliveira CA. 2004. IL1B and IL1RN polymorphic genes and Helicobacter pylori cagA strains decrease the risk of reflux esophagitis. Gastroenterology 127(1):73–79. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. 2004. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118(2): 229–241. Rath HC, Herfarth HH, Ikeda JS, Grenther WB, Hamm TE Jr, Balish E, Taurog JD, Hammer RE, Wilson KH, Sartor RB. 1996. Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats. Journal of Clinical Investigation 98(4):945-953. Rath HC, Wilson KH, Sartor RB. 1999. Differential induction of colitis and gastritis in HLA-B27 transgenic rats selectively colonized with Bacteroides vulgatus and Escherichia coli. Infection and Immunity 67(6):2969-2974. Rath HC, Schultz M, Freitag R, Dieleman LA, Li F, Linde HJ, Scholmerich J, Sartor RB. 2001. Different subsets of enteric bacteria induce and perpetuate experimental colitis in rats and mice. Infection and Immunity 69(4):2277–2285. Rauws EA, Langenberg W, Houthoff HJ, Zanen HC, Tytgat GN. 1998. Campylobacter pyloridis-associated chronic active antral gastritis: A prospective study of its prevalence and the effects of antibacterial and antiulcer treatment. Gastroenterology 94(1):33–40. Rehnberg-Laiho L, Rautelin H, Koskela P, Sarna S, Pukkala E, Aromaa A, Knekt P, Kosunen TU. 2001. Decreasing prevalence of helicobacter antibodies in Finland, with reference to the decreasing incidence of gastric cancer. Epidemiology and Infection 126(1):37–42. Rosebury T. 1962. Microorganisms Indigenous to Man. New York: McGraw Hill. Rothenbacher D, Blaser MJ, Bode G, Brenner H. 2000. An inverse relationship between gastric colonization by Helicobacter pylori and diarrheal illnesses in children: Results of a population-based cross-sectional study. Journal of Infectious Diseases 182(5):1446–1449.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Salyers A, Gupta A, Wang Y. 2004. Human intestinal bacteria as reservoirs for antibiotic resistance genes. Trends in Microbiology 12(9):412–416. Sartor RB. 2004. Microbial influences in inflammatory bowel disease: Role in pathogenesis and clinical implications. In: Sartor RB, Sandborn WJ, eds. Kirsner’s Inflammatory Bowel Diseases. Philadelphia, PA: Elsevier Publishers; Pp. 138–162. Sartor RB. 2005 (March 16). Session I: Host-Pathogen Interactions: Defining the Concepts of Pathogenicity, Virulence, Colonization, Commensalism, and Symbiosis. Presentation at the Forum on Microbial Threats Workshop Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship, Washington, D.C., Institute of Medicine, Forum on Microbial Threats. Sartor RB, Hoentjen F. 2005. Proinflammatory cytokines and signaling pathways in intestinal innate immune cells. In: Mestecky J, Lamm ME, Strober W, Bienenstock J, McGhee JR, Mayer L, eds. Mucosal Immunology. London: Elsevier Academic Press; Pp. 681–701. Savage DC. Microbial ecology of the gastrointestinal tract. 1977. Annual Review of Microbiology 31:107–133. Schreiber S, Rosenstiel P, Albrecht M, Hampe J, Krawczak M. 2005. Genetics of Crohn disease, an archetypal inflammatory barrier disease. Nature Reviews Genetics 6(5):376–388. Segal ED, Cha J, Lo J, Falkow S, Tompkins LS. 1999. Altered states: Involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proceedings of the National Academy of Sciences USA 96(25):14559–14564. Segal S, Hill AV. 2003. Genetic susceptibility to infectious disease. Trends in Microbiology 11(9): 445–448. Sellon RK, Tonkonogy S, Schultz M, Dieleman LA, Grenther W, Balish E, Rennick DM, Sartor RB. 1998. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infection and Immunity 66(11): 5224–5231. Smythies LE, Sellers M, Clements RH, Mosteller-Barnum M, Meng G, Benjamin WH, Orenstein JM, Smith PD. 2005 Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. Journal of Clinical Investigation 115(1):66–75. Sobhani I, Buyse M, Goiot H, Weber N, Laigneau JP, Henin D, Soul JC, Bado A. 2002. Vagal stimulation rapidly increases leptin secretion in human stomach. Gastroenterology 122(2): 259–263. Stappenbeck TS, Hooper LV, Gordon JI. 2002. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proceedings of the National Academy of Sciences USA 99(24):15451–15455. Strober W, Fuss I, Boirivant M, Kitani A. 2004. Insights into the mechanism of oral tolerance derived from the study of models of mucosal inflammation. Annual of the New York Academy of Sciences 1029:115–131. Suerbaum S, Smith JM, Bapumia K, Morelli G, Smith NH, Kunstmann E, Dyrek I, Achtman M. 1998. Free recombination with Helicobacter pylori. Proceedings of the National Academy of Sciences USA 95(21):12619–12624. Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M, Weber J, Hoffmann U, Schreiber S, Dietel M, Lochs H. 2002. Mucosal flora in inflammatory bowel disease. Gastroenterology 122(1):44–54. Tajima K, Aminov RI, Nagamine T, Ogata K, Nakamura M, Matsui H. 2001a. Rumen bacterial diversity as determined by sequence analysis of 16S rDNA libraries. FEMS Microbiology Ecology 29:159–169. Tajima K, Nagamine T, Matsui H, Nakamura M, Aminov RI. 2001b. Phylogenetic analysis of archaeal 16S rRNA libraries from the rumen suggests the existence of a novel group of archaea not associated with known methanogens. FEMS Microbiology Letters 200(1):67–72.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Tham KT, Peek RM, Atherton JC, Cover TL, Perez-Perez GI, Shyr Y, Blaser MJ. 2001. Helicobacter pylori genotypes, host factors, and gastric mucosal histopathology in peptic ulcer disease. Human Pathology 32(3):264–273. Tomb JF, White O, Kerlavage AR, Clayton RA, Sutton GG, Fleischmann RD, Ketchum KA, Klenk HP, Gill S, Dougherty BA, Nelson K, Quackenbush J, Zhou L, Kirkness EF, Peterson S, Loftus B, Richardson D, Dodson R, Khalak HG, Glodek A, McKenney K, Fitzegerald LM, Lee N, Adams MD, Hickey EK, Berg DE, Gocayne JD, Utterback TR, Peterson JD, Kelley JM, Cotton MD, Weidman JM, Fujii C, Bowman C, Watthey L, Wallin E, Hayes WS, Borodovsky M, Karp PD, Smith HO, Fraser CM, Venter JC. 1997. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388(6642):539–547. Tummuru MKR, Cover TL, Blaser MJ. 1993. Cloning and expression of a high molecular weight major antigen of Helicobacter pylori: Evidence of linkage to cytotoxin production. Infection and Immunity 61(5):1799–1809. Tummuru MKR, Sharma SA, Blaser MJ. 1995. Helicobacter pylori picB, a homologue of the Bordetella pertussis toxin secretion protein, is required for induction of IL-8 in gastric epithelial cells. Molecular Microbiology 18(5):867–876. Vaezi MF, Falk GW, Peek RM, Vicari JJ, Goldblum JR, Perez-Perez GI, Rice TW, Blaser MJ, Richter JE. 2000. cagA-positive strains of Helicobacter pylori may protect against Barrett’s esophagus. American Journal of Gastroenterology 95(9):2206–2211. Van Soest PJ. 1994. Nutritional Ecology of the Ruminant. Ithaca, NY: Comstock. Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, Athman R, Memet S, Huerre MR, Coyle AJ, DiStefano PS, Sansonetti PJ, Labigne A, Bertin J, Philpott DJ, Ferrero RL. 2004. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nature Immunology 5(11):1166–1174. Vicari JJ, Peek RM, Falk GW, Goldblum JR, Easley KA, Schnell J, Pérez-Pérez GI, Halter SA, Rice TW, Blaser MJ, Richter JE. 1998. The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease. Gastroenterology 115(1):50–57. Villedieu A, Diaz-Torres ML, Hunt N, McNab R, Spratt DA,Wilson M, Mullany P. 2003. Prevalence of tetracycline resistance genes in oral bacteria. Antimicrobial Agents in Chemotherapy 47(3): 878–882. Warburton-Timmsa VJ, Charlettd A, Valorib RM, Uffc JS, Shepherdc NA, Barrb H, McNultya CAM. 2001. The significance of cagA+ Helicobacter pylori in reflux oesophagitis. Gut 49(3):341–346. Warren JR, Marshall BJ. 1983. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1(8336):1273–1275. Watanabe T, Kitani A, Murray PJ, Strober W. 2004. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nature Immunology 5(8):800–808. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schaffeler E, Schlee M, Herrlinger KR, Stallmach A, Noack F, Fritz P, Schroder JM, Bevins CL, Fellermann K, Stange EF. 2004. NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal alpha-defensin expression. Gut 53(11):1658–1664. Whitford MF, Forster RJ, Beard CE, Gong J, Teather RM. 1998. Phylogenetic analysis of rumen bacteria by comparative sequence analysis of cloned 16S rRNA genes. Anaerobe 4:153–163. Wirth HP, Yang M, Peek RM, Hook-Nikanne J, Fried M, Blaser MJ. 1999. Phenotypic diversity in Lewis expression of Helicobacter pylori isolates from the same host. Journal of Laboratory and Clinical Medicine 133(5):488–500. Wu AH, Crabtree JE, Bernstein L, Hawtin P, Cockburn M, Tseng C, Forman D. 2003. Role of Helicobacter pylori cagA+ strains and risk of adenocarcinoma of the stomach and esophagus. International Journal of Cancer 103(6):815–821. Yamaji Y, Mitsushima T, Ikuma H, Okamoto M, Yoshida H, Kawabe T, Shiratori Y, Saito K, Yokouchi K, Omata M. 2001. Inverse background of Helicobacter pylori anti-cancer: Analysis of 5732 Japanese subjects. Gut 49(3):335–340.

OCR for page 102
Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Yamaoka Y, Kodama T, Kashima K, Graham DY, Sepulveda AR. 1998. Variants of the 3’ region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases. Journal of Clinical Microbiology 36(8):2258–2263. Ye W, Held M, Lagergren J, Engstrand L, Blot WJ, McLaughlin JK, Nyrén O. 2004. Helicobacter pylori infection and gastric atrophy: Risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. Journal of the National Cancer Institute 96(5):388–396.