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3 Pathogen Evolution OVERVIEW As Lederberg (2000) observed, the host-microbe relationship is a dynamic equilibrium. Physiological or genetic changes in either partner may prompt com- mensal microbes to invade the tissue of their host, thereby triggering an immune response that destroys the invaders, but may also injure or kill the host. As they explored this process from the perspectives of pathogen and host, the workshop speakers featured in this chapter proposed a variety of possible evolutionary routes to the host-microbe relationships that underlie infectious diseases. The chapter’s first paper, by Stanley Falkow of Stanford University, consid- ers the nature of bacterial pathogenicity as it has been viewed historically, and as revealed by his research and that of his colleagues at Stanford University. He explains how key discoveries—beginning with Lederberg’s fundamental work on bacterial genetics—shaped the developing field of molecular biology, and more specifically, Falkow’s nearly 50 years of research on the genetic basis of bacterial pathogenicity. Using the tools of molecular genetics to study Salmonella, Falkow and coworkers have observed how bacteria manipulate host cell functions, how hori- zontal gene transfer shapes pathogen specialization, and how inherited pathoge- nicity islands transform commensal bacteria into pathogens. Having screened the entire Salmonella genome for genes that are associated with different stages of infection with a microarray-based negative selection strategy, they have identified many pathogen genes expressed in the multistage process of host invasion. Using a mouse model, they have also identified host genes and gene pathways expressed in response to Salmonella infection. 

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 MICROBIAL EVOLUTION AND CO-ADAPTATION Falkow also considers the importance of the microbes he refers to as “com - mensal pathogens”: bacterial species (e.g., Streptococcus pneumoniae, Neis- seria meningitidis, Haemophilus influenzae type b, Streptococcus pyogenes) that typically inhabit the human nasopharynx without symptom, but sometimes cause disease. Their existence raises a host of scientific questions regarding the relationship between microbial pathogenicity, infectious disease, and immune function—questions that, he argues, should be approached by studying microbial pathogenicity as a biological phenomenon, and not merely from the perspective of its role in causing disease. Just as there is more to microbial pathogenicity than disease, there is more to infectious disease than the actions of pathogens on host cells and systems. The chapter’s second paper, coauthored by Elisa Margolis and workshop speaker Bruce Levin of Emory University, considers the host response to microbial virulence, which, the authors note, does not correspond to simple evolutionary models. They examine why bacteria harm the (mostly human) hosts they need for their survival, offering evidence that “much of the virulence of bacterial infections can be blamed on the seemingly misguided overresponse of the immune defenses.” These immunological failings include responding more vigorously than needed, as occurs in bacterial sepsis; responding incorrectly to a pathogen, as occurs in lepromatous leprosy; or responding to the wrong signals, as occurs in toxic shock syndrome. Margolis and Levin explore these and other examples of the “perversity of the immune system” and consider this view in light of various current hypotheses for the evolution of bacterial virulence. They offer possible explanations as to why natural selection has not tempered immune overresponse to bacterial infections and discuss the implications of their host-response perspec- tive on virulence for the treatment of bacterial infections. Two additional speakers, Gordon Dougan and Julian Parkhill, of the Wellcome Trust Sanger Institute in Cambridge, United Kingdom, contrib- , uted to workshop discussions concerning the evolution of the host-pathogen relationship. Each presenter discussed the evolutionary pathways taken by Salmonella serovars to become diverse pathogens. These include Salmonella enterica serovar Typhimurium (hereinafter S. typhimurium), which infects a wide range of hosts and is a major cause of gastroenteritis in humans, and S. enterica serovar Typhi (hereinafter S. typhi), the human-specific agent of the systemic infection typhoid fever. In humans, S. typhimurium infections are generally (but not always; see below) contained within the intestinal epithelium. S. typhi evades destruction by the immune system and is transported, via the liver and spleen, to the gall bladder and bone marrow, in which the bacteria can persist (Figure WO-9). Thus, significant numbers of people infected with typhoid—including those asymptomatically infected with S. typhi—become chronic carriers of the pathogen and reservoirs of a disease that poses a con- siderable threat to public health. From the perspective of S. typhi, however, this “stealth” strategy is essential to its survival.

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 PATHOGEN EVOLUTION Like many human-adapted pathogens, such as Yersinia pestis, Bacillus anthracis, and Mycobacterium tuberculosis, S. typhi is monophyletic; that is, it is restricted in terms of genomic variation, Dougan noted. “These human-restricted and recently evolved pathogens entered the human population, like many patho- gens, no more than about 30,000 to 40,000 years ago,” and thus, he explained, S. typhi has coevolved with humans, and at a similar evolutionary rate. In his presentation, Parkhill presented evidence that, in addition to acquir- ing genes that confer invasiveness (pathogenicity islands, as described by Falkow), monophyletic pathogens become virulent through loss of function in genes that regulate the expression of virulence factors (e.g., the pertussis toxin in Bordetella spp., as described in detail in Box WO-2). Much of this evidence derives from determining the identity of the few differences among the genomes of monophyletic pathogens, as revealed by comparator genomics. “We do comparator genomics in the hope that the comparison between the genomes will tell us something about the comparison between the phenotypes,” Parkhill said. “We might expect that we can go and look in those genes and find [virulence factors],” he continued, but in the case of Bordetella spp., that did not happen (Box WO-2). Rather, their comparisons revealed that Bordetella pertus- sis, the primary causative agent of whooping cough in humans, evolved toward host restriction and greater virulence by losing function in genes associated with host interaction (thereby narrowing host ranges) and also genes that regulate the expression of virulence factors, such as the pertussis toxin (Parkhill et al., 2003). Similar events appear to have influenced the evolution of a variety of human, equine, and plant pathogens, Parkhill noted. In the case of S. typhi, a large num- ber of pseudogenes (recently inactivated genes, as indicated by the presence of point mutations) have inactivated cell surface proteins and pathogenicity proteins (McClelland et al., 2001). “This is the signature of an organism that has changed its niche,” he said. “It has gone from a fecal-oral-transmitting pathogen that is limited to the cells lining the gut [to] become a systemic pathogen. It has lost function. It has inactivated genes that are involved in pathogenicity, genes that were involved in its previous lifestyle.” “Almost certainly, some of these inactivations are selective,” he continued. “They are necessary for that change in niche, [such as the inactivation of] type III secreted effector genes that we know are important in the interaction of S. typhimurium with its host. We can see that genes that we know are involved in host range determination in S. typhimurium have been inactivated.” However, he added, “a lot of these changes, we believe, are probably collateral damage. There is a massive event, massive changes, that the organism can’t control.” Such circumstances produced an evolutionary bottleneck, during which a massive number of pseudogenes became fixed as the pathogen’s host range and virulence changed. The comparative sequencing of S. typhi and a second, independent derivative

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 MICROBIAL EVOLUTION AND CO-ADAPTATION of the ancestor Salmonella enterica, S. enterica serovar Paratyphi A (hereinafter S. paratyphi A), provides further evidence for Parkhill’s hypothesis (McClelland et al., 2004). Like S. typhi, S. paratyphi A has become a systemic pathogen restricted to infecting humans. Each serovar contains approximately 200 pseudo- genes, but only about 30 of them are common to both. Those shared pseudogenes comprise a “list of genes that we thought were important and we thought might be selective for Salmonella starting to become an invasive pathogen, [such as] secreted effector proteins, genes involved in host range, and shedding genes, amongst others,” Parkhill observed. Moreover, he said, “The interesting thing about most of these common pseudogenes in typhi and paratyphi A is that they don’t have the same inactivating mutation. They have been acquired indepen- dently. That suggests that they are probably selectively required.” The same evolutionary processes have also produced less-virulent patho- gens, Parkhill said. For example, the sequence of the bacterium Streptococcus thermophilus, used to ferment yogurt, reveals its descent from an oral human pathogen, Streptococcus salivarius (Bolotin et al., 2004). “That suggests—and it seems likely—that people started fermenting yogurt 10,000 years ago on the Russian steppes while spitting into milk to initiate fermentation,” he explained. “After a while, they probably realized that this was quite disgusting or they found some really good strains and they propagated them because they made nice yogurt. Basically, what people have been doing with yogurt is a 10,000-year microbiology experiment. What happens if you take a pathogen and adapt it to a new niche—fermenting yogurt—that has not existed before? What happens is, you get a massive increase . . . in pseudogenes, which has knocked out most of the genes that were involved in making this an oral pathogen.” Thus, he concluded, the presence of many pseudogenes in an organism’s genome bespeaks recent and precipitous evolutionary change, but not necessarily change toward pathogenicity. Pseudogenes are what remain in the chromosome of an organism that has adapted rapidly to a new niche, Parkhill observed; the loss of those nonfunctional genes occurs much more slowly. “This suggests that a large proportion of the changes we see in these organisms is really due to drift,” he said. “There are a few selective changes, but a lot of it is random drift.” Turning to more recent events in evolution in S. typhi, Dougan described a sequencing study he and coworkers conducted to compare 200 gene fragments of approximately 500 base pairs, each from 105 globally representative S. typhi isolates.1 In this monophyletic pathogen, they identified only 88 single nucleotide polymorphisms (SNPs), which included at least 15 independent mutations to the same crucial gene encoding a DNA gyrase subunit (Roumagnac et al., 2006). 1 Using various advanced sequencing techniques, Dougan and coworkers have also attempted to classify variation across the entire S. typhi genome (Roumagnac et al., 2006). Interestingly, this comparison detected no evidence of genetic recombination, indicating that the species is genetically isolated, Dougan said, adding that this may be a feature of other host-adapted pathogens.

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 PATHOGEN EVOLUTION These mutations confer resistance to fluoroquinolone (nalidixic acid) antibiotics, which were introduced in the late 1980s for the treatment of multiantibiotic- resistant S. typhi infections. Using this information, Dougan and colleagues constructed a phylogenetic tree of S. typhi. Based on its SNP content, “any new isolate can be unequivocally assigned to the tree,” Dougan said. Moreover, “the SNPs actually associate with different types of mutations in different parts of the backbone of the protein, which give rise to different nalidixic acid-resistant clones.” Thus, the tree can be used to discriminate among isolates, but also “to stratify the acquisition even down to the point mutation of a drug resistance marker.” Dougan predicted that this method, which he termed DNA-based signature typing, will give rise to a “new era” of field- and clinic-based microbial patho- genesis studies. Researchers will be able to link phenotypes with particular SNP markers present in bacteria isolated from patients, he said; applications could include efforts to identify the genetic basis of enhanced transmission or virulence in emergent pathogen strains, to trace carriers of infectious diseases, and to con- duct type-specific vaccine efficacy studies. In addition to SNPs, Dougan noted another route to antibiotic resistance that appears recently to have been taken by non-typhoidal serovars of Salmonella, including S. typhimurium. These invasive infections—by pathogens that normally cause gastroenteritis—have become a major cause of morbidity and mortality in African children (Gordon et al., 2008; Graham, 2002). “Most of the children and people in Africa who were dying of salmonellosis, invasive disease, were not dying of S. typhi; they were actually dying of the strains that normally cause gastroenteritis, like S. typhimurium and enteritidis,” Dougan observed. Sequences of strains causing non-typhoidal salmonellosis (NTS) proved genetically distinct from Salmonella strains (of the same serovars) that cause gastroenteritis in West- ern populations: they bore plasmids containing two distinct genetic elements that conferred resistance to multiple antibiotics, as well as to quaternary ammonium (a disinfectant; Graham et al., 2000). “It’s almost designed by nature to be the perfect solution to man’s attempt to treat with antibiotics,” Dougan said, as well as with antibiotics such as chloramphenicol. Dougan warned that these resistance genes could spread rapidly through horizontal transfer to other Salmonella strains following the planned introduc- tion of large-scale antibiotic prophylaxis (trimethoprim-sulfonamide) for human immunodeficiency virus (HIV)-infected African children. “We talked about the relationship between commensals and pathogens: they know no boundaries,” he observed. “I can’t think it’s going to be very long [after the introduction of large-scale antibiotic prophylaxis] before we actually trigger the movement of this potential transporter around the population of Africa. I’m very alarmed at this, and I think we need to think a little bit further about how we go about doing that.” Meanwhile, as they attempted to understand the genetic origins of NTS,

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 MICROBIAL EVOLUTION AND CO-ADAPTATION Dougan and coworkers discovered that antibody protects against the disease, which disproportionately affects children between four months of age (before which they are protected by maternal antibodies) and two years of age (after which their own immune systems develop effective defense against the pathogen; MacLennan et al., 2008). This finding suggests that vaccines against NTS may be effective in inducing protective antibody in the vulnerable age group. BACTERIAL PATHOGENICITY: AN HISTORICAL AND ExPERIMENTAL PERSPECTIVE Stanley Falkow, Ph.D.2 Stanford University Joshua Lederberg noted in his 1987 essay that “the importance of bacteria as agents of infectious disease was clearly established by 1876, but this motivated little interest in their fundamental biology until about sixty-five years later” (Lederberg, 1987). He was taught, as I was, that bacteria were Schizomycetes— asexual primitive plants—so it was hard to think of them as being inherently pathogenic. Salvador Luria said of those times that microbiology was the last stronghold of Lamarckism. Lederberg, while he was a student, was influenced by several pivotal discov- eries in the mid-1940s that paved the way for his subsequent work on bacterial conjugation, including the demonstration of the mechanism of bacterial transfor- mation by Avery, MacLeod, and McCarty (1944) and of bacterial mutagenesis and selection by Luria and Delbrück (1943). Lederberg’s discovery of bacterial conjugation permitted investigators for the first time to study microbial genetics and biochemistry. It was a dream come true for the young Lederberg; he recalled that he had worn out the pages of the book on physiological chemistry that he received for his Bar Mitzvah. Josh also realized from the outset that the tech- niques he was developing might have practical applications for vaccine improve- ment and also in attaining “an understanding of virulence, a latter-day extension of Pasteur’s primitive techniques” (Lederberg, 1987). Lederberg, with his student Norton Zinder and collaborator Bruce Stocker, discovered in the early 1950s that any piece of bacterial DNA can be incorpo- rated into a bacteriophage genome (Stocker et al., 1953). He understood from this that gene recombination, termed generalized transduction, probably occurred in nature because phages were shown to be the basis for several of the different kinds of known Salmonella serotypes. Lederberg’s fundamental studies in bacterial genetics were a major factor for the discoveries, in subsequent years, of messenger RNA, the genetic code, and the work of Jacob and Monod (1961) on gene regulation. This revolutionary body of 2 Robert W. and Vivian K. Cahill Professor of Microbiology and Immunology.

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 PATHOGEN EVOLUTION work became the foundation for modern molecular biology and also set the stage for the present-day study of bacterial pathogenicity. Since I have been asked to talk about bacterial pathogenicity in both an historical as well as experimental perspective, perhaps I will be forgiven for using some of my own work as well as some of the work of my Stanford colleagues for the discussion of this topic. I began my work on the genetic basis of pathogenicity in 1959, working on the typhoid bacillus with Louis S. Baron at the Walter Reed Army Institute of Research. Baron had worked in Lederberg’s laboratory (Lou once told me that Lederberg claimed that if an experiment had more than six plates and four pipettes, it was over-designed). My goal at the time can be simply stated: I wanted to know the genetic differences between Salmonella and non-pathogenic residents of the bowel such as Escherichia coli. I worked with medical microbiologists who thought, as many still do, that a pathogen is any organism that causes disease. Microbiologists at the time char- acterized pathogenic bacteria as degenerate forms that have lost their way and that simply grew at the expense of the host, thereby causing damage (disease). I thought, as I said at a seminar at Cold Spring Harbor in 1964, that pathogens have evolved unique genetic traits that made them that way (to which a very famous scientist in the audience replied, “Falkow, no one gives a s––t about typhoid or pathogens. Why don’t you work on something important?”). Alas, there was a point to this criticism. While I attempted to show that there were unique patho- genicity genes, I lacked the necessary genetic and molecular experimental tools to make the point. Instead, I turned to the study of episomes, later to be called plasmids (a term Lederberg coined). Josh and Esther Lederberg discovered the first plasmid, the F factor, which appeared to be a transmissible genetic element that determined the fertility of E. coli K-12. Strains harboring F could transfer their genes to other bacteria. The work of William Hayes and later Jacob, Monod, Wollman, and oth- ers subsequently refined the biology of bacterial fertility. Soon, other examples of plasmids were reported, including transferable resistance to a number of antibi- otic drugs. Infectious multiple-drug resistance was described to the Western world around 1960 by Tsutomu Watanabe, and confirmed by the work of Naomi Datta in England and David Smith and others in the United States. These R plasmids, as they were called, became the focus of a large number of scientists during the mid-1960s. Another scientist’s work on plasmids—that of a veterinarian named H. Williams Smith—has not been well appreciated. He demonstrated that some plasmids could transmit bacterial toxins, adhesins, and, to some extent, host specificity, from one bacterial cell to another (Smith and Halls, 1967). Smith used the classic Lederberg approach, using only pipettes, Petri dishes, and simple genetic crosses to make these significant discoveries. In 1972, Stanley N. Cohen and Herbert Boyer discovered that genes could be cut and spliced by using R plasmids and their derivatives, thus signaling the dis-

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 MICROBIAL EVOLUTION AND CO-ADAPTATION covery of gene cloning. This elegant new technique, as well as the development of DNA sequencing, made it possible to finally study pathogenicity genes. Redefining Bacterial Pathogenicity Using the Tools of Molecular Genetics Among the things we have learned about bacterial pathogenicity are these fundamental characteristics: • athogens are impressive cell biologists. Twenty-five years of accumu- P lated data demonstrate that bacteria manipulate the normal functions of the host cell in ways that benefit the bacteria (Figure 3-1). • orizontal gene transfer via mobile genetic elements has been an extremely H important force in the evolution of bacterial specialization, including that of pathogens. The genes for many specialized “bacterial” products, like toxins and adhesins, actually reside on transposons and phages. • he inheritance of blocks of genes, called pathogenicity islands, is often T the key to the expression of pathogenicity in bacteria. FIGURE 3-1 Pathogenic bacteria interfere with or manipulate for their own benefit the Figure 3-1.eps normal function(s) of the host cell. bitmap image SOURCE: Figure reprinted from Wilson et al. (2002) with permission from Cambridge University Press. Copyright 2002.

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 PATHOGEN EVOLUTION FIGURE 3-2 Salmonella infection. IFN-γ = gamma interferon; MLN = mesenteric lymph Figure 3-2 COLOR.eps node. SOURCE: Monack et al. (2004b). bitmap image When we began using the tools of molecular genetics to examine virulence genes and identify their functions, we first tried to isolate particular genes for tox- ins and other likely virulence products. Today, we take a very different approach, which reflects our understanding of pathogen behavior. For example, unlike com- mensal bacteria, Salmonella breaches the host’s epithelial barrier, usually in areas of the intestinal epithelium known as Peyer’s patches, and becomes engulfed by phagocytic cells. Instead of being killed, the pathogen replicates there and is then distributed to the liver and the spleen. Eventually, in many cases, the pathogen will be shed by the host, often over long periods of time. These key events in the pathogenesis of infection, in addition to the interaction of the pathogen with the host’s innate and adaptive immune systems, are illustrated in Figure 3-2. The difference between the pathogen Salmonella and ancestral, commensal organisms in the bowel is based on the inheritance of pathogenicity islands, which give these bacteria the ability to leave the confines of the colon for loca- tions where other bacteria would be killed. There the evolving pathogen can act free from competition. To identify the genes that enable such incursions into the host, we use a microarray-based negative selection strategy, as shown in Figure 3-3, which allows us to screen the entire Salmonella genome for genes that are associated with different stages of infection (Chan et al., 2005). Using this strategy, one finds that while many genes are expressed within

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0 MICROBIAL EVOLUTION AND CO-ADAPTATION Generate a transposon Infect mice intraperitoneally with 8x104 CFU mutant library Isolate colonies from spleen Passage library on a and liver at 1, 2, 3, 4, and 7 plate (in vitro pool) weeks (in vivo pool) Bacteria harboring a transposon insertion in a gene critical for survival Isolate genomic DNA from both pools within the mouse do not regrow on the plate A A The “gene C” B B mutant is absent from C C the in vivo D D selected DNA E E Using a T7 promoter within the transposon, in vitro transcribe RNA that corresponds to the gene that is disrupted. Label the RNA from each pool with a different fluorophore A A B B C D D E E Hybridize to a microarray where each spot corresponds to a gene A B C D E FIGURE 3-3 Microarray-based negative selection strategy. hyb = hybridization; IP = Figure 3-3 COLOR.eps intraperitoneal. SOURCE: Figure courtesy of Kaman Chan, Ph.D., Stanford University.

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 PATHOGEN EVOLUTION the first week of disease, there is a group of genes that are not expressed until the second week of the disease, and even others that are not expressed until the third or fourth week of disease (Figure 3-4; Lawley et al., 2006). These results indicate that particular genes are required for different stages of persistent infec- tion within the mouse. Some of the genes are involved in the ability of Salmonella to excrete proteins that kill macrophages during initial infection, while others FIGURE 3-4 Time-dependent selection of persistence genes. A yellow box indicates that the persistence gene is absent. A blue or black box indicates that the persistence gene is Figure 3-4 COLOR.eps present. CFU = colony-forming units; LPS = lipopolysaccharide; PMNs = polymorpho- bitmap image nuclear leukocytes; prot = protein; RES = reticuloendothelial system. SOURCE: Modified from Lawley et al. (2006).

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 PATHOGEN EVOLUTION This continued stimulation of the immune and inflammatory cells (termed chronic atrophic gastritis) results in the destruction of the gastric epithelium, formation of peptic ulcers, and increased risk for gastric cancers. Presumably, but not yet formally demonstrated, the induction of the inflammatory response and the sub- sequent diseases provides no advantage to H. pylori in a colonized host or its transmission to new hosts. In this sense, the virulence of H. pylori in colonized humans is coincidental. While they are commonly described as pathogens, especially in grant pro- posals and by people suffering from the symptoms they can generate, a number of bacteria responsible for morbidity and mortality in humans also have good credentials as commensals. Like H. pylori they are carried asymptomatically by many and cause disease in few. Included among the more prominent of these commensal pathogens for humans are S. aureus, Haemophilus influenzae, S. pneumoniae, and Neisseria meningitidis. From an evolutionary perspective, invasive disease seems to be the wrong thing for these bacteria to do—dead ends. The sites of their virulence, blood and meninges, are certainly not good for their transmission to new hosts by their normal route, through respiratory droplets. The rare virulence of these commensal bacteria can be accounted for by an immune overresponse in these sites (Bergeron et al., 1998; Braun et al., 1999). The occa- sional movement of bacteria into a site where they can cause disease (the red in Figure 3-8) may be due to chance or coincidental evolution or as we argue below may be a consequence of within-host evolution of the bacterial population. Within-Host Evolution In accord with this hypothesis, the virulence of bacteria is the product of selection favoring more pathogenic members of a population colonizing an individual host (Levin and Bull, 1994). The advantage gained by the bacteria by generating symptoms in a colonized host is restricted to that host and may be to its disadvantage in its transmission to a new host; this evolution is short-sighted. A mutant commensal bacterium with the capacity to establish and maintain populations in normally sterile sites, cells, or tissues could be favored within a colonized host because in those sites there is less competition for nutrients and/or those mutant bacteria are somewhat protected from the host immune defenses. Although we can make a good case and even cite evidence for the virulence of some viruses, such as poliovirus and Coxsackievirus, being the product of within-host evolution (Gay et al., 2006; Levin and Bull, 1994), for bacteria the best we can do at this stage is present arguments founded on plausibility and consistency with observations (see, for example, Meyers et al., 2003). Central to these arguments are the results of studies with mice and rats demonstrating that the bacteria responsible for invasiveness (blood infection) are commonly derived from one of very few cells (Meynell, 1957; Moxon and Murphy, 1978; Pluschke et al., 1983; Rubin, 1987). One possible explanation for these observations is that

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 MICROBIAL EVOLUTION AND CO-ADAPTATION the bacteria responsible for the blood infections are the products of single, mutant cells with an enhanced capacity to invade and proliferate in blood. While supporting the within-host evolution hypothesis for virulence, these observations are also consistent with the coincidental evolution hypothesis: that, by chance alone, only one or a few cells establish blood infections can be attrib- uted to very small holes in the host’s defenses through which only one or very few bacteria traverse the arrow above 7 in Figure 3-8. Although the coincidental and within-host hypotheses could be distinguished by demonstrating that the bacteria establishing a blood infection have an inherited propensity for the invasion of blood, to our knowledge there are no published studies that have done this test. However, whether the invasiveness of the blood or other normally sterile sites is coincidental or due to within-host evolution, the virulence of bacteria in these sites can be attributed to a host’s immune overresponse. The Evolution of Virulence Determinants Not all bacteria or even all members of the same species of bacteria capable of colonizing mammals are responsible for disease. One explanation for why some bacteria cause disease and others do not is what have become known as virulence factors or virulence determinants, the expression of which are, by definition, essential for that bacteria to cause disease in (or on) colonized hosts (Finlay and Falkow, 1989). Included among these are characters that facili- tate adhesion to host cells, evade the host constitutive and inducible immune defenses, and produce toxins. Appropriately, much of contemporary bacteriol- ogy is devoted to understanding the molecular biology, genetics, evolutionary origin, and mode of action of virulence determinants as a way to understand bacterial diseases and ideally prevent or treat them. While virulence determi- nants (factors) are almost certainly the products of adaptive evolution in bacte- rial populations, not so clear are the selection pressures responsible for their evolution and maintenance. Are they favored because of virulence, i.e., the morbidity and mortality of the host promotes the colonization, persistence, and infectious transmission of bacteria that express these determinants? Are viru- lence factors by-products of selection for other functions, e.g., their expression provides protection against grazing protozoa (Wildschutte et al., 2004) and/or facilitates competition with other microbes? Or is the virulence attributed to these factors an inadvertent by-product of their normal function in a host, a primitive character that will be lost on or before equilibrium day. While these hypotheses may be mutually exclusive for any specific bacterium-host and virulence factor, they are clearly not so collectively. Whether they evolve in response to selection for virulence or not, some of these virulence factors are responsible for triggering the immune overresponse.

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 PATHOGEN EVOLUTION Why Does the Immune System Overrespond? In the preceding, we have portrayed the host immune system as misguided, overresponding in ways that cause rather than prevent the morbidity and mortality of a bacterial infection. From the perspective of evolutionary biology, however, “misguided” is hardly an explanation. Colonization by bacteria is not a rare event but rather something mammals confront all the time, and overresponding in a way that results in their morbidity and mortality would almost certainly be selected against. In their review of “immunopathogy,” Graham and colleagues postulated a number of reasons for this transgression of the immune response (Graham et al., 2005). Here we offer our perspective on this issue. As we see it, there are two general classes of explanations for the mainte- nance of an overresponse of the immune system. (i) While infectious disease may be a major source of morbidity and mortality (Haldane, 1949), disease- mediated selection can be relatively weak, and extensive amounts of time would be required to evolve mechanisms to modulate the immune response to specific bacterial infections. (ii) Functional constraints on the immune system limit the ability of natural selection to totally prevent and maybe even partially mitigate an immune overresponse to bacterial infections. (a) Even if selection universally favors tempering the immune overresponse to infections, and the favored genotypes could be generated (which we question below [b]), the time required for temperance to evolve could be considerable, especially if the overresponse is specific for particular bacteria and/or their products. This is due to two factors. (a) At its maximum the intensity of selec- tion for modulating the immune overresponse to an infection would equal the fraction of the population with that infection. It would be substantially lower if the symptoms of the infection were not expressed in all colonized hosts, were rarely lethal or sterilizing, or were primarily manifest after reproductive years or if the magnitude of the reduction of the overresponse of the favored genotype was less than absolute. For most of the diseases listed in Table 3-1 virulence is a rare occurrence in colonized hosts (less than 1%), and therefore the intensity of selection against an immune overresponse would be relatively weak. (b) It can take a considerable amount of time for a rare beneficial mutant to ascend to substantial frequencies. For example, if the selection for a reduced overresponse is operating on genotypes at a single locus (the best case), the initial frequency of a favored allele is 10–3, the favored genotype has a 1% selective advantage, and there is no dominance, it would take 1,381 generations (more than 20,000 years for humans) for that gene to reach a gene frequency of 50%. If the favored genotype is recessive, the corresponding number of generations would be 100,491 (Crow and Kimura, 1971). What about the role of the bacteria in the evolution of a more temperate immune system? As a consequence of their vastly shorter generation times, hap- loid genomes, and propensity to receive genes and pathogenicity islands by hori-

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0 MICROBIAL EVOLUTION AND CO-ADAPTATION zontal transfer, it seems reasonable to assume that bacteria would have an edge in an evolutionary arms race with their mammal hosts. We suggest, however, that this edge contributes little if anything to the slowing pace at which mammalian evolution could modulate the immune overresponse. Although there maybe situ- ations where virulence is positively correlated with the infectious transmission of bacteria, in most of these cases the morbidity and mortality associated with their transmission is not to the bacteria’s advantage and may be to their disadvantage. Even greater transmission of these bacteria would be possible if the hosts were not debilitated or killed as a result of diarrhea or if the bacteremias required for vector-borne transmission did not result in sepsis. In this interpretation evolution in the bacteria population would not oppose the evolution of a more temperate host immune system. Of all the examples considered in this chapter, the only one in which evolution in the bacterial population might favor an immune over- response is Carniel’s suggestion that by killing their host, Y. pestis acquires a transmission advantage. (ii) While the above realities of the ecology and genetics of natural selection may be part of the answer to the question of why evolution has not eliminated the immune system’s overresponse to bacterial (and other) infections, we suggest it is not the most important reason. We conjecture that the primary reason mammalian evolution has not tempered and perhaps cannot temper the immune overresponse to bacterial and other infections is functional constraints that limit the extent to which the immune system can be modified. The immune system has roles other than clearing bacterial infections. It has been postulated that these other roles dominated the evolution of the mammalian immune system (Burnet, 1970). These different roles as well as the extraordinary diversity of organisms colonizing mammals, bacteria, viruses, fungi, and worms of various ilks and the variety of sites of colonization impose different and potentially conflicting demands on the immune defenses, phenomena referred to as antagonistic pleiotropy. An appealing hypothesis for the immunopathogy known as allergies is an overresponse of those elements of the immune system that in less-pristine times would otherwise be occupied with the control of helminth infections (Wilson and Maizels, 2004). There is a fine line between responding (1-6 in Figure 3-8) and overre- sponding (7 in that figure), which may be difficult for the systems regulating the immune response to perceive, much less avoid. As suggested by Frank (Andre et al., 2004), the intensity of an immune response may be determined by a trade- off between increasing the strength and rapidity of an immune defense and the virulence from an immune system overresponse. Is there evidence in support of these two hypotheses for why evolution has not eliminated the virulence resulting from the immune overresponse? Not much—at least not yet. We suggest, however, that some of the considerable amount of inherited variability in the susceptibility to infectious disease in human populations (Bellamy and Hill, 1998; Bellamy et al., 2000; Segal and Hill, 2003; Sorensen et al., 1988) can be interpreted as support for these hypotheses. To be

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 PATHOGEN EVOLUTION sure, there is good and even overwhelming evidence that some of this variation is maintained by disease-mediated balancing or frequency-dependent selection, but this is not the case for all or even the majority of it. We suggest that much of the standing genetic variation in disease susceptibility in human populations is a reflection of the myopia and limitations of natural selection: (i) the relative weakness of selection for modulating the immune overresponse and (ii) even more, the impotency of natural selection due to the constraints on the immune system—antagonistic pleiotropy. Genetic variation that is not or is poorly per- ceived by natural selection will build up and persist (Crow and Kimura, 1971). Implications While the morbidity and mortality of most bacterial infections can be attrib- uted to an immune overresponse, virtually all of our efforts to treat these infections are directed at controlling the proliferation and clearing the bacteria, primarily with antibiotics. This approach has been and continues to be effective, but not completely so. Antibiotic treatment commonly fails, and patients die or remain ill for extended periods. Resistance of the pathogen to the antibiotics employed for treatment is only one of the reasons for this failure and for some infections is not the major one, at least not yet (Levin and Rozen, 2006; Yu et al., 2003). The obvious alternative approach to treating infections is to reduce the morbidity and prevent the mortality by modulating the immune system’s over- response. There have been attempts to do just that for the treatment of bacteria- mediated sepsis. Clinical trials have evaluated the use of glucocorticoids (Bone et al., 1987), drugs designed to neutralize endotoxins (Ziegler et al., 1991), tumor necrosis factor α (Fisher et al., 1996), and IL-1β (Fisher et al., 1994), but none of these treatments was effective. The most successful trials in humans to date have been with a component of the natural anticoagulant system, activated protein C, which has substantial anti-inflammatory properties along with being a potent anticoagulant (reduces the formation of clots that are responsible for organ fail- ure in late stages of sepsis) (Fourrier, 2004). In addition, new agents redirect the immune response and hold promise as effective future therapies for sepsis, such as IL-12 (O’Suilleabhain et al., 1996) and antibodies against complement (C5a) (Czermak et al., 1999). However, understanding the specifics of the immune over- reaction and the intricacies of the feedback mechanisms that control an immune response is necessary for therapies to be directed at enhancing or inhibiting the patient’s immune response. At this time, taken at large, the success of these immune modulating methods in preventing the morbidity and mortality of bacterial infections can at the very best be described as modest. However, in maintaining the speculative nature of this rant, and desiring an optimistic conclusion, we suggest that as we learn more about the regulation of the immune response and develop procedures to monitor

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 MICROBIAL EVOLUTION AND CO-ADAPTATION as well as administer regulatory immune molecules in real time, these methods will become increasingly effective for the treatment of bacterial infection. Acknowledgments We thank Elisabeth Carniel for sharing her ideas about the evolution of the virulence of Y. pestis. We are grateful to Jim Bull and Harris Fienberg for insight- ful comments and suggestions. B. R. L. acknowledges his continuous gratitude to Fernando Baquero, for inspiration, ideas, never-ending whimsy, support, and friendship. This endeavor was supported by a grant from the NIH, AI40662 (B. R. L.), and an NIH Training Grant (E. M.). REFERENCES Overview References Bolotin, A., B. Quinquis, P. Renault, A. Sorokin, S. D. Ehrlich, S. Kulakauskas, A. Lapidus, E. Goltsman, M. Mazur, G. D. Pusch, M. Fonstein, R. Overbeek, N. Kyprides, B. Purnelle, D. Prozzi, K. Ngui, D. Masuy, F. Hancy, S. Burteau, M. Boutry, J. Delcour, A. Goffeau, and P. Hols. 2004. Complete sequence and comparative genome analysis of the dairy bacterium Streptococ- cus thermophilus. Nature Biotechnology 22(12):1554-1558. Gordon, M. A., S. M. Graham, A. L. Walsh, L. Wilson, A. Phiri, E. Molyneux, E. E. Zijlstra, R. S. Heyderman, C. A. Hart, and M. E. Molyneux. 2008. Epidemics of invasive Salmonella enterica serovar Enteritidis and S. enterica serovar Typhimurium infection associated with multidrug resistance among adults and children in Malawi. Clinical Infectious Diseases 46(7):963-969. Graham, S. M. 2002. Salmonellosis in children in developing and developed countries and popula- tions. Current Opinion in Infectious Diseases 15(5):507-512. Graham, S. M., E. M. Molyneux, A. L. Walsh, J. S. Cheesbrough, M. E. Molyneux, and C. A. Hart. 2000. Nontyphoidal Salmonella infections of children in tropical Africa. Pediatric Infectious Disease Journal 19(12):1189-1196. Lederberg, J. 2000. Infectious history. Science 288(5464):287-293. MacLennan, C. A., E. N. Gondwe, C. L. Msefula, R. A. Kingsley, N. R. Thomson, S. A. White, M. Goodall, D. J. Pickard, S. M. Graham, G. Dougan, C. A. Hart, M. E. Molyneux, and M. T. Drayson. 2008. The neglected role of antibody in protection against bacteremia caused by nontyphoidal strains of Salmonella in African children. Journal of Clinical Investigation 118(4):1553-1562. McClelland, M., K. E. Sanderson, J. Spieth, S. W. Clifton, P. Latreille, L. Courtney, S. Porwollik, J. Ali, M. Dante, F. Du, S. Hou, D. Layman, S. Leonard, C. Nguyen, K. Scott, A. Holmes, N. Grewal, E. Mulvaney, E. Ryan, H. Sun, L. Florea, W. Miller, T. Stoneking, M. Nhan, R. Waterston, and R. K. Wilson. 2001. Complete genome sequence of Salmonella enterica serovar Typhimurium LT2. Nature 413(6858):852-856. McClelland, M., K. E. Sanderson, S. W. Clifton, P. Latreille, S. Porwollik, A. Sabo, R. Meyer, T. Bieri, P. Ozersky, M. McLellan, C. R. Harkins, C. Wang, C. Nguyen, A. Berghoff, G. Elliott, S. Kohlberg, C. Strong, F. Du, J. Carter, C. Kremizki, D. Layman, S. Leonard, H. Sun, L. Fulton, W. Nash, T. Miner, P. Minx, K. Delehaunty, C. Fronick, V. Magrini, M. Nhan, W. Warren, L. Florea, J. Spieth, and R. K. Wilson. 2004. Comparison of genome degradation in paratyphi A and typhi, human-restricted serovars of Salmonella enterica that cause typhoid. Nature Genetics 36(12):1268-1274.

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