Microbial Evolution and Co-Adaptation A Tribute to the Life and Scientific Legacies of Joshua Lederberg: Workshop Summary (2009) / Chapter Skim
Currently Skimming:
3 Pathogen Evolution
3 Pathogen Evolution
Pages 121-157
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 121... ...
Using the tools of molecular genetics to study Salmonella, Falkow and coworkers have observed how bacteria manipulate host cell functions, how horizontal gene transfer shapes pathogen specialization, and how inherited pathogenicity 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.
|
From page 122... ...
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.
|
From page 123... ...
In his presentation, Parkhill presented evidence that, in addition to acquiring 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)
|
From page 124... ...
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.
|
From page 125... ...
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 pathogenesis 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 conduct type-specific vaccine efficacy studies.
|
From page 126... ...
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)
|
From page 127... ...
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)
|
From page 128... ...
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)
|
From page 129... ...
. 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 toxins and other likely virulence products.
|
From page 130... ...
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.
|
From page 131... ...
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.
|
From page 132... ...
With the technology now available to us, we can now identify all such genes quite readily, but it will take many years before we will be able to determine their exact biological function in Salmonella-host interactions. The Host as a Reporter of Response to Infection The host can also tell us what happens during acute and persistent bacterial infections.
|
From page 133... ...
Each column under the pink box corresponds bitmap image to the gene activation in a single animal after wild-type infection (days 4-9 post-challenge)
|
From page 134... ...
. The transcriptional response of peripheral blood cells in animals similarly challenged with a vaccine strain (aroA–; yellow)
|
From page 135... ...
Nevertheless, several members of the human bacterial flora that usually live uneventfully in the human nasopharynx -- including Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b, and Streptococcus pyogenes -- sometimes cause disease. These microbes, which I call "commensal pathogens," have virulence determinants that suggest that they regularly come into intimate contact with elements of the innate and adaptive immune system (Falkow, 2006)
|
From page 136... ...
Over the course of the last century, as Western society has eliminated this pathogen through basic public health measures, it seems that we may actually have eliminated a microbe with which our species had a dialog, a microbe that "talked" to the human immune system and kept it primed for defensive action. Perhaps, as Pogo cartoonist Walt Kelly has suggested, "we have met the enemy and he is us." If the nature of microbial pathogenicity is schizophrenic -- characterized by inconsistent or contradictory elements -- then it is important to study every aspect A B Incidence of Infectious Diseases (%)
|
From page 137... ...
My remarks at this symposium were summarized by Eileen Choffnes and her staff and formed the basis for this paper. I am grateful to Lucinda Thompson and Denise Monack for permitting me to present here some of their previously unpublished results on the host response in naïve and immunized mice to Salmonella infection.
|
From page 138... ...
. We consider how this perversity of the immune system fits with current hypotheses for the evolution of virulence, the evolution of the so-called virulence factors, and speculate on the reasons natural selection has failed to or is unable to blunt the immune overresponse to bacterial infections.
|
From page 139... ...
In this scheme the immune defenses can prevent virulence in one or more of seven related ways: 1. Limiting the entry of bacteria into the asymptomatic site 2.
|
From page 140... ...
Examples of virulence being a direct product of the interaction between bacteria and host cells appear to be rare relative to those in which the morbidity and mortality can be attributed to the indirect damage due to an immune overresponse. As illustrated in Table 3-1, the morbidity and mortality of bacterial infections can be attributed to the host's immune system operating in one of three inappropriate ways: (i)
|
From page 141... ...
In this section we consider how the observation that morbidity and mortality of bacterial infections can be attributed to the hosts' immune overresponse fits each of these hypotheses for the evolution of the virulence of bacteria. The Conventional Wisdom This phrase, which the late John Kenneth Galbraith coined to describe ideas and explanations that are widely accepted as true by the public, was applied by
|
From page 142... ...
Toxic shock Circulatory system, systemic Staphylococcus, Extreme inflammation Superantigens → indiscriminate syndrome/scarlet Streptococcus activation of T cells (McCormick et leading to septic shock fever al., 2001) Duodenal ulcers Gastric and duodenal mucosa Helicobacter pylori Mucosal atrophy Bacterial persistence → chronic inflammation (Czinn and Nedrud, 1997)
|
From page 143... ...
tumor necrosis factor alpha.
|
From page 144... ...
It may seem that the proposition that the virulence of bacterial infections can be attributed to host immune overresponse fits quite well with this conventional wisdom. To wit, the immune system has not yet had the time to evolve to moderate the response to these novel bacteria and their products and/or these bacteria have not yet evolved into being nice.
|
From page 145... ...
rather than the red site (9 in Figure 3-8) , these epidemiological models can be seen as the theoretical basis of the conventional wisdom (also see Lenski and May, 1994)
|
From page 146... ...
For both diarrheal diseases and plague, the virulence resulting from the host overresponse is associated with transmission. Clearly more empirical work would be necessary to confirm the existence of a trade-off between bacterial transmission and an immune overresponse and the postulated exploitation of this overresponse for the epidemiological advantage of the parasite.
|
From page 147... ...
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)
|
From page 148... ...
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)
|
From page 149... ...
, diseasemediated 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.
|
From page 150... ...
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)
|
From page 151... ...
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
|
From page 152... ...
enterica serovar Typhimurium infection associated with multidrug resistance among adults and children in Malawi. Clinical Infectious Diseases 46(7)
|
From page 153... ...
2004b. Persistent bacterial infections: the interface of the pathogen and the host immune system.
|
From page 154... ...
1972. Natural History of Infectious Diseases.
|
From page 155... ...
2001. Why we don't get sick: the within-host population dynamics of bacterial infections.
|
From page 156... ...
May (ed.) , Population Biology of Infectious Diseases.
|
From page 157... ...
2005. Role of Helicobacter pylori in gastric carcino genesis: the origin of gastric cancers and heterotopic proliferative glands in Mongolian gerbils.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.