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Evolution of Bacterial Pathogens within the Human Host
Kimberly A. Bliven and Anthony T. Maurelli#
Department of Microbiology and Immunology, F. Edward Hébert School of Medicine, Uniformed
Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814,
USA
Abstract
Selective pressures within the human host, including interactions with innate and adaptive immune
responses, exposure to medical interventions such as antibiotics, and competition with commensal
microbiota all facilitate the evolution of bacterial pathogens. In this chapter, we present examples
of pathogen strategies which emerged as a result of selective pressures within the human host
niche, and discuss the resulting co-evolutionary ‘arms race’ between these organisms. In bacterial
pathogens, many of the genes responsible for these strategies are encoded on mobile pathogenicity
islands (PAIs) or plasmids, underscoring the importance of horizontal gene transfer (HGT) in the
emergence of virulent microbial species.
INTRODUCTION
The success or failure of a pathogen is entirely dependent on its ability to survive,
reproduce, and spread to a new host or environment. Host immune systems, predators,
microbial competitors, parasites, and environmental resource limitations all exert selective
pressures that shape the genomes of microbial populations (1). Host evolutionary fitness,
meanwhile, is reliant on its capability to survive and reproduce; the host must effectively
curtail diseases that weaken either of these abilities.
Dawkins et al. (1979) suggest that the conflicting drives between host and pathogen have led
to an evolutionary arms race, where an asymmetric ‘attack-defense’ strategy has come into
play (2). At the basic level, this concept suggests that when a host evolves new defenses to
thwart a pathogen’s attack, the pathogen is forced to adapt a more impressive attack strategy
to penetrate the heightened defenses. In response, the host must once again develop new
defenses to cope with the new attack mechanism, and the cycle continues. Evolutionarily fit
pathogens, which are able to survive, replicate, and spread effectively within the host, have
an improved chance of passing their genes on to the next generation. Similarly, host
genotypes are more likely to persist within the population if those particular individuals are
more capable of controlling or resisting infection. Evolution, therefore, is driven by positive
directional selection in the ‘arms race’ model; eventually, beneficial alleles should become
fixed in a population. Another model favors frequency-dependent (balancing) selection, a
#Corresponding author: Anthony T. Maurelli, Department of Microbiology and Immunology, F. Edward Hébert School of
Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, anthony.maurelli@usuhs.edu, Phone: 1 301
295 3415, Fax: 1 301 295 1545.
HHS Public Access
Author manuscript
Microbiol Spectr. Author manuscript; available in PMC 2016 March 23.
Published in final edited form as:
Microbiol Spectr. 2016 February ; 4(1): . doi:10.1128/microbiolspec.VMBF-0017-2015.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Kimberly A. Bliven and Anthony T. Maurelli#
Department of Microbiology and Immunology, F. Edward Hébert School of Medicine, Uniformed
Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814,
USA
Abstract
Selective pressures within the human host, including interactions with innate and adaptive immune
responses, exposure to medical interventions such as antibiotics, and competition with commensal
microbiota all facilitate the evolution of bacterial pathogens. In this chapter, we present examples
of pathogen strategies which emerged as a result of selective pressures within the human host
niche, and discuss the resulting co-evolutionary ‘arms race’ between these organisms. In bacterial
pathogens, many of the genes responsible for these strategies are encoded on mobile pathogenicity
islands (PAIs) or plasmids, underscoring the importance of horizontal gene transfer (HGT) in the
emergence of virulent microbial species.
INTRODUCTION
The success or failure of a pathogen is entirely dependent on its ability to survive,
reproduce, and spread to a new host or environment. Host immune systems, predators,
microbial competitors, parasites, and environmental resource limitations all exert selective
pressures that shape the genomes of microbial populations (1). Host evolutionary fitness,
meanwhile, is reliant on its capability to survive and reproduce; the host must effectively
curtail diseases that weaken either of these abilities.
Dawkins et al. (1979) suggest that the conflicting drives between host and pathogen have led
to an evolutionary arms race, where an asymmetric ‘attack-defense’ strategy has come into
play (2). At the basic level, this concept suggests that when a host evolves new defenses to
thwart a pathogen’s attack, the pathogen is forced to adapt a more impressive attack strategy
to penetrate the heightened defenses. In response, the host must once again develop new
defenses to cope with the new attack mechanism, and the cycle continues. Evolutionarily fit
pathogens, which are able to survive, replicate, and spread effectively within the host, have
an improved chance of passing their genes on to the next generation. Similarly, host
genotypes are more likely to persist within the population if those particular individuals are
more capable of controlling or resisting infection. Evolution, therefore, is driven by positive
directional selection in the ‘arms race’ model; eventually, beneficial alleles should become
fixed in a population. Another model favors frequency-dependent (balancing) selection, a
#Corresponding author: Anthony T. Maurelli, Department of Microbiology and Immunology, F. Edward Hébert School of
Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, anthony.maurelli@usuhs.edu, Phone: 1 301
295 3415, Fax: 1 301 295 1545.
HHS Public Access
Author manuscript
Microbiol Spectr. Author manuscript; available in PMC 2016 March 23.
Published in final edited form as:
Microbiol Spectr. 2016 February ; 4(1): . doi:10.1128/microbiolspec.VMBF-0017-2015.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
process that maintains rare alleles and therefore preserves polymorphic diversity within a
population (3). Simply put, allele fixation is prevented because different bacterial alleles
confer distinct advantages to the pathogen in the presence of different host alleles. Evidence
exists within nature for both directional and frequency-dependent selection, and both types
probably occur in bacterial populations.
In this chapter, we explore the host-pathogen interface and offer examples of pathogen
adaptation in response to common host selective pressures (Table 1). Although we will
focus our attention exclusively on bacterial pathogens within the human host, many of the
concepts discussed in this review are readily applicable to other organisms, such as viruses,
parasites, and fungi, which can infect a wide range of hosts including plants, animals, and
amoeba (4-6).
As a final note, much of the evidence presented here to support presumed evolutionary
events is either speculation from what is currently known or suspected about host and
microbial biology, or the result of artificial laboratory-induced evolution during serial
passaging of bacterial strains. Due to the sheer enormity of evolutionary timescales, defining
the precise origins of and factors driving natural evolutionary events is often a difficult
undertaking.
ANTAGONISTIC PLEIOTROPY AND THE FITNESS COST/BENEFIT
ANALYSIS
At the most basic level, the theory of natural selection stipulates that, within a bacterial
population, beneficial traits will be conserved (selected for), and deleterious traits eventually
discarded (selected against). The actual evolutionary process is considerably more complex,
however, due to the existence of genetic drift (the change in genetic diversity of a population
due to random chance) and antagonistic pleiotropy.
Antagonistic pleiotropy is the concept that a single gene may control more than one
phenotype, some of which may be beneficial to the organism, and some deleterious (7).
Therefore, a gene may confer a selective advantage within one particular environment, but
its expression could be detrimental within a different environment. Conservation of this gene
ultimately is determined by the overall necessity of the gene to the organism’s fitness.
Bacterial pathogens may evolve mechanisms to neutralize the deleterious effects arising
from antagonistic pleiotropy, while at the same time conserving the beneficial ones.
Temporal regulation is a powerful tool to ensure that specific genes are only turned on when
required, and turned off to prevent detrimental expression within a particular environment.
Certain outer membrane proteins or systems are temporally regulated within the host, as
they may provide a marker for recognition by the host immune system. Flagella expression,
for example, is down-regulated by Salmonella enterica serovar Typhi in vivo to avoid
activation of the host inflammatory response; however, outside the host, motility is likely
important for the bacterium to seek out and scavenge nutrients from the environment (8).
Other bacteria avoid the deleterious effects of a gene through gene inactivation; mutants that
lose functionality of the gene once it becomes deleterious can out-compete the wild type
parent strain, and eventually these mutants will dominate the population. Pseudomonas
Bliven and Maurelli Page 2
Microbiol Spectr. Author manuscript; available in PMC 2016 March 23.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
population (3). Simply put, allele fixation is prevented because different bacterial alleles
confer distinct advantages to the pathogen in the presence of different host alleles. Evidence
exists within nature for both directional and frequency-dependent selection, and both types
probably occur in bacterial populations.
In this chapter, we explore the host-pathogen interface and offer examples of pathogen
adaptation in response to common host selective pressures (Table 1). Although we will
focus our attention exclusively on bacterial pathogens within the human host, many of the
concepts discussed in this review are readily applicable to other organisms, such as viruses,
parasites, and fungi, which can infect a wide range of hosts including plants, animals, and
amoeba (4-6).
As a final note, much of the evidence presented here to support presumed evolutionary
events is either speculation from what is currently known or suspected about host and
microbial biology, or the result of artificial laboratory-induced evolution during serial
passaging of bacterial strains. Due to the sheer enormity of evolutionary timescales, defining
the precise origins of and factors driving natural evolutionary events is often a difficult
undertaking.
ANTAGONISTIC PLEIOTROPY AND THE FITNESS COST/BENEFIT
ANALYSIS
At the most basic level, the theory of natural selection stipulates that, within a bacterial
population, beneficial traits will be conserved (selected for), and deleterious traits eventually
discarded (selected against). The actual evolutionary process is considerably more complex,
however, due to the existence of genetic drift (the change in genetic diversity of a population
due to random chance) and antagonistic pleiotropy.
Antagonistic pleiotropy is the concept that a single gene may control more than one
phenotype, some of which may be beneficial to the organism, and some deleterious (7).
Therefore, a gene may confer a selective advantage within one particular environment, but
its expression could be detrimental within a different environment. Conservation of this gene
ultimately is determined by the overall necessity of the gene to the organism’s fitness.
Bacterial pathogens may evolve mechanisms to neutralize the deleterious effects arising
from antagonistic pleiotropy, while at the same time conserving the beneficial ones.
Temporal regulation is a powerful tool to ensure that specific genes are only turned on when
required, and turned off to prevent detrimental expression within a particular environment.
Certain outer membrane proteins or systems are temporally regulated within the host, as
they may provide a marker for recognition by the host immune system. Flagella expression,
for example, is down-regulated by Salmonella enterica serovar Typhi in vivo to avoid
activation of the host inflammatory response; however, outside the host, motility is likely
important for the bacterium to seek out and scavenge nutrients from the environment (8).
Other bacteria avoid the deleterious effects of a gene through gene inactivation; mutants that
lose functionality of the gene once it becomes deleterious can out-compete the wild type
parent strain, and eventually these mutants will dominate the population. Pseudomonas
Bliven and Maurelli Page 2
Microbiol Spectr. Author manuscript; available in PMC 2016 March 23.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
aeruginosa, an opportunistic pathogen of cystic fibrosis patients, often switches to a mucoid
phenotype in vivo as a result of overproduction of the exopolysaccharide alginate, which
allows for the production of a bacterial biofilm in the lung (9, 10). MucA is a P. aeruginosa
transmembrane protein that binds to and represses the sigma factor AlgU, which acts as the
transcriptional activator of the alginate synthesis operon. AlgU activates AlgR, a suppressor
of T3SS expression; when mucA is expressed, therefore, so are the T3SS genes. During
acute infection, the T3SS plays an essential role in establishment of the bacterium within the
respiratory tract. Once infection has been established, however, chronic infection appears to
favor loss of T3SS and a switch to biofilm production (11). Both of these phenotypes are at
least partially driven by various mutations in mucA which lead to derepression of AlgU,
subsequent production of alginate, and suppression of the T3SS (9). Hauser (2009)
speculates that loss of the T3SS protects the bacterium from eventual recognition by the
host, as patients infected with P. aeruginosa develop antibodies against T3SS effector
proteins; conversely, biofilm production likely allows for the persistence of the organism in
the respiratory tract (11). Finally, certain bacteria simply tolerate deleterious fitness costs if
the benefits of expressing the gene outweigh the negative effects. Antibiotic resistance
mutations that allow bacteria to survive exposure to antimicrobials often come with a
significant fitness disadvantage, for example, and secondary compensatory mutations in
these strains may eventually arise to restore fitness rather than lose resistance (12).
THE IMPACT OF HOST-PATHOGEN INTERACTIONS ON MICROBIAL
EVOLUTION
Inside the host, a successful pathogen will pilfer resources to survive, replicate, and
eventually escape; concomitantly, the host will attempt to recognize and subsequently rid the
body of the intruder. Co-evolution between host and pathogen naturally occurs as a result of
these interactions (13). For practical purposes, we restrict our discussion to bacterial
adaptation within the human host, but it is important to recognize that many of these
concepts are applicable to pathogens of other hosts as well, such as plants or amoeba
(14-16). As novel genetic variants within the human population emerge which prove more
successful at preventing or overcoming infection, only pathogen variants that can surmount
or avoid this new response will be successful. Within the last century, these natural host
defenses, which take much longer to evolve than their microbial counter-parts, have been
supplemented by man-made developments, such as antibiotics and modern medical
interventions, which place added pressures on microbes to adapt (17). Host innate and
adaptive immune responses and modern medical interventions are all selective pressures that
contribute to pathogen evolution within the human host. Furthermore, microbial
competition, either against other pathogens or commensal bacteria, also shapes pathogen
genomes.
Bacteria have several advantages over the human host when it comes to evolution: first, their
generation times are significantly shorter, leading to a much more rapid selection of
beneficial alleles within a population. In conjunction with a shorter generation time,
bacterial populations are typically larger, which may allow for greater genetic diversity from
which to select. Lastly, many bacteria utilize horizontal gene transfer (HGT), which
Bliven and Maurelli Page 3
Microbiol Spectr. Author manuscript; available in PMC 2016 March 23.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
phenotype in vivo as a result of overproduction of the exopolysaccharide alginate, which
allows for the production of a bacterial biofilm in the lung (9, 10). MucA is a P. aeruginosa
transmembrane protein that binds to and represses the sigma factor AlgU, which acts as the
transcriptional activator of the alginate synthesis operon. AlgU activates AlgR, a suppressor
of T3SS expression; when mucA is expressed, therefore, so are the T3SS genes. During
acute infection, the T3SS plays an essential role in establishment of the bacterium within the
respiratory tract. Once infection has been established, however, chronic infection appears to
favor loss of T3SS and a switch to biofilm production (11). Both of these phenotypes are at
least partially driven by various mutations in mucA which lead to derepression of AlgU,
subsequent production of alginate, and suppression of the T3SS (9). Hauser (2009)
speculates that loss of the T3SS protects the bacterium from eventual recognition by the
host, as patients infected with P. aeruginosa develop antibodies against T3SS effector
proteins; conversely, biofilm production likely allows for the persistence of the organism in
the respiratory tract (11). Finally, certain bacteria simply tolerate deleterious fitness costs if
the benefits of expressing the gene outweigh the negative effects. Antibiotic resistance
mutations that allow bacteria to survive exposure to antimicrobials often come with a
significant fitness disadvantage, for example, and secondary compensatory mutations in
these strains may eventually arise to restore fitness rather than lose resistance (12).
THE IMPACT OF HOST-PATHOGEN INTERACTIONS ON MICROBIAL
EVOLUTION
Inside the host, a successful pathogen will pilfer resources to survive, replicate, and
eventually escape; concomitantly, the host will attempt to recognize and subsequently rid the
body of the intruder. Co-evolution between host and pathogen naturally occurs as a result of
these interactions (13). For practical purposes, we restrict our discussion to bacterial
adaptation within the human host, but it is important to recognize that many of these
concepts are applicable to pathogens of other hosts as well, such as plants or amoeba
(14-16). As novel genetic variants within the human population emerge which prove more
successful at preventing or overcoming infection, only pathogen variants that can surmount
or avoid this new response will be successful. Within the last century, these natural host
defenses, which take much longer to evolve than their microbial counter-parts, have been
supplemented by man-made developments, such as antibiotics and modern medical
interventions, which place added pressures on microbes to adapt (17). Host innate and
adaptive immune responses and modern medical interventions are all selective pressures that
contribute to pathogen evolution within the human host. Furthermore, microbial
competition, either against other pathogens or commensal bacteria, also shapes pathogen
genomes.
Bacteria have several advantages over the human host when it comes to evolution: first, their
generation times are significantly shorter, leading to a much more rapid selection of
beneficial alleles within a population. In conjunction with a shorter generation time,
bacterial populations are typically larger, which may allow for greater genetic diversity from
which to select. Lastly, many bacteria utilize horizontal gene transfer (HGT), which
Bliven and Maurelli Page 3
Microbiol Spectr. Author manuscript; available in PMC 2016 March 23.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
accounts for the rapid spread of advantageous alleles between strains or even species (18).
Virulence genes are commonly located on transferred pathogenicity islands (PAIs),
segments of the genome associated with mobility elements, such as integrase genes or
transposons, and a G+C content that differs from the remainder of the genome (19).
Host selective pressures: The innate and adaptive immune systems
The innate immune system is one of the first challenges encountered by the incoming
pathogen following host contact. These diverse host defenses include physical barriers such
as the mucosal epithelium, activation of the complement cascade, circulating antimicrobial
peptides and cytokines, leukocytes, activation of the adaptive immune system, and
sequestration of host nutrients away from pathogenic bacteria. In addition to evading innate
immune mechanisms, the bacteria must also prevent or avoid adaptive immune responses
which include B cell antibody production and T cell-mediated cytotoxicity. Pathogenic
bacteria have evolved different approaches to overcome these host defenses.
In the human colon alone, intestinal microbiota concentrations average 1011 microorganisms
per gram gut content, while 3 × 108 prokaryotes are thought to colonize the entire skin
surface of the human adult (20). Consequently, bacteria that exploit more hostile and less
frequently occupied niches may gain a selective edge in survival by avoiding sites of high
competition. Natural structural barriers, however, typically prevent pathogens from
engaging deeper host tissues. Physical blocks to infection include the intestinal and
respiratory mucosa, the blood-brain barrier, the blood-CSF (cerebral spinal fluid) barrier,
and the placental barrier (21). Most of these structures consist of a single layer of epithelial
or endothelial cells bound closely together by tight junctions, adherens junctions, and
desmosomes, which preclude bacteria from passively crossing (21, 22). Gastric and
respiratory epithelia support an additional protective coating of mucus, which consists
primarily of mucin glycoproteins and antimicrobial molecules (23). Mucin glycoproteins,
produced by epithelial goblet cells and submucosal glands, can either remain cell-associated
or undergo secretion into the mucosa, where they contribute to the viscous layer of mucus
that can effectively trap microbes (24). Additionally, non-specific antimicrobials, such as
defensins and lysozymes, and specific antimicrobials, such as IgG and secretory IgA, also
limit the growth of microbes within the mucosa (23). Bacterial pathogens have developed
numerous mechanisms to counteract these defenses.
The mucosal barrier can be broken down by mucinases such as the Pic enzyme of Shigella
and Enteroaggregative Escherichia coli (EAEC) (25, 26). The pic gene is located on a
chromosomal pathogenicity island in Shigella, and bounded upstream and downstream by
insertion (IS)-like elements in EAEC, indicating a history of horizontal gene transfer in
these pathogens (26). This potential gene transfer is intriguing as mucin degradation is also
important for certain gastrointestinal commensals, which metabolize mucin glycoproteins
for energy (27). It is tempting to speculate that these enzymes first evolved within human
commensal bacteria as a means of nutrient acquisition, and only later spread to emerging
pathogens to confer passage through the mucosal surface. Such a concept would support the
hypothesis proposed by Rasko et al., who suggest that commensal E. coli act as ‘genetic
sinks’ for pathogenic E. coli isolates (28). Other pathogens, such as Yersinia enterocolitica
Bliven and Maurelli Page 4
Microbiol Spectr. Author manuscript; available in PMC 2016 March 23.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Virulence genes are commonly located on transferred pathogenicity islands (PAIs),
segments of the genome associated with mobility elements, such as integrase genes or
transposons, and a G+C content that differs from the remainder of the genome (19).
Host selective pressures: The innate and adaptive immune systems
The innate immune system is one of the first challenges encountered by the incoming
pathogen following host contact. These diverse host defenses include physical barriers such
as the mucosal epithelium, activation of the complement cascade, circulating antimicrobial
peptides and cytokines, leukocytes, activation of the adaptive immune system, and
sequestration of host nutrients away from pathogenic bacteria. In addition to evading innate
immune mechanisms, the bacteria must also prevent or avoid adaptive immune responses
which include B cell antibody production and T cell-mediated cytotoxicity. Pathogenic
bacteria have evolved different approaches to overcome these host defenses.
In the human colon alone, intestinal microbiota concentrations average 1011 microorganisms
per gram gut content, while 3 × 108 prokaryotes are thought to colonize the entire skin
surface of the human adult (20). Consequently, bacteria that exploit more hostile and less
frequently occupied niches may gain a selective edge in survival by avoiding sites of high
competition. Natural structural barriers, however, typically prevent pathogens from
engaging deeper host tissues. Physical blocks to infection include the intestinal and
respiratory mucosa, the blood-brain barrier, the blood-CSF (cerebral spinal fluid) barrier,
and the placental barrier (21). Most of these structures consist of a single layer of epithelial
or endothelial cells bound closely together by tight junctions, adherens junctions, and
desmosomes, which preclude bacteria from passively crossing (21, 22). Gastric and
respiratory epithelia support an additional protective coating of mucus, which consists
primarily of mucin glycoproteins and antimicrobial molecules (23). Mucin glycoproteins,
produced by epithelial goblet cells and submucosal glands, can either remain cell-associated
or undergo secretion into the mucosa, where they contribute to the viscous layer of mucus
that can effectively trap microbes (24). Additionally, non-specific antimicrobials, such as
defensins and lysozymes, and specific antimicrobials, such as IgG and secretory IgA, also
limit the growth of microbes within the mucosa (23). Bacterial pathogens have developed
numerous mechanisms to counteract these defenses.
The mucosal barrier can be broken down by mucinases such as the Pic enzyme of Shigella
and Enteroaggregative Escherichia coli (EAEC) (25, 26). The pic gene is located on a
chromosomal pathogenicity island in Shigella, and bounded upstream and downstream by
insertion (IS)-like elements in EAEC, indicating a history of horizontal gene transfer in
these pathogens (26). This potential gene transfer is intriguing as mucin degradation is also
important for certain gastrointestinal commensals, which metabolize mucin glycoproteins
for energy (27). It is tempting to speculate that these enzymes first evolved within human
commensal bacteria as a means of nutrient acquisition, and only later spread to emerging
pathogens to confer passage through the mucosal surface. Such a concept would support the
hypothesis proposed by Rasko et al., who suggest that commensal E. coli act as ‘genetic
sinks’ for pathogenic E. coli isolates (28). Other pathogens, such as Yersinia enterocolitica
Bliven and Maurelli Page 4
Microbiol Spectr. Author manuscript; available in PMC 2016 March 23.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
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