Evolutionary Medicine
Miriam Nývltová Fišáková
Department of Physiology
Coevolution,
infection, and
immunity
• Rates of extrinsic mortality (the risk of death as a result of environmental
hazards) have had major effects on the evolution of life-history traits such as growth
rate, timing of maturation, allocation of resources to repair and maintenance, and
lifetime reproductive strategy. The major causes of extrinsic mortality are biotic, and
include competition for nutrient supplies with other organisms of the same or
different species, predation, infection by micro-organisms, many of which rely on a
parasitic relationship for their own survival, and injury, which may be accidental or
the result of conspecific competition and violence. This last cause is a particular
feature of human biology. Human cultural evolution has resulted in mechanisms to
ameliorate the risks of predation and accidental injury, and technological advances
have reduced the impact of infection by micro-organisms in many parts of the world.
Yet infectious disease still causes 25% of all deaths worldwide, with wide variations
between high- and low-income countries. Evolved mechanisms to cope with the
impact of infectious disease are a major feature of the human genome (QuintanaMurci
et al. 2007). Not all human relationships with micro-organisms are deleterious
to the host. Our associated microflora, principally in the gut, contribute to nutrition
and metabolic regulation. Beneficial micro-organisms participate in controlling the
growth of pathogens, and may have a role in the evolution and individual
development of the host immune system. In this lecture we describe some
fundamental aspects of coevolution and then apply them to the evolution of the
relationship between humans and micro-organisms, discuss why and how some of
those micro-organisms are pathogenic, and examine the benefits and occasional
costs of our evolved defenses again micro-organisms through our innate and
adaptive immune systems. Finally, we examine the three main types of human
technological (cultural) response to the threat of infectious disease—public health
measures, vaccination, and antimicrobial chemotherapy.
Coevolution
• Organisms live and evolve in environments that include other
organisms. Coevolution occurs when one species reciprocally influences
the evolution of another. A simple example is the evolution of a
predator–prey relationship where the prey evolves a mechanism to
evade the predator (perhaps running faster) and the predator, faced with
the selection pressure of reduced food supply, responds by evolving a
countering mechanism (perhaps running faster still or developing a new
attack strategy). In turn, the prey evolves a response to the countering
mechanism, and so on. Such processes of adaptation and counteradaptation
have been referred to as evolutionary arms races, by analogy
with the desire by the military not to be left vulnerable to a potential
enemy’s developing arsenal.
• Modeling studies show that coevolution is an important driving force
for evolution. A common metaphor in classical evolutionary theory
suggests that species evolve “uphill” towards fitness peaks in their
adaptive landscapes, where they are well adapted to their physical
environment. As the physical environment generally only changes slowly,
the rate of evolution is predicted to slow down as the peak is
approached.
Inclusion of other species into the notion of “environment” changes this perspective,
because other species, particularly micro-organisms, can evolve rapidly and this
rapidly changing biological environment (which thus changes the shape of the
landscape) requires equally rapid counter-adaptive change from the host species;
this is then matched by a further adaptive response from the interacting species.
Continuous adaptations by all species in the system are required for survival,
although relative fitness as determined by classical measures of reproductive success
does not increase. This concept was named the Red Queen hypothesis after the
remark by the Red Queen in Lewis Carroll’s Through the Looking Glass that Alice
needs to undertake “all the running you can do, to keep in the same place” (van
Valen 1973). The Red Queen hypothesis as applied to host–parasite interactions has
been proposed as an explanation for the evolution of sex. The argument is that the
requirement for slowly evolving multicellular eukaryotes to compete with their more
rapidly evolving parasites is facilitated by the continuous generation of new
genotypes containing novel combinations of parasite resistence alleles, and that can
only be achieved by meiotic recombination during the gametogenesis of sexual
reproduction. There is some limited experimental evidence from organisms such as
roundworms that can reproduce either sexually or by self-fertilization to suggest that
the sexually reproducing forms do better when exposed to parasites (e.g., Morran
et al. 2011).
• Coevolution does not only occur in the context of parasite–
host or predator–prey relationships, where one participant may
be “running for its life, rather than just its dinner.” There are
many different types of species interactions with different
coevolved allocations of costs and benefits. Symbiosis refers to
any long-term interactions between species: this can be
subdivided into mutualism (where both participants benefit),
commensalism (where one participant benefits and the other is
unaffected), parasitism (where one participant benefits and the
other is harmed by, e.g., reduced growth as the parasite
extracts resources), and predation (where one participant
benefits and the other reaches a sudden evolutionary dead
end). Pathogens can be considered as a type of parasite with an
evolved strategy of causing disease in their host. Some species
with complex life cycles (such as the unicellular organism that
causes malaria) may be parasites in a vector species
(mosquitoes) but pathogens in an intermediate host during
their life cycle (in this case humans). Some commensal species,
such as certain micro-organisms in the human gut, may become
opportunistic pathogens in their hosts when defenses such as
epithelial barriers or the immune system are weakened.
Humans and Their Associated Species
• Humans have coevolved with many species, ranging from
large mammals to viruses. Coevolution of a mutualistic
relationship of humans with domesticated animals is
exemplified by cattle, where human-directed selection has
resulted in multiple strains of animals selected for nutritionally
and economically beneficial traits while the coevolved trait of
lactase persistence in humans has spread as milk consumption
and then dairy farmin became established practices.
• In this lectures, we are mostly concerned with the
relationships between humans and their associated microorganisms.
Those relationships can be commensal (e.g., many
skin and gut bacteria), mutualistic (many of the gut microbiota),
parasitic (e.g., intestinal worms and body lice), or pathogenic
(e.g., bacterial diseases such as cholera and tuberculosis and
viral pathogens such as HIV and measles). Nevertheless, the
distinction between a commensal and a pathogen is sometimes
blurred, as for example when the normally harmless Escherichia
coli acquires a virulence factor such as the bacteriophageencoded
Shiga toxin, giving rise to the pathogenic O157:H7
strain.
• It is only recently that the complexity and physiological importance of the
community of symbiotic micro-organisms associated with humans (i.e., the
microbiome) has come to be appreciated. The human body consists of about
1013 human cells, but this is outnumbered about ten-fold by the bacterial,
archaeal, fungal, and protozoal cells found on all body surfaces (on the skin, in
the mouth and nose, and in other orifices) and in particularin the lower
gastrointestinal tract, which contains 1 to 2 kg of bacterial cells representing
at least 500 species. However, most of the mass of the gut mikroflóra comes
from 30 to 40 dominant anaerobic species, predominantly from the phyla
Bacteroidetes and Firmicutes. The composition of the gut microbiome varies
in type and diversity between individual humans according to factors such as
age, geographical location, and diet. Families tend to share similar
microbiomes, although this seems to be environmentally rather than
genetically determined since monozygotic and dizygotic twins have similar
levels of variability in their microbiomes and newborn infants take some
months to achieve similar gut microbiomes to the rest of their family. The
diversity of the microbiome, which is generally taken as an indicator of
ecosystem health, is much higher in modern hunter- gatherer populations
than in Westernized industrial populations.
• The gut of the human neonate is generally sterile, but is rapidly colonized by
maternal and environmental microflora; the composition matures during early life
and then remains relatively stable, although subject to dietary and other
environmental influences (Sekirov et al. 2010). Interestingly, establishment of the
infant microbiome is promoted by, and the composition may be affected by,
components of breast milk such as IgA and oligosaccharides, as well as by the
tolerogenicity of the developing infant’s immune system. Some studies have shown
correlations between the composition of the microbiome in a mother and her
offspring; this can be considered a further form of non- genomic inheritance. Infants
born by cesarean section as opposed to a vaginal delivery have different gut
microflora from each other, as do infants fed on formula as opposed to breast milk. It
may be that these evolutionary novelties in childrearing have later consequences for
health; for example, it is known that breastfed infants have a lower risk of obesity
and metabolic disease and greater cognitive development than do formula- fed
infants. The human gut offers an attractive environment to its microbial colonizers,
being warm and damp and providing regular delivery of nutrients. Nevertheless, the
relationship should be seen as mutual rather than commensal, since both parties
derive benefit. The gut microflora provide numerous benefits to the host, including
digestion of nutrients such as dietary fiber, synthesis of vitamins such as folate and
biotin, and metabolism of potentially toxic food constituents. There is growing
evidence for a link between the gut microflóra and the brain, affecting aspects of
mood and behavior (see Sampson and Mazmanian 2015). Importantly the gut
microflora also act to protect the host organism by preventing colonization of the
gastrointestinal tract by pathogenic competitors and by modulating the development
of the host’s adaptive immune system.
• On the other hand, some parasitic species use
the human intestine as a host environment.
Tapeworms, trematodes (flatworms or flukes), and
roundworms pass their eggs/larvae to other hosts
via human feces. Some infestation is direct, by
contamination of water or vegetation, and
sometimes it involves an intermediate host, for
example the water snail in schistosomiasis. These
parasites compete for nutrients and can cause
considerable malnutrition in the host, with longterm
consequences such as stunting, as well as
abdominal disorders such as enlargement of the
liver or spleen. Gut parasitism is particularly
prevalent in low-income countries.
The Challenge of Infectious Disease
There are over 1200 species of recognized human pathogen, although the majority of
infection-related mortality and morbidity is now caused by just a few of these,
particularly malaria, HIV/AIDS, and tuberculosis. This multiplicity of threats imposes a
continual interplay between our defense systems and the transmissibility and
virulence of these organisms. Micro-organisms evolve in relation to their hosts and
the vectors they rely on for their survival and fitness. There are great differences in
population size and generation times between micro-organisms and humans, giving
microbes the advantage of being able to evolve much more rapidly. Indeed, in
bacteria, stress may produce an increase in their mutation rate (often termed the
SOS response)- see Baharoglu and Mazel (2014) which makes it more likely that new
variants will appear and that gene flow will be preserved. This difference in
generation times is well demonstrated by the development of bacterial resistance to
antibiotics, which is one of the best-characterized manifestations of evolutionary
processes operating in real time. Humans with their long generation time must deal
with this microbial challenge, and the biological complexity of vertebrates has
allowed the evolution of a number of defensive strategies that can cope with fasterevolving
organisms—in particular the innate and adaptive immune systems. In
historical times humans have added additional strategies in the form of technologies
such as vaccination and antimicrobial chemotherapy. Thus an evolutionary arms race
is played out with different weapons employed on each side—rapid mutational
change on one hand, and multivalent immune and defense mechanisms on the other
Pathogen
Emergence
• Most infections originate and are sustained by close interpersonal
contact and/or by contact with animals. Many viruses that infect humans
have their origin in domesticated animals. For example, the influenza
virus originated in pigs and poultry, and it is possible that the human
measles virus evolved from the closely related morbillivirus that causes
the cattle disease rinderpest (see Sharp 2002)—the close similarity
between measles virus and the morbillivirus that causes canine
distemper suggests a later jump in the opposite direction, from humans
to dogs (see Uhl et al. 2011). It is generally accepted that HIV is derived
from the lentivirus simian immunodeficiency virus (SIV); this is a slowQAUASI-
M growing subtype of retrovirus that infects Old World
primates.
• There are many previous incidences of the transmission of such
viruses between species, but the critical event for the origin of human
HIV was likely to have been transmission from (depending on the strain
of HIV) chimpanzees or sooty mangabeys to humans, most likely as
result of blood contact during hunting and butchering of these species
for bush-meat. We may never know the precise location or time of the
transmission, but research suggests that the origins were south central
Cameroon and possibly Guinea Bissau during the 1940s or 1950s. What
determines the transmission of an infectious disease from animals to
humans? Why is it a relatively rare event? The answer seems to be that a
successful shift in host from animal to human involves several distinct
events. Consider the influenza A virus H5N1, a strain of avian influenza
which has only infected a few humans who have been in particularly
close contact with infected poultry, but about which there is much
concern for the potential for human-to-human transmission. Studies of
the influenza pandemics of 1918, 1957, and 1968 give some clues.
• Influenza viruses are endemic in bird populations, both in the wild and in
domesticated species, and in some other animals such as pigs, and they are
highly mutable. Each pandemic is thought to represent the emergence of
mutated forms that have escaped the immunity of previous influenza infections
in humans and successfully made the transition from reproducing in an animal
host to reproducing in a human host. The so-called Spanish flu virus, which
produced the 1918 pandemic in which 50 million people died worldwide, may
have been due to the transfer of a complete avian virus into humans, although
others have proposed an intermediate mammalian vector (see Taubenberger et
al. 2012). In contrast, the more common influenza A virus shows relatively linear
evolution. The antigenic properties of the influenza virus change from year to
year as a result of mutation (antigenic drift), necessitating the production of
new vaccines and annual vaccination of susceptible members of the population.
But on top of this there have been several large shifts in antigenicity in the past
century, such as the “Asian flu” in 1957 and “Hong Kong flu” in 1968, arising
from reassortment of genes between two viral strains co-╉infecting an
individual. Close proximity between humans and animal hosts offers the
potential for initial direct inoculation (e.g., through a cut). In the case of H5N1,
the first transmission to humans was reported in 1997 and this is the stage at
which H5N1 currently exists: infection from the animal host can occur, but
human-o-human transmission remains unconfirmed. The critical next step will
be if the H5N1 virus exchanges genomic material with a flu virus that has the
potential to be transmitted between humans because it can bind to surface
receptors on cells in the human respiratory tract. If this happens a pandemic
could result, because there may be little resistance in the human population in
any country. Given that viruses replicate with very short generation times, the
chances of individual mutations are high. The cumulative effect of those
mutations in inducing a virulent pathogen depends on whether the human
defense mechanisms are adequate or whether technology in the form of
isolation, vaccination, or medication can reduce the spread of the organism and
contain the epidemic.
Pathogen
Virulence
and
Transmission
• The evolutionary aim of a parasite, like that of all other species, is to
maximize its reproductive success. The parasite does this by shaping
aspects of its life cycle to optimize survival and replication in its host and
transmission to its next host. Two of the traits that evolution uses to
optimize reproductive success are virulence and transmissibility. By
definition, a pathogen is a parasite that causes morbidity and mortality
in its host. It may do this by secreting a toxin, damaging cellular function,
competing for nutrients, or simply by causing mechanical damage. The
extent of this damage is termed its virulence. Virulence may appear as
incidental damage to the host that does not benefit the infecting
organism, or as damage that does benefit the infecting organism, such as
by increasing resource extraction from the host or enhancing the
transmission of the pathogen. For example, the principal morbidity
caused by HIV is gradual destruction of the host’s immune system,
increasing susceptibility to opportunistic infections and malignancy. This
type of damage to the host does not benefit the virus by directly
enhancing its sexual transmission, although the temporal pattern of the
infection, with a long asymptomatic period during which numerous
sexual partners can be infected, does promote transmission. Contrast
this with cholera, ingested for example via water contaminated with
feces containing the cholera bacterium. The organism clings to the wall
of the gut and secretes a toxin which triggers the secretion of serous
fluid and rapidly produces violent diarrhea. This trait is adaptive for the
cholera organism in that it allows greater spread to other hosts; it may
also serve to displace commensal gut microbiota, giving the pathogen a
competitive advantage in the gut environment.
• For a pathogen to be evolutionarily successful, it must also be
transmitted to a new host. Parasite fitness is often expressed as basic
reproductive ratio, R0, the average number of new host individuals
infected during the life cycle of the parasite. R0 must be at least 1 if a
parasite is to persist within its host population; high values of R0 indicate
that the parasite is spreading rapidly. Conversely, if R0 is below 1,
because of poor transmission or strong host defenses, the infection will
die out. A pathogen will evolve to an equilibrium established by the
optimal trade- off of virulence against transmission to ensure that it
infects the greatest possible number of new hosts. High virulence kills
the host quickly, so the pathogen needs to be highly transmissible.
Conversely, low virulence allows the host to survive for long enough to
infect many other hosts, so the pathogen can afford to be less
transmissible. Optimization of this trade- off depends on a number of
factors. These include whether transmission is vertical (between mother
and offspring) or horizontal (across all members of a species) as well as
the method of transmission. Pathogens can be transmitted horizontally
by many routes, for example by airborne droplets (exemplified by the
common cold virus and influenza), by contaminated water (e.g., cholera
and typhoid), by contact with infected body fluids (e.g., HIV, Ebola), by
contact with dormant organisms in the environment (e.g., smallpox), by
sexual intercourse (e.g., syphilis, HIV) or by an intermediate vector (e.g.,
malaria).
The converse situation is relatively common, however, for organisms that normally infect other hosts but are opportunistic pathogens in humans,
where their virulence can be very high. The Ebola virus is a good example. Its natural host is a species of fruit bat, in which it appears to have little or
no virulence. However, when transmitted to humans, possibly via consumption of infected bush- meat, it is highly contagious and the resulting
hemorrhagic fever has a very high case fatality rate. But this very high virulence limits the ability of the virus to spread to a large number of hosts,
and isolation and quarantine, properly applied, are effective in further restricting the pool of potential hosts and containing the outbreak. The
virulence/ transmission trade- off can be manipulated artificially, and this is the basis of the live attenuated vaccines developed in the 1950s and still
used for immunization against some diseases such as poliomyelitis. The process relies on serial passage of the pathogen in the laboratory in cell or
tissue culture under “ideal” conditions where transmission is assured (high R0) and the host (the cell culture) cannot evolve resistance or tolerance
because each passage is into naiive tissue previously unexposed to the pathogen. The result is that the pathogen evolves towards high virulence in its
new host but decreased virulence in its natural (human) host, and this “attenuated” strain is used for vaccination.
https://www.youtube.com/watch?v=I_xh-
bkiv_c&ab_channel=AndresTrevino
Whether or not we succumb to an infection is often not simply a question of whether we have come into contact with the pathogen,
but rather the size of the infectious load to which we are exposed. Simple procedures such as hand- washing greatly reduce the risk
of cross-infection in hospitals by reducing the infectious load; the major advance in patient survival after surgery afforded by Lister’s
invention in 1869 of the crude but effective carbolic acid spray was due to the reduction of the infectious load rather than achieving
complete sterility, a principle that stills holds true in operating theatres today. The estimated infective dose for pathogens—that is,
the number of organisms required to infect a host—varies widely (Leggett et al. 2012), ranging from just one cyst for the gut parasite
Entamoeba histolytica, ten or fewer organisms for Ebola virus and Mycobacterium tuberculosis (the causative bacterium of tuberculosis),
and up to 104–106 organisms for Staphylococcus aureus (a cause of skin infections) and other common bacterial pathogens. Generally,
the greater the virulence of the pathogen, the lower the infective dose, as would be predicted from the virulence/transmission trade-
off.
Host Defenses
Humans have evolved in the presence of a large repertoire of associated micro-organisms. Some of these are
pathogens or potential pathogens, but the human “meta-organism” (i.e., the body plus its microbiome) also contains
a large number of mutualistic or commensal species, which normally vastly outnumber the pathogens. From this
perspective, our evolved antimicrobial strategies should be seen not only as defenses against pathogens but also as
mechanisms to ensure peaceful coexistence with our commensals. Reciprocally, not only do commensals themselves
provide protection against pathogens, but exposure to commensals in early life appears to be a prerequisite for
maturation of the adaptive immune system (see Belkaid and Hand 2014).
Innate Immunity
All multicellular animals possess an innate immune system; this protects them from infection by maintaining defensive barriers against
penetration by micro-organisms and by mounting chemical and cellular defenses against any microbes that do reach the interior of the organism.
Innate immunity is non-specific and, unlike the adaptive immune system, does not lead to any lasting protective immunity (or “memory”). The
innate immune system is phylogenetically ancient, and many of its features are conserved across both vertebrates and invertebrates. The
physical barriers that resist invasion by micro-organisms include the skin as well as the epithelial mucosa lining the alimentary tract and parts of
the respiratory and reproductive tracts. These barriers are equipped with sensory receptors that are deployed at strategic points, where they
have greater sensitivity. Sensitivity is greatest on the most frequently exposed parts of our skin such as the fingers and face; mechanoreceptors
can detect very small inhaled particles in the nose or larynx and, on the skin, can detect small wounds. Tight junctions between epithelial cells
provide good protection against the passage of micro-organisms; the waterproofing of the skin limits passage of water-borne organisms, and the
mucus-secreting glands and ciliary action of the mucous membranes help to expel ingested or inhaled organisms. Some attackers have evolved
highly effective ways of penetrating these barriers, such as the proboscis of the mosquito, and other parasites such as the malaria protozoan use
this as a way of gaining access to a host’s body.
Other barriers within the body have different degrees of penetrability and defensive strategies (see Doran et al. 2013). The human placenta, for example, is
somewhat “leaky,” prioritizing exchange and transport functions over defense, and so some micro-organisms such as the syphilis spirochete (Treponema
pallidum), rubella virus, Toxoplasma gondii, Listeria bacteroides, and cytomegalovirus can pass from mother to fetus. At the other extreme the barrier between
the blood and the brain is very tight apart from at the cribriform plate, which conducts the olfactory nerves from the nose—this provides a route for infection
leading to meningitis. Amoebic meningitis, a very rare disease, can arise when contaminated water found in natural hot springs enters the nose. The epithelial
mucosae, such as those lining the respiratory tract and gut, are among the sites most exposed to the microbiota, yet they must allow the passage of oxygen and
nutrients. Epithelial cells and their associated inflammatory and phagocytic cells, such as macrophages and neutrophils, secrete mucus, IgA, and other
antimicrobial substances such as those of the complement system to provide physical and chemical barriers to the penetration of micro-organisms. The
triggering of these defenses to invading organisms involves recognition of chemical structures, called pathogen-associated molecular patterns (PAMPs), that are
common to micro-organisms but not found in more complex animals. In other words, this form of discrimination between self and non-self takes the form of a
generalized ability to distinguish between multicellular and single-celled organisms. PAMPs include microbial proteins such as flagellin, cell wall molecules such
as mannose and lipopolysaccharides, as well as unmethylated DNA (most eukaryotic DNA is methylated). The family of pattern recognition receptors that sense
PAMPs can trigger phagocytic and inflammatory responses in mucosal tissue, leading to engulfment and destruction of invading micro-organisms (see Albiger et
al. 2007).
Treponema pallidum
The release of cytokines such as interleukin-6 from cells of the innate immune system (e.g., macrophages) in response to PAMPs causes fever, one of the most
characteristic responses to infection. In mammals, fever is mediated centrally by hypothalamic mechanisms that drive thermogenesis and promote peripheral
vasoconstriction to reduce heat loss. In turn, this induced hyperthermia drives further activation of both the innate and adaptive immune systems (see Evans et al.
2015). This may occur by secretion of heat-shock proteins into the circulation. Heat-shock proteins are a diverse group of proteins with multiple intracellular
functions, so named because they are induced in a cell when it is exposed to elevated temperatures (see Srivastava 2002). These proteins control the transcription
of a range of genes, such as those involved in glucocorticoid secretion, as well as expression of cytokine and chemokine genes. Thus a febrile response may be part
of an evolved defense mechanism that uses the resulting expression of heat-shock proteins to stimulate the immune system. Although microbial replication may be
less efficient in a hyperthermic host, some pathogens such as the malaria parasite produce their own heat shock proteins that probably serve to protect the
organism during episodes of fever (see Przyborski et al. 2015).
Competition for the essential nutrient iron illustrates another form of interaction between host and invader. Microbial growth in host tissues is limited by the availability of free iron, and
infection induces secretion by the host of iron-binding proteins such as transferrin, which act to sequester iron intracellularly and make it unavailable for bacterial metabolism. For their
part, bacteria secrete siderophores, which are small peptides that bind iron and transport it into their cells. In turn, the host processes that detect PAMPs stimulate the secretion of a small
protein called lipocalin 2, which binds the bacterial siderophores with very high affinity and deprives the pathogens of iron. In experimental animals the absence of this defense mechanism
can result in sepsis and death. Infection-associated anemia is a common clinical finding, particularly with chronic infection, leading to the question of whether iron supplementation in such
situations is deleterious or beneficial. For example, iron deficiency appears to be protective against severe malaria in children (see Gwamaka et al. 2012), and untargeted iron
supplementation of children in an area with a high risk of malaria has been shown to increase hospitalization and mortality (see Sazawal et al. 2006). Nevertheless, current WHO
recommendations favor iron supplementation of children in areas endemic for malaria, in conjunction with measures to prevent, diagnose, and treat the disease. Protection against
pathogens can also result from direct action of the commensal microflora. The mechanisms involved include colonization resistance, which is the exclusion of pathogens by the
commensals in competition for nutrients, and niche manipulation, for example by altering the local pH, as well as secretion of antimicrobial peptides and production of metabolites such as
short chain fatty acids that can alter the virulence profile of invading pathogens. In this way, the innate immune system of the host has evolved barrier and defensive functions to control the
growth of commensal organisms but can also co-opt these organisms to control invasive pathogens.