Evolutionary Medicine
Miriam Nývltová Fišáková
Department of Physiology
Adaptive
Immunity
• The adaptive immune system is the key weapon in the vertebrate war against
microbial infection. The adaptive immune system differs from the innate immune
system in two general ways. First, it is able to respond to any antigen that is
perceived by the individual as non-self rather than to a non-specific pattern signaling
the presence of a pathogen. Second, although the initial response of the adaptive
immune system to a new challenge is relatively weak, it has a “memory” that ensures
that subsequent encounters with the same antigen cause faster and stronger
responses than did the first challenge. It is this second feature that gives the adaptive
immune system its name. The adaptive immune system provides vertebrates with a
powerful defense against microbial infection and immune surveillance against
aberrant clones of its own cells, but its exquisite specificity has two clinically relevant
consequences: susceptibility to autoimmune and atopic disease, and rejection of
transplanted tissue. The adaptive immune system has evolved as a highly complex
and multilayered mechanism. Briefly, however, it comprises two arms: cell-mediated
immunity and humoral immunity. As its name implies, cell-mediated immunity
involves direct counter-attack by the effector cells of the immune system, mostly T
(for “thymus”) cells and natural killer cells. Cell-mediated immunity has its major role
in defense against intracellular pathogens such as viruses and in immune surveillance
against host tumor cells. Humoral or antibody-mediated immunity involves the action
of circulating immunoglobulins, made by B (for “bone marrow”) cells, which bind to
their target antigens on pathogens and inactivate them directly or mark them for
destruction by other components of the immune system. Humoral immunity
generally functions against extracellular pathogens such as bacteria.
• As well as acting as effector cells, some subtypes of T cell also initiate and promote (T
helper or Th cells) and regulate (Treg cells) immune reactions. The ability to discriminate
between self and non- self is critical to the function of the adaptive immune system, and
defects in this process of immunological tolerance underlie autoimmune diseases (see
Romagnani 2006). The fundamental basis of recognition of self or non- self macromolecules
by the adaptive immune system is the display of fragments of those molecules on the cell
surface bound to proteins of the major histocompatibility complex (MHC). There are two
classes of MHC molecule: nearly all cells of the body express class I molecules, which display
fragments of the normal proteins of the cell, allowing the immune system to detect whether
the cell’s protein synthetic machinery has been subverted by viral infection or tumorigenesis.
Conversely, class II molecules are only expressed by specialized antigen- presenting cells,
which phagocytose and degrade micro- organisms and display protein fragments from
foreign antigens. Recognition by a Th cell of a displayed peptide as non- self triggers an
immune response: in general, recognition of non- self in the context of MHC class I causes a
cell- mediated response that kills the subverted cell, whereas recognition in the context of
MHC class II causes both a cell- mediated and an antibody- mediated response.
• The multi- subunit MHC molecules are coded for by genes on chromosome 6, each of
which is extraordinarily diverse (up to several hundred alleles), much of which is expressed
at the peptide- binding site of the molecule. This combination of allelic variation and subunit
pairing means that the resulting MHC complexes are capable of binding a huge variety of
different peptides. Such genetic diversity is best explained by balancing selection, driven by
the different ability of particular MHC alleles to protect against particular pathogens. Even in
a small population there will be many different combinations of MHC alleles that protect
against the multiple pathogens in the environment and thwart the evolution of new
pathogen epitopes
• In humans, the MHC system is also known as the human leukocyte antigen (HLA) system. The HLA system is the
predominant determinant of tissue compatibility after transplantation, and the wide diversity of HLA alleles makes tissue
rejection likely unless careful matching is performed. Another situation where tolerance between HLA- incompatible
individuals is critical is at the maternal– fetal interface. The fetal trophoblast cells that contact maternal tissues during
pregnancy do not express classical MHC class I or II molecules on their surface, and instead express a set of minor HLA
genes with restricted allelic diversity and immunosuppressive properties towards maternal cells. Two facets of the
adaptive immune system use selective processes at a cellular level to ensure immunological self- tolerance and strong
antibody affinity. First, recognition of self antigens is critical for immunological tolerance and the avoidance of
autoimmune disease. The “education” of the immune system to distinguish self from non- self is a selective process that
takes place in the thymus during early life. Immature T cells, each of which carries a T- cell receptor on its surface that
binds to just one of the estimated 10 million different types of epitope recognized by the human immune system, are
normally programmed to undergo apoptosis and die shortly after they are formed. In the thymus, they are exposed to the
full range of self antigens, and those that fail to react are “rescued” from the apoptotic process and released into the
blood. This “fail- safe” mechanism of negative selection ensures that the organism develops with a set of T cells that only
respond to foreign antigens. The second process is the clonal expansion of B cells. During their development, each B cell
is programmed to produce a single one from the wide range of possible immunoglobulins, and this is displayed on its
surface as part of the B- cell receptor. Once released into the circulation, if it encounters that epitope it is stimulated to
proliferate, leading to the production of millions of identical B cells that secrete immunoglobulins with the correct
specificity. In the course of this clonal expansion, further fine- tuning of immunoglobulin specificity occurs by a process of
somatic hypermutation, which promotes erroneous DNA repair and increases the mutation rate in the variable region of
the immunoglobulin gene by about a million- fold. The resulting variations in immunoglobulin amino acid sequence are
random, but only those cells with the highest affinity for antigen are selected to survive and proliferate. The end results of
this Darwinian process of variation and selection, which can be seen as a form of somatic evolution, are two- fold: plasma
cells that secrete large amounts of immunoglobulin of high specificity, and the development of memory B cells containing
the relevant DNA sequence that persist for years in lymph nodes and are activated rapidly on new exposure to the
antigen. It is the existence of this immunological memory that forms the basis of vaccination
• The adaptive immune system has evolved in the presence of the associated commensal
microflora which, because of its extent and diversity, must represent a major antigenic
challenge to the host. How is it that the adaptive immune system does not respond to this
challenge, and how does it filter out signals of pathogen intrusion from the noise of the
millions of commensally derived antigens? To do so, the commensal antigenic burden must
either be minimized or tolerated. The first is achieved by limiting exposure of host tissue to
commensals using the barrier defenses, while the second involves development of tolerance
to the commensal microflora so that the host immune system sees it as “self” rather than
“nonself” (see Lee and Mazmanian 2010). Development of this tolerance occurs early in life,
facilitated by the immature immune system of the neonate which is oriented towards
immunoregulation— discovering “self” and establishing tolerance towards it— rather than to
mounting effective immune and inflammatory responses. This early life deficit in protective
immunity underlines the importance for neonatal health of the passive immunity transferred
in breast milk. The importance of early exposure to the gut microflora for development of
the adaptive immune system is shown by the impaired phenotype of animals reared under
sterile (“germ- free”) conditions. Such animals show deficiencies in the development of their
intestinal mucosal barrier and immune system tissues, both in the gut and systemically. They
also have defects in immunoregulation, as indicated by the properties of their Th and Treg
cell populations, and are more susceptible to pathogen infection.
• Experimentally, replacement of the mikroflóra with a
single species of gut micro- organism, Bacteroides
fragilis, can ameliorate these immunoregulatory defects.
This effect can be mimicked by a single secretory
product (polysaccharide A or PSA) from the bacterium,
suggesting that factors secreted from the gut microflora
can direct the maturation of the host immune system
(see Ivanov and Honda 2012).
How
Pathogens
Evade Host
Defenses
• Pathogens have evolved mechanisms to evade and neutralize the defenses mounted by
the innate and adaptive immune systems, buying themselves enough time to survive,
proliferate, and be transmitted to the next host. Host barriers against infection can be
overcome by the secretion of toxins that inhibit ciliary action or the production of a
protective biofilm. Many bacteria shield themselves from the PAMP recognition system by
secreting masking molecules on their cell surface; the intracellular pathogen Mycobacterium
tuberculosis uses lipids both to mask its cell surface PAMPs and to attract benign (to it)
macrophages in the lower respiratory tract that engulf it and transport it into lung tissues
(see Cambier et al. 2014). The trick of hiding inside host cells is used by many pathogens,
from the retroviruses such as HIV that hide within the genome to the malarial parasites such
as Plasmodium that live within red blood cells. Other pathogens hide from the adaptive
immune system by constantly changing their cell surface antigens, so that the host’s immune
response always lags behind the pathogen’s antigenic appearance. One example concerns
the contingency loci found in several genera of bacterial pathogens. These loci, usually
associated with gene products that interact in some way with the host, contain short
sequence repeats that are liable to mis-pair, resulting in frameshift mutations in the resulting
cell surface proteins and therefore high phenotypic diversity that enables the pathogen to
evade host responses. A somewhat similar process is used by the trypanosomes that cause
sleeping sickness to generate the variant surface glycoproteins (VSGs) that act as decoys for
the host immune response, although here the variants arise from an archive of pre-existing
VSG genes rather than from de novo mutations. A final example is provided by the extreme
diversity in the envelope proteins and drug-target molecules of HIV, originating from
mutations promoted by the low fidelity of the virus’s reverse transcriptase.
• Some evasion mechanisms directly target the adaptive
immune system. Viruses such as herpesvirus,which cause
persistent lifelong infections, inhibit the host antigen
presentation machinery that would normally alert the
immune system to their presence within cells (see Zuo and
Rowe 2012). Other pathogens, including trypanosomes,
hepatitis C virus, and HIV, can subvert B-cell-mediated
immune responses (see Nothelfer et al. 2015). Some
pathogens interfere with the cytokine signaling required for
an effective immune response; for example, interferon is a
cytokine secreted in response to viral infection, and many
viruses, including papillomavirus and measles virus, are able
to inhibit the production or action of interferon (see
Devasthanam 2014).
Over-reaction of
Host Defenses
Can Cause
Morbidity and
Mortality
• The interplay between host defenses and pathogen biology represents the sum of two
evolved trade-offs. The pathogen must balance how much it damages its host by its virulence
and evasion mechanisms against the need for the host to be able to transmit the infection,
and the host must calibrate its defensive response to the severity of the threat while
avoiding collateral damage to its own tissues. Nevertheless, exaggerated host responses can
contribute to morbidity and mortality. The case fatality rate in the 1918 Spanish influenza
pandemic was particularly high because the virus elicited an aberrant host immune response
that caused extensive tissue damage in the lungs, which may explain its unusual pattern of
age-specific mortality (see Morens and Fauci 2007).
• Another example of an exaggerated immune response is that to staphylococcal
enterotoxins. These secretion products of Staphylococcus aureus cause mild gastrointestinal
symptoms, but when introduced systemically act as “superantigens,” causing widespread
activation of the immune system and massive release of cytokines (a “cytokine storm”). The
resulting toxic shock syndrome involves vascular leakage, hypotension, and disseminated
intravascular coagulation, leading to multiorgan failure (see Krakauer 2013). Such a dramatic
outcome can be envisaged as an unintentional consequence of the evolved virulence of the
bacterium, which exists as a human commensal and opportunistic pathogen that has little
evolutionary interest in the rapid death of its host. To the patient, host defenses like fever
and cough can appear as debilitating over-reactions to relatively mild infections, such as with
the common cold virus. In this situation, symptomatic treatment with antipyretics and
antitussives makes the patient feel better and is generally unlikely to have effects on the
eventual outcome of the infection. Suppressing these evolved defensive responses may not
always be a good idea. For example, there is some evidence that suppressing fever in
critically ill patients increases mortality (see Schulman et al. 2005).
Autoimmu
ne and
Allergic
Disorders
• The autoimmune, inflammatory, and allergic disorders have their proximal cause in the
dysregulation of the immune system. Diseases in which the immune system attacks the body’s own
cells, as if mistaking them for non-self pathogens, are termed autoimmune diseases. Examples include
type 1 diabetes and multiple sclerosis. Other conditions such as Crohn’s disease and ulcerative colitis
result from inappropriate activation of the inflammatory response. Allergies such as allergic rhinitis
(“hay fever”) are caused by hypersensitivity of the immune system to environmental antigens that are
inappropriately perceived as harmful. In this book we have seen repeatedly that environmental change
producing evolutionary novelty can pose a threat to human health. We can contrast the fall in
morbidity from infectious diseases seen in high-income countries over the past 100 years or so with the
dramatic increase in the prevalence of autoimmune, inflammatory, and allergic disorders. What could
explain this apparent negative association? There are both genetic and environmental determinants of
susceptibility to disorders caused by immune dysregulation. The genetic determinants are often
associated with particular alleles of the HLA system. For example, HLA-DR2 is associated with systemic
lupus erythematosus (more common in females) and ankylosing spondylitis is associated with HLA-B27
(more common in males). Ankylosing spondylitis develops gradually during adolescence and young
adulthood, causing chronic inflammation and structural changes in joints, especially the spine. The rapid
change in the prevalence of immune-related disorders makes any genetic explanation unlikely. For
example, not all HLA-B27 males develop ankylosing spondylitis, so there must be some other
environmental trigger. There is evidence to suggest that the trigger in some cases is a response to
Klebsiella commensals which inhabit the gut, perhaps itself triggered by an acute infection, since there
are cross-reacting epitopes between Klebsiella and human cell-surface antigens (Husby et al. 1989).
There are other subtleties in the environmental associations of immunoregulatory disorders that may provide clues to the underlying mechanisms. For
example, there is a lower prevalence of asthma and atopic disorders in children in rural compared with urban communities. Inflammatory bowel disease
is common in highly sanitized, industrialized areas of the world, but uncommon in rural areas where living quarters are crowded and unhygienic.
Breastfeeding in infants has a protective effect in reducing the later risk of asthma, and it is known that breast- and formula-fed infants are exposed to
different types of bacterial flora. We described how the vertebrate adaptive immune system has coevolved with both commensal and potentially pathogenic
micro-organisms, and that appropriate exposure to microbes early in life is essential for establishing immunoregulatory pathways. For instance, germ-free
mice experience abnormal development of their immune system, which can be corrected by re-introduction of intestinal commensal bacteria. A unifying
mechanism to explain all these observations, termed the hygiene hypothesis, proposes that lack of early exposure to the full range of microbes leads to
inappropriate activation of immune responses which are then manifest as allergic or autoimmune disease. In other words, such deficient exposure has
changed the set-point of the trade-off between efficient pathogen defense and susceptibility to autoimmunity (see Bergstrom and Antia 2006). Although
early versions of the hygiene hypothesis tended to emphasize common childhood infections as the contributing exposures, many such infections have only
become prevalent in recent human history because of the crowding caused by the post-Neolithic move to large settlements. A more nuanced version of the
hypothesis proposes that the contributing organisms are the “old friends” of commensals and parasites that were present during the evolution of the human
adaptive immune system (see Rook 2012). Other candidate organisms are helminth worms. Intestinal infestation with helminths was nearly universal in
human evolutionary history, but is now rare in high-income countries. Areas with high infestations of helminths have low levels of autoimmune disease,
although as ever there is a trade-off—because of parasite-associated immunosuppression, vaccine response rates in these areas are lower than in unaffected
areas (see LaBeaud et al. 2009). Although infestation with helminths can cause IgE-mediated responses, the organisms are difficult to clear and the host
tends to develop tolerance rather than mounting a futile and self-damaging immune reaction. Experimental studies show that helminth infestation is
protective against a number of immune-mediated diseases. Observational studies in patients with one autoimmune disease, multiple sclerosis, suggest that
disease progression is inversely correlated with parasite load, such that antihelminthic therapy leads to worsening of the autoimmune disorder (see Correale
and Farez 2011). Clinical trials involving deliberate helminth infestation of patients who have inflammatory bowel disease (the pig whipworm, Trichuris suis,
was used since it is not pathogenic in humans) have indicated a reduction in disease activity in patients with ulcerative colitis and Crohn’s disease (see Heylen
et al. 2014). If such trials are successful and a clear link is established between parasite-driven immunoregulation and immune disorders, then new
possibilities for treatment will become available. Conversely, efforts to clear helminth infections from low-income countries may need to take account of a
possible rise in the level of allergies and inflammation (see Wammes et al. 2014).
Public Health Measures
• In addition to our immune systems, the evolved extended human phenotype now
includes technological defenses against microbial infection. The three arms of these
defenses are public health innovations, vaccination, and antibiotics. Improved
nutrition and sanitation underpin much of the fall in morbidity and mortality from
infectious disease over the past 150 years. The interaction between poor nutrition
and infection is particularly important in low- and middle-income countries, and
especially in children. An early effect of malnutrition is the suppression of immune
function. For example, in a population of subsistence farmers in The Gambia with
highly seasonal food availability, people born in the “hungry season” showed ten-fold
higher infection-related mortality as young adults and decreased life expectancy,
suggesting that immune function may be compromised by events early in life. In this
population, thymus development was sensitive to early life nutrition, with smaller
thymuses observed in those born in the hungry season. Furthermore, size at birth
was positively correlated with antibody responses to vaccination (see Moore et al.
2006). Such observations may represent the results of trade-offs in which the body
prioritizes resource use and favors immediate survival over investment in long-term
defense mechanisms. The importance of uncontaminated water supplies and
efficient removal of sewage in limiting the oro-fecal transmission of disease have
been known since Dr. John Snow removed the handle of a public pump in London in
1854 to curb an outbreak of cholera. Because waterborne diseases such as cholera
and typhoid are easily transmitted to multiple new hosts, and retain their virulence
because transmission is not dependent on continued host viability, improvement of
sanitation is one of the most effective measures to combat infectious disease.
Vaccination
• Vaccination takes advantage of the ability of the adaptive immune system
to retain a memory of previous antigen challenges, so that future exposure to
the antigen results in prompt and vigorous protective responses
(immunization). Vaccination has eradicated one human disease (smallpox), is
close to eradicating another (poliomyelitis), and in high-income countries
controls several acute childhood infections, such as rubella and measles. It is a
characteristic of these diseases that natural infection with these agents, if not
fatal, generally provides lifelong protection against a second infection since
the causative viruses show little or no antigenic drift (mutation of the sites to
which protective antibodies bind) in the wild; vaccine-induced immunity
against these pathogens similarly results in lifelong protection. However,
recent reports of a vaccine-resistant strain of poliovirus should be a reminder
that antigenic stability should not be taken for granted see (Drexler et al.
2014). In contrast, pathogens that are able to evolve their antigenic properties
in the wild can cause repeated infections. Influenza virus shows both antigenic
drift and antigenic shift (where virus subtypes combine to produce a new
strain), which means that the immune response to one strain is ineffective
against a new strain. For such diseases, public health strategies require
continual surveillance of circulating viruses and the regular administration of
new vaccines formulated against their predicted antigen profile.
• Where a pathogen is pathogenic by way of a toxin, immunization against the toxin
(which is likely to be less variable) may address the pathogenic process while leaving the host
immune system to eradicate the actual infection. This is the basis of protection against
tetanus. There are also several examples of existing human and veterinary vaccines where
evolution of the targeted organism in the host has been demonstrated in response to the
selection pressure of the vaccine, and in the case of one veterinary disease (Marek’s disease,
a virus- induced neoplasm in poultry) this has led to large- scale failure of the vaccine. How
might a pathogen respond to a vaccine? First, it might evolve by selection against the
epitopes recognized by the vaccine. Such epitope shifting, potentially leading to loss of
effectiveness of the vaccine, has been observed for several human viral and bacterial
vaccines including those for hepatitis B, pertussis, and pneumococcal disease. For example, a
resurgence of whooping cough infections in high- income countries has been linked to strains
of Bordetella pertussis that have evolved to no longer express pertactin, a virulence factor
that is an antigen included in modern acellular vaccines (see Lam et al. 2014). Secondly, the
pathogen might evolve to change its virulence, a situation that particularly applies to socalled
“imperfect” vaccines that are not sterilizing (i.e., preventing all infection) but are
rather partially effective in preventing transmission or reduce the severity of any infection
that does occur. Recall from the discussion of virulence that a pathogen will evolve to a
particular level of the virulence/ transmission trade- off that optimizes its reproductive
success. If vaccination acts to increase the survival of an infected host, giving it more time to
transmit the pathogen to the next host, then the set point of the trade- off will move
towards increased pathogen virulence (Gandon et al. 2003; Mackinnon et al. 2008). Although
vaccinated hosts will not be affected, unprotected hosts who do not benefit from the
survival advantage conferred by vaccination will experience more severe disease. At a
population level, pathogen evolution of this kind may negate the benefit of a vaccination
program by increasing the cost of managing the disease in unprotected individuals. The
failure of the Marek’s disease vaccine in chickens was caused by vaccine driven increases in
viral virulence.
• For some infections, vaccination of an entire population is not necessarily
essential to prevent outbreaks of disease. As long as a sufficiently high proportion of
the population is vaccinated, any outbreak will be contained because it is likely that
the potential hosts exposed to the pathogen will already be immune and unable to
develop and transmit the disease. The vaccination coverage necessary to produce
this “herd immunity” (or, more elegantly, “social immunity”) varies from disease to
disease depending on transmissibility; it is estimated to be 90– 95% for a highly
transmissible disease such as measles. One advantage of herd immunity is that
members of the population who cannot be vaccinated, for example frail or
immunocompromised individuals, also benefit from vaccination programs. On the
other hand, “freeloaders” who take advantage of the protection conferred by
community vaccination without exposing themselves to the (very small) risk involved
in receiving vaccines will also benefit. This, together with misplaced antivaccine
attitudes, has led to vaccination coverage in some areas of high- income countries
declining below that necessary for herd immunity, allowing outbreaks of previously
controlled childhood diseases (see Fine et al. 2011). Current vaccine development is
aimed at diseases where host immunity fails to control the pathogen and initial
infection becomes chronic; such diseases include HIV and malaria. For these
pathogens, the important issue is the agility of their epitope composition that
presents an ever- shifting target for the host immune system and for the vaccine
developer. The genetic diversity of HIV is a function of its highly error- prone reverse
transcriptase (see Smyth et al. 2012). The malaria parasite uses antigenic variation
and polymorphism, as well as active immune evasion strategies, to slow and
misdirect the immune response of the host; these properties are likely to have
coevolved with the human immune system (see Pierce and Miller 2009). The failure,
despite decades of effort, to develop vaccines against these diseases suggests that
knowledge of the coevolutionary relationships of the human immune system might
provide us with new therapeutic approaches.
Antibiotics
• Antimicrobial chemotherapy kills or inhibits the growth of micro-organisms,
and is used to prevent or treat infection. In this section we particularly discuss
antibiotics, which are substances used against bacteria; antivirals and
antifungals are also mentioned briefly. There is a wide variety of mechanisms of
action of antibiotics. Molecular targets include the bacterial cell wall (e.g.,
pencillin and its derivatives), DNA replication (quinolones), RNA synthesis
(rifamycins), protein synthesis (macrolides and aminoglycosides), and
metabolism (sulfonamides). A characteristic of these targets is that the affected
pathway does not exist or is only weakly affected in eukaryotes, ensuring that
the toxic effect is confined to the prokaryotic organism. Most antibiotics are
derivatives of naturally occurring compounds that have evolved in microorganisms
as defenses against other micro-organisms; the classic example is the
production of penicillin by the mold Penicillium. The evolution of these
defensive chemicals places selective pressure on the targeted micro-organism;
consequently, all microbial defense mechanisms, and their countermeasures,
will have been tested by millions of years of coevolution. This implies that
resistance mechanisms against most if not all naturally derived antibiotic classes
will already have evolved. Samples of bacteria from a cave thought to have been
isolated for over 4 million years were found to be resistant to multiple classes of
modern antibiotics (see Bhullar et al. 2012). The mechanism underlying
resistance generally involves denying the antibiotic access to its target site. For
example, this could be by the acquisition of degradative enzymes such as betalactamases
or of efflux pumps that remove the antibiotic from the bacterial cell.
Alternatively, the sensitivity of the target site to the antibiotic may be
decreased, for example by point mutations in the active sites of the DNAreplicating
enzymes inhibited by the quinolone antibiotics such as ciprofloxacin.
A particular feature of antibiotic resistance, with implications for the
therapeutic use of these compounds, is the ease with which pathogens can
acquire the trait. Resistance can evolve by de novo mutations as a result of the
selective pressure of exposure to the antibiotic, because the large population
size and short generation time of bacteria mean that resistance-conferring
mutations will frequently occur and spread even within the human host.
Additionally, resistance can be acquired by horizontal gene transfer, not only
from members of the same bacterial species but also from phylogenetically
distant prokaryotes. Together, these processes mean that clinically relevant
levels of resistence usually appear within 2–4 years of the introduction of a new
class of antibiotic (see Hawkey 2008). However, the innovation pipeline for new
antibiotics is narrow, with fewer new drugs being approved each year
• Hospital-associated (nosocomial) infection with resistant bacteria is a particular threat. This arises
because of the high rates of antibiotic use within the hospital setting, generating strong selective pressure
favoring resistant strains and clearing sensitive ones, making colonization of patients and staff by resistant
strains more likely. In addition, the high turnover of patients in a hospital imposes selective pressure for a
resistant strain to transmit rapidly so as to remain endemic within the hospital. In 2013, the US Centers for
Disease Control and Prevention reported that each year in the USA at least 2 million people acquire
serious infections with antibiotic-resistant bacteria, and at least 23,000 people die each year as a direct
result (Centers for Disease Control and Prevention 2013). The financial impact of resistence may be as
high as US$20 billion in excess direct healthcare costs, with additional costs to society for lost productivity
of as much as US$35 billion a year. Antibiotic resistance clearly presents a considerable problem, and
there is a fear that bacterial strains with multiple resistance to all known antibiotics could arise, with
disastrous consequences. However, we must remember that major progress in reducing deaths from
infectious disease occurred in the pre-antibiotic era as a result of advances in vaccination, nutrition, and
sanitation, and so the application of more traditional methods must not be overlooked. Antibiotic
resistance is another consequence of human manipulation of the environment. Overuse through
unnecessary prescribing is a major cause, but antibiotics are also added to animal feedstuffs to promote
growth. Measures to prevent over- use include reduction of the use of antibiotics in animal feed, as well
as education of prescribers and patients to promote “antibiotic stewardship,” using protocols that ensure
antibiotics are used only when necessary and that the right antibiotics are prescribed and administered in
the right way. There has been interest in evolutionary- based treatment protocols to reduce the
development of antibiotic resistance in hospitals. These include antibiotic cycling (where use of different
classes of antibiotics is alternated across the whole hospital on a regular schedule) and antibiotic mixing
(where individual patients receive one of several antibiotic classes used simultaneously in the hospital).
The rationale behind these approaches is that if strains resistant to one antibiotic evolve, they will be
susceptible to the new agent (in the case of cycling) or will not spread to nearby patients (in the case of
mixing). Although there have been many theoretical studies of such protocols (see Bergstrom et al. 2004),
it is only recently that trials have begun to test their efficacy (van Duijn and Bonten 2014)
• Another potential approach is to adjust antibiotic administration schedules to
ensure a better balance between curing the infection and preventing the evolution of
resistance (see Kouyos et al. 2014). Traditionally, aggressive therapy with high
dosages for long durations has been used to achieve maximum bacterial kill.
However, clinical cure can be achieved by use of moderate dosages and durations if
the treatment buys time for the patient’s immune response to kill the pathogen or
develop tolerance to it (see Rĺberg et al. 2009). In this situation, lower dosages of
antibiotics could prevent the evolution of resistance, first by allowing the survival of
susceptible strains to compete with resistant strains, and second by reducing the
emergence of resistance in “bystander” non- pathogenic commensals and
subsequent horizontal gene transfer into the pathogen. Targeting secreted bacterial
“public goods. Antivirals and antifungals also act against the survival or replication of
the infecting microorganism, but the range of molecular targets of these agents is
potentially limited by the characteristics of the pathogen. Viruses often use part of
the host’s biochemistry for their replication, ruling out targeting those pathways.
Consequently, antivirals target other virus- specific features, as exemplified by the
reverse transcriptase inhibitors used to inhibit replication of retroviruses such as HIV
(e.g., nevirapine). Another approach is to inhibit the release of viruses from infected
cells; the HIV protease inhibitors (such as ritonavir) and the influenza virus
neuraminidase inhibitors (such as zanamivir) work in this way. Development of
resistance to antiviral drugs is the result of the high mutability of viruses in the face
of the selection pressures caused by the antiviral treatment. An extreme example is
HIV, in which the high mutation rate conferred by an error- prone replicative
mechanism leads to rapid evolution of resistance to antiretrovirals, even in individual
patients. Consequently, antiretroviral therapy in patients with HIV infection is based
on combination therapy to delay development of resistance, along with (in highincome
countries at least) monitoring of viral load and resistance testing to guide
treatment changes.
• By analogy with the situation of “imperfect” vaccines,
evolutionary theory predicts that intensive treatment of HIV
infection in a population will increase its virulence. Transmission will
be favored by rapid progression to high viral load, and this higher
virulence that might lead to death of the host before transmission
can be offset by treatment. Conversely, in an untreated population
virulence should decrease, because lower viral load and the
consequent greater host longevity favor transmission. This
prediction appears to be confirmed by reports of opposing trends in
HIV virulence in Europe (see Pantazis et al. 2014) and Africa (Payne
et al. 2014). Fungi, like their hosts, are eukaryotes, meaning that
molecular targets unique to the prokaryote domain are not
available. Most antifungals target the fungal cell membrane, which
differs in lipid composition from animal cell membranes; examples
include amphotericin, which disrupts membrane structure, and
ketoconazole, which prevents membrane lipid synthesis.
Key Points
• Many causes of extrinsic mortality are biotic, including competition for nutrient supplies with other organisms of the same
or different species, predation, and infection by micro-organisms.
• Humans have evolved with their pathogens, parasites, and commensals. This process of coevolution has shaped aspects of
human physiology as well as the biology of the microbiota.
• The role of the human gut microbiome in human physiology is increasingly understood; it contributes to defense against pathogens, metabolic
health, and regulation of the immune system.
• The adaptive immune system of vertebrates is a key component of protection against microbial infection. Its specificity is a consequence of
Darwinian processes of variation and selection.
• Trade- offs between virulence and transmissibility influence the ways in which microbial infections progress in individuals and
populations. The balance between these attributes of the pathogen can evolve and change rapidly under some circumstances, with important
consequences for therapeutic strategies.
• Human technology in the form of public health measures, vaccination, and antibiotics has greatly reduced the threat from infectious disease in
high- income countries. Infection is still a major cause of morbidity and mortality in low- income countries.
• The concerning development of antimicrobial resistance in pathogens can be understood in terms of an evolutionary arms race. This
understanding can provide insights into how to reduce this risk by adjusting treatment regimens.
Thank you for your
attention!