14  The natural history of infection
M. R. Barer
KEY POINTS
• Symptomatic infection is a rare outcome when
human beings and micro-organisms meet. None the
less, some organisms, known as obligate pathogens,
must cause disease to survive; this applies to most
viral pathogens. Many bacterial pathogens appear to
derive little benefit from causing infection.
• Micro-organisms that form short- or long-term
associations with humans do so in a number of
recognizable forms and stages, including: entry/
establishment, colonization, commensalism, spread,
survival and multiplication, damage, and carriage.
Where these associations lead to bacterial disease,
the different stages are often associated with the
virulence determinants described in Chapter 13.
• Infections can generally be recognized in one of
four categories: toxin mediated, acute, subacute
and chronic.
• The capacity of a particular micro-organism to cause
disease is known as its virulence. Where suitable
experimental models are available, we can recognize
virulence quantitatively by the ability of a low
number of organisms to produce infection or death
in the host population. Such measurements can be
useful in identifying virulence determinants and in
developing vaccines.
The purpose of this chapter is to link the basic proper-
ties of micro-organisms with the patterns of infective
disease experienced in public health and clinical prac-
tice, and with the tissue and organ pathology that can
be observed. Although there are numerous exceptions
to the general patterns described, the intention is to
give an underlying structure that can be used to make
sense of the many different types of organism and the
diseases they cause. The term ‘natural history’ is used
in two senses here: first, to denote an overall biological
168
consideration of the life cycle of the infective agent
and how this intersects with the human host and,
second, to consider the process of infection from the
point of the encounter between the agent and the
susceptible host through to its outcome.
MEETINGS BETWEEN HUMAN BEINGS
AND MICRO-ORGANISMS
The vast majority of micro-organisms do not form
stable associations with human beings. Clearly patho-
gens must do so, at least temporarily. However, it is
worth briefly considering how important this asso­
ciation is to the micro-organism concerned. In some
cases, humans constitute the only environment in
which micro-organisms can survive (i.e. they are obli-
gate parasites of human beings). Thus, humans are the
reservoir and immediate source of the infections
caused by this group (see Ch. 1). In other cases colo-
nization or infection of human beings may be entirely
incidental to the life cycle of the organism. These
organisms may need to live in animals, as in the case
of zoonoses, or in specific environmental reservoirs.
Their life cycles in these habitats are critical to the
epidemiology of the infections they cause. This bio-
logical perspective is difficult to avoid when consider-
ing the complex life cycles of parasitic protozoa and
helminths, but such considerations are equally appli-
cable to bacterial and viral pathogens.
In the previous chapter a division was made between
primary and opportunistic pathogens. Here this divi-
sion is maintained but the primary group is further
subdivided.
Obligate pathogens
These organisms have to cause disease in human
beings in order to continue to survive and propagate.
This is true for most viruses that cause human disease
and for which humans are the only natural host. The

major caveat to this is that the degree to which these
agents cause symptomatic infections can vary over
a very wide range. Thus asymptomatic infections
with smallpox were virtually unknown, whereas they
are very common with polio. This contributed sub-
stantially to the eradication of smallpox as it was rela-
tively straightforward to identify where transmission
was taking place. Among bacterial pathogens, Myco-
bacterium tuberculosis is a prime example of an agent
that has to cause symptomatic disease in order to
survive and propagate. In some cases pathogenicity
reflects an early stage in the development of host-
parasite relations, with pathogens evolving towards
a more benign association with their host. Clearly, if
a parasite kills all of its potential hosts then it has
destroyed its own habitat. However, this does not
always hold true. Some pathogens actually become
more virulent as a means of increasing their potential
to survive.
Accidental or incidental pathogens
This term applies to many bacterial pathogens.
Causing disease confers no obvious biological advan-
tage on the organism and indeed may be a dead end.
There are two groups of bacterial pathogen for which
this is probably the case. The first group have their
natural habitat in humans but cause disease in only
a small minority; these include the major pathogens
of bacterial pharyngitis (Streptococcus pyogenes),
acute pneumonia (Streptococcus pneumoniae) and the
principal agents of acute pyogenic meningitis (Strep-
tococcus pneumoniae, Neisseria meningitidis and Hae-
mophilus influenzae type b). The second group have a
habitat (or reservoir) in nature but, if they encounter
a susceptible host in a particular way, infection may
ensue. For example, the agent of cholera, Vibrio chol-
erae, lives in brackish water and causes human disease
only when ingested. Clostridium tetani, the agent of
tetanus, probably propagates in animal gastrointesti-
nal tracts and infects wounds contaminated by soil
containing animal excreta.
Pathogens in the environment
Whatever the method of acquisition, the organism
must survive long enough to encounter a susceptible
human host if it is going to cause human disease. The
dynamics of pathogen survival in various environ-
ments are relevant to the control of infection. The
capacities of different pathogens to survive and prop-
agate in food and water are of particular concern, as
is survival in aerosols and through desiccation and
many other common environmental stresses. These
The natural history of infection 14
properties provide the biological basis for the trans-
mission of infection and many opportunities for
improved control of specific pathogens.
STAGES OF INFECTION
Most infections can be broken down into a core series
of steps:
• encounter
• entry and establishment
• spread
• survival and multiplication
• damage
• outcome.
It should be noted that the virulence determinants
described in Chapter 13 were related to all but the first
and last of these stages. Most pathogens can cause
infection only via a limited set of routes (see above).
Thus Vibrio cholerae must be ingested; it cannot cause
infection if rubbed on the skin. Human immunodefi-
ciency virus (HIV) must gain access to circulating
CD4+ cells via a parenteral route, and so on. Some
general points concerning the passage through alter-
native stages of infection are made in Figure 14.1.
Note that, although the simple direct pathway (A)
reflects the norm for an exogenous infection, there are
intermediates between this and D, endogenous infec-
tion. A single organism may be capable of following
multiple routes to infection. For example, Staphylo-
coccus aureus may be introduced exogenously into a
wound. Around 30% of individuals are colonized with
this organism at any point in time but in only one-
third of these (10%) does the organism appear to be a
member of the normal microbiota. Both temporary
and permanent relationships may provide for endog-
enous infections due to Staph. aureus.
Many opportunistic pathogens become part of the
normal microbiota before they cause infection. They
may be assisted in colonizing a new host by interven-
tions such as repeated use of antibiotics. This appears
to be the case with Pseudomonas aeruginosa, which is
resistant to most routinely used antibacterial agents,
and is probably also the case for methicillin-resistant
Staph. aureus (MRSA) and vancomycin-resistant
enterococci (VRE). Most members of the normal
microbiota appear to have very little capacity to cause
disease. The number and identities of readily cultur-
able bacteria varies in different parts of the body
(Table 14.1) and it is clear that a ‘healthy’ normal
microbiota provides some protection against invading
pathogens. Indeed the composition of the microbiome
of particular individuals may prove to be critical in
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14 INFECTION AND IMMUNITY

PATHOGEN NON-PATHOGEN concerned with the immune response, clearly reflect

the selection pressure provided by infection. Before
1. Encounter 1. Encounter the development of antibiotics and immunization at
F least 50% of deaths were attributable to infection (this
Transition is still the case in many resource-poor countries). Nev-
2. Entry/establishment 2. Entry/establishment ertheless, owing to our inherent and highly efficient
A B defence mechanisms, many infections resolve without
medical intervention. All doctors must have some skill
Colonization
in recognizing those infections for which an interven-
tion is unnecessary. This is particularly important in
C
Normal the case of antibiotic use because of the dangers of
microbiota encouraging resistance.
D

Infection (asymptomatic)
3. Spread
E
Increasing
4. Survival/
damage/
dysfunction
multiplication
5. Damage
6. Outcome
Infective disease (symptomatic)
Fig. 14.1  Pathways to and stages of infection following encounter
between a host and a micro-organism. The blue sector includes the
possible outcomes for a pathogen, the yellow a non-pathogen, and the
green either of these. An organism detected in a diagnostic laboratory
might reflect one or more of the stages identified, including transition.
The possibility of transition from yellow to blue zones reflects the lack
of a rigid division between pathogen and non-pathogen, and one aspect
of opportunism. Detection in a diagnostic laboratory is most likely
following colonization or multiplication. Infection may become apparent
as a result of many different pathways: A, directly, without any
colonization phase; B, many pathogens colonize first then proceed to
infection either C after a brief period of colonization or D after a
sustained period in which they live as commensals as part of the
normal microbiota (progression here is not inevitable). Note that
infection becomes symptomatic only when the level of damage or
dysfunction is sufficient. At the end of the symptomatic infection a
small number of pathogens may enter the normal microbiota (E) and
the convalescent host is then described as a carrier for the organism
concerned. F, Some organisms may simply be passing through and form
no stable association with the host.
PATHOLOGICAL PATTERNS ASSOCIATED
WITH INFECTION
All of the foregoing reflects a set of proposed mecha-
nisms that, by and large, fit and make sense of the
available facts concerning the epidemiology and
detailed pathogenesis of infection. In this section the
link to clinical practice is developed by describing the
pattern of pathology directly observable in various
infections. Most infections can be placed into one of
four patterns:
1. Toxin mediated (mainly bacterial).
2. Acute (including acute viral syndromes and acute
pyogenic bacterial infections).
3. Subacute (many virus and several ‘atypical’
bacterial infections).
4. Chronic (chronic viral infections, chronic
granulomatous bacterial, fungal and parasitic
infections).
Simply by recognizing the basic characteristics of a
suspected infection against these four possibilities, the
possible range of causal agents can be narrowed down
substantially. Their features are summarized and
exemplified from the perspective of bacterial infec-
tions in Table 14.2.

Toxin-mediated bacterial infections

the balance between health and disease. As noted
earlier, culture methods have only been able to reveal
a minority of the bacterial species present in different
samples and there is considerable excitement at the
potential yield of a project to characterize all the
organisms present by nucleic acid sequencing in
the Human Microbiome Project.
The survival of humankind to the present day
reflects the fact that most untreated infections are not
fatal. Indeed, many human genes, particularly those
This was the first recognized pathogenic mechanism
in bacterial infection and resulted in early successful
therapeutic and preventive measures. When a single
toxin is responsible for most of the features of an
infection, the dysfunction or damage is often distant
from the site of bacterial multiplication, the disease
may be reproduced by administration of the pure
toxin alone and it can be prevented with antibodies
directed against the toxin. The clostridial diseases
tetanus and botulism are toxin-mediated. In the latter

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 The natural history of infection 14

Table 14.1  Normal human microbiotaa

Locationb Compositionc Abundanced

Dry skin (face, forearm) Gram-positive anaerobes (e.g. propionibacteria) 102

Moist skin (axilla, groin) Staphylococci (esp. coagulase negative); corynebacteria; Gram-negatives rare but more frequent 106–7
after prolonged hospital stay
Oropharynx Anaerobes; streptococci; neisseria; candida 109
Small intestine Anaerobes, lactobacilli, peptostreptocccus, porphyromonas 105–7
Large intestine Anaerobes, clostridium, bacteroides; enterobacteria; enterococci, candida, protozoa 109–11
Vagina Anaerobes, lactobacillus; streptococci, candida 108–9

a
The term microbiota is preferred to ‘flora’ as the latter refers back to a period when bacteria were classified with plants.
b
These are extremely broad. In practice each micro-niche in the body constitutes a different environment colonized with different organisms;
for example, the microbiota associated with the lumen and the mucosa of the gut are different.
c
A very rough introductory guide. Note the predominance of anaerobes.
d
Per square centimetre of surface or gram of fluid.

Table 14.2  Patterns in the presentation and pathology of bacterial infection

Pattern Examples

Toxin-mediated disease
Pathology often distant from site of bacterial growth Diphtheria, tetanus
Protective immunity may be mediated by anti-toxin antibodies alone Staphylococcal food poisoning, cholera
Disease may be fully reproduced by administering the toxin alone Pseudomembranous colitis

Acute pyogenic infection

Generally rapid growing organisms Streptococcal pharyngitis
Interaction with innate immune system and acute inflammation Staphylococcal abscess, bacterial meningitis, lobar pneumonia,
predominates acute cystitis
Where immune damage occurs, it is ‘post-infective’ Post-streptococcal glomerulonephritis

Subacute infection
No pattern to growth rate Subacute bacterial endocarditis
Site of infection may be only partially accessible to the immune system ‘Atypical’ pneumonia
Immunopathology often in parallel with direct effects of organism

Chronic (granulomatous)
Bacterial growth rate often moderate or slow Tuberculosis, brucellosis
Organisms often survive and grow intracellularly
Immune damage occurs with infection – predominantly cell mediated (Some fungal and parasitic infections have this pattern)

case, as in several other forms of food poisoning,
ingestion of only the toxin is required, so many cases
of botulism are not strictly infections. Once the patho-
gen has grown and produced toxin, the onset of
disease can be very rapid.
It is often possible to abolish the biological activity
of toxins without affecting their immunogenicity.
Such toxoids were among the first effective immuniza-
tions against bacterial infection. Diphtheria and
tetanus toxoid vaccines have controlled these infec-
tions in the UK. In life-threatening toxin-mediated
disease, the administration of pre-formed antibodies
can be life-saving. Antibiotics are not effective in
treating established disease, but may prevent further
toxin formation. In the special case of Escherichia coli
O157 infections, however, some antibiotics actually
stimulate further synthesis of toxin.
Acute pyogenic bacterial infections
Pyogenic means pus inducing. Pus is composed
primarily of live and dead neutrophil polymorphs.
The presence of pus generally reflects an acute inflam-
matory process and activation of the innate immune
system. The inflammatory process may be localized,
as in the formation of an abscess, or more diss­
eminated through tissue planes. Anything more
than a trivial acute pyogenic infection is usually

171
14 INFECTION AND IMMUNITY
accompanied by an increase in the blood neutrophil
count. The acuteness of these infections is reflected in
their rapid onset. Accordingly the bacteria that cause
them generally grow rapidly, producing visible colo-
nies within 24 h of inoculation. Medical intervention
is most effective when given early in infection before
the development of acquired immunity, which, when
successful, terminates the illness. Serological evidence
of acquired immunity cannot be used in the diagnosis
of infection during its acute phase. Occasionally,
immunopathology occurs after the causal organism is
no longer detectable in the host; classic examples are
poststreptococcal glomerulonephritis and rheumatic
fever. Similarly, Guillain-Barré syndrome, a paralytic
disease, sometimes follows acute campylobacter
infection.
Many bacteria that cause acute pyogenic infections
also produce toxins. Thus there may be both acute
pyogenic and toxin-mediated components to the
damage and dysfunction that develops. This is par-
ticularly true of staphylococcal and streptococcal
infections. The complex mixture of the pathogenic
processes attributable to different virulence determi-
nants can make the most severe of these infections
very difficult to treat.
Subacute bacterial infections
These have a more insidious onset than acute infec-
tions and are accompanied by less prominent signs of
acute inflammation. Classically, bacterial endocar­
ditis was described as subacute, although this is no
longer considered a suitable catch-all term for this
type of infection. Because such diseases have a more
protracted course, the adaptive immune response
often contributes to damage. Hence subacute forms
of bacterial endocarditis are often accompanied by
immune complex-mediated pathology, whereas Myc-
oplasma pneumoniae infection (a form of atypical
pneumonia) may be accompanied by several different
immunopathological reactions reflecting specific
immune responses (see Ch. 41).
Chronic granulomatous bacterial infections
When bacterial infections persist over months or even
years they tend to elicit a pathological entity known
as a granuloma. Granulomas are a common form of
localized cell-mediated immune response directed to
antigens or other foreign bodies that appear to be
refractory to elimination from tissues. An ordered
accumulation of lymphocytes and macrophages
occurs around a central focus in a manner that, to
the experienced pathologist, can be more or less
172
specific to the eliciting stimulus. Persisting bacterial
infections, notably those due to mycobacteria (e.g.
tuberculosis) and, to a lesser extent Brucella spp.,
produce chronic granulomatous infections. The
agents concerned are generally slow growing and have
the capacity to survive inside host cells, notably mac-
rophages. Cell-mediated immunopathology (delayed-
type hypersensitivity; see Ch. 9) is a prominent feature
of these infections.
Timing of key events in infection
As different infections proceed at different rates, the
timing of the symptoms, their relation to immune
responses and the ability to detect the causal agent all
vary. The incubation period, the time between the
encounter with the pathogen and the onset of symp-
toms, is an important practical consideration in
understanding and managing infection. This is char-
acteristic for different pathogens and can be vital in
determining whether an individual is still at risk of
developing disease after exposure to a particular
agent. Incubation periods for the four patterns of
infection discussed above are illustrated in Figure
14.2, along with the time-frames over which immune
responses and presence of the pathogen are expected.
A more dynamic view of individual infections is
shown in Figure 14.3, in which the additional con-
cepts of recurrent, latent and reactivated infections
are illustrated. Figure 14.3 introduces the notion that
the progression of an infection is related to the
numbers of the pathogen. Although many other
Minutes Hours Days Weeks Months Years
Presence of organism
Incubation period
Acute
Innate immune response
Adaptive immune response
Subacute
Chronic
Anaphylaxisa
Boxes denote
Acute toxinosis onset and duration
of symptoms
Fig. 14.2  Timescales for key events in infection.
a
Anaphylaxis is included for comparison and to illustrate the timescale
when the adaptive immune response is primed against the antigen(s)
concerned.
 The natural history of infection 14

100
Incubation 80
Organism no. (log scale)

% affected
period 60
40
20 ID50
0
Log dose of organisms

Fig. 14.4  Quantitative relationships between organism dose and

outcome in experimental infection. The organism has been administered
by a single route to a uniform host population. Note that the outcome
(percentage affected – which could be percentage infected, percentage
Organism no. (log scale)

who died or many other endpoints) depends on the dose. This approach
allows virulence to be compared between strains of a particular
micro-organism. A more virulent organism shifts the curve to the left
(blue curve) and a less virulent organism to the right (red curve). Lesser
or greater host resistance would, respectively, have the same effect. The
approach allows for the specific recognition of virulence determinants
and the effects of immunization. The dose required to produce the
specified endpoint in 50% of the target population is often reproducible
and can be used for statistical comparisons. The 50% infected endpoint
is known as the ID50.
Organism no. (log scale)

system to resist. Accordingly, when the immune

system is suppressed, progression may be exception-
ally rapid and the response must be equally so.

VIRULENCE AND INFECTIVITY

Encounter/establishment
Asymptomatic infection
Death
Recovery
Threshold for symptoms
Fig. 14.3 A model for incubation periods, progression and latency
related to organism number.
factors are involved, the concept is useful because it
illustrates how, in some rapidly developing infections,
the interval between the onset of symptoms and death
may be short. The slope of increasing pathogen
numbers clearly also reflects the balance between
growth of the pathogen and the efforts of the immune
Time By now it should be apparent that what makes a
Recurrent symptoms pathogen more or less virulent is, in most cases,
Latent infection extremely complex. None the less, when infections can
Reactivation be studied in animal experimental systems, virulence
can be seen as a quantifiable property. As the dose
administered to a group of susceptible hosts is
increased, the number acquiring infections also
increases in a fairly well defined dose–response rela-
tionship (Fig. 14.4). Not only does recognition of this
relationship help explain why, when a group of indi-
viduals is exposed to a pathogen only some get
infected, it also provides a framework for understand-
ing the effects of immunization and immune defi-
ciency, as well as a systematic basis for identifying
individual traits that contribute to virulence and host
resistance.

RECOMMENDED READING

Burnet FM: Natural History of Infectious Diseases, Cambridge, 1970, Salyers AA, Wilson BA, Whitt DD: Bacterial Pathogenesis: A Molecular
Cambridge University Press. Approach, ed 3, Washington, DC, 2011, ASM Press.
Ewald PW: Evolution of Infectious Disease, USA, 1996, Oxford University
Press.
Mims C, Nash A, Stephen J: Mims’ Pathogenesis of Infectious Disease, ed
Websites
5, London, 2000, Academic Press. The Human Microbiome Project: http://commonfund.nih.gov/hmp/

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