International Journal of Food Microbiology 74 (2002) 177 – 188

www.elsevier.com/locate/ijfoodmicro

The physiology of Campylobacter species and its relevance

to their role as foodborne pathogens
Simon F. Park*
School of Biomedical and Life Sciences, University of Surrey, Guildford, GU2 7XH, UK

Accepted 1 July 2001

Abstract

Campylobacter jejuni and C. coli are recognised as the leading causes of bacterial foodborne diarrhoeal disease throughout
the development world. While most foodborne bacterial pathogens are considered to be relatively robust organisms, as a
consequence of the necessity to survive the inimical conditions imposed by food processing and preservation, Campylobacter
species have uniquely fastidious growth requirements and an unusual sensitivity to environmental stress. Campylobacters also
lack many of the well characterised adaptive responses that can be collerated with resistance to stress in other bacteria. The aim
of this review is to outline the unusual physiology of campylobacters (C. jejuni and C. coli) and to describe how this influences
their role as foodborne pathogens. D 2002 Elsevier Science B.V. All rights reserved.

Keywords: Campylobacter jejuni; C. coli; Stress response; Physiology

1. Introduction bacterial foodborne diarrhoeal disease throughout the

Members of the genus Campylobacter have been
recognised as agents of disease for nearly a century.
Intriguingly, the first observation of these pathogens
may even date to 1886, if the uncultivable Campylo-
bacter-like organisms isolated from the colons of
infants by Escherich in this year were indeed repre-
sentatives of this genus. It is remarkable then that it
was not until 1972 that certain campylobacters were
recognised as significant causes of foodborne illness
(Dekeyser et al., 1972). Since this date, however,
following the introduction of active monitoring, the
incidence of disease due to these bacteria has increased
annually and, today, as we start a new millennium,
campylobacters are recognised as the leading cause of
*
Tel.: +44-1483-879024; fax: +44-1483-300374.
E-mail address: s.park@surrey.ac.uk (S.F. Park).
developed world. In England and the United States,
Campylobacter species are isolated from about 5% of
patients with diarrhoea and the annual incidence of
infection is estimated to be 50/100,000, an isolation
rate which even exceeds that reported for Salmonella
species (Skirrow, 1987). Whilst the genus Campylo-
bacter comprises 15 species, 12 of which have been
associated with human disease (Lastovica and Skir-
row, 2000), Campylobacter jejuni and C. coli together
account for over 95% of Campylobacter infections in
humans and, accordingly, are the only campylobacters
considered here.
Most foodborne bacterial pathogens are considered
to be relatively robust organisms, as a consequence of
the necessity to survive the inimical conditions
imposed by both food processing and the application
of food preservation practices. In this context, Cam-
pylobacter species appear to be unlikely foodborne

0168-1605/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 1 6 8 - 1 6 0 5 ( 0 1 ) 0 0 6 7 8 - X
178 S.F. Park / International Journal of Food Microbiology 74 (2002) 177–188

pathogens since amongst this category of pathogen, C.
jejuni and C. coli possess uniquely fastidious growth
requirements and an unusual sensitivity to environ-
mental stress. In this context, campylobacters appear
to lack many of the adaptive responses that can be
correlated with resistance to stress in other foodborne
pathogens (Table 1; Park, 2000). The aim of this
review, therefore, is to outline the unusual physiology
of campylobacters (C. jejuni and C. coli) and to
highlight how this influences their role as foodborne
pathogens.
2. Campylobacters in the food supply
2.1. A uniquely sensitive foodborne bacterial patho-
gen
When observed under a microscope, C. coli and C.
jejuni are slender, spirally curved, Gram-negative rods
with a characteristic corkscrew-like darting motility.
Compared to other foodborne bacterial pathogens, the
growth conditions required for the culture of campy-
lobacters are unusual and this places unique limitations

Table 1
The distribution of key orthologues from pathways responsible for resistance to environmental stress in C. jejuni and model bacterial species
Protein Function Presence in:
C. jejuni E. coli B. subtilis
Oxidative stress
SoxRS Positive regulators of the response to superoxide stress +
OxyR Positive regulator of the response to peroxide stress +
PerR Negative regulator of the response to peroxide stress + + +
SodB or SodF Iron cofactored superoxide dismutase + + +
SodA Manganese cofactored superoxide dismutase + +
KatA or KatE HPII, catalase + + +
KatG HPI, catalase +
AhpC Alkyl hydroperoxide reductase + + +

Osmoregulation
ProP Low-affinity uptake of proline/glycine betaine + + +
ProU or OpuC High-affinity osmoregulatory uptake of compatible solutes + +
OtsAB Osmoregulatory trehalose synthesis +
BetAB or GbsAB Osmoregulatory choline – glycine betaine synthesis pathway + +

Stationary phase/starvation
CsrA Carbon storage regulator + + +
RpoS General stress/stationary phase sigma factor in Gram-negative bacteria +
SigB General stress sigma factor in Gram-positive bacteria +

Heat and cold shock

RpoH Alternative sigma factor regulating the heat shock response +
HspR Negative regulator of the heat shock response +
HrcA Negative regulator of the heat shock response +
GroELS, DnaJ, DnaK and Lon Heat shock proteins + + +
CspA Major cold shock protein + +

Quorum sensing
LuxI Homoserine lactone synthesis
LuxS Autoinducer 2 synthesis protein + + +
ComQX Peptide pheromone synthesis +
PhrC CSF, extracellular signalling pentapeptide synthesis +

Global regulation
Lrp Global regulator of metabolism + +
Crp/Fnr Catabolite gene activator or anaerobic regulatory protein + + +
 S.F. Park / International Journal of Food Microbiology 74 (2002) 177–188
on the range of food environments in which the species
can multiply. For example, the organisms are generally
considered to be microaerophilic, that is they are un-
able to grow in the presence of air and grow optimally
in atmospheres containing 5% oxygen. In addition,
campylobacters have a restricted temperature growth
range and whilst they grow optimally at 42
C, the
organisms do not grow at temperatures below 30
C.
These two growth characteristics place severe restric-
tions on the ability of campylobacters to multiply
outside of an animal host and, consequently, unlike
most other bacterial foodborne pathogens, these bac-
teria are not normally capable of multiplication in food
during either processing or storage.
Campylobacters are also highly susceptible to a
number of other environmental conditions and are
generally less able to tolerate environmental stress
than other foodborne pathogens. Thus, whilst certain
other foodborne pathogens, such as Listeria mono-
cytogenes, are characteristically tolerant to drying
(Wong, 1998), campylobacters are very sensitive to
desiccation and accordingly do not survive well on
dry surfaces (Fernandez et al., 1985). Similarly, cam-
pylobacters are more sensitive to osmotic stress than
other bacterial foodborne pathogens and will not grow
in concentrations of sodium chloride of 2% (Doyle
and Roman, 1982). For comparison, Salmonella typhi-
murium and L. monocytogenes will grow in concen-
trations of sodium chloride of 4.5% and 10%,
respectively (ICMSF, 1996). Again, when compared
to other foodborne pathogens, campylobacters exhibit
greater sensitivity to low pH, the organisms being
incapable of growth below pH 4.9 and being killed
readily at pH values less than this (Blaser et al.,
1980a). Finally, despite being thermophilic in their
growth requirements, C. jejuni and C. coli are also
sensitive to exposure to high temperatures and, con-
sequently, the organisms will not survive in food that
has been pasteurised or adequately cooked.
2.2. The major vehicles for foodborne transmission
In humans, Campylobacter infections are consid-
ered primarily to be the result of the ingestion of
contaminated foods of animal origin although an
unknown number of human illnesses may be a con-
sequence of infections associated with pet animals or
surface waters. The vast majority of infections are
179
sporadic cases and large community outbreaks are rare
but have been associated with the consumption of raw
milk and untreated water (Tauxe, 1992).
Much of the world’s poultry production is conta-
minated with campylobacters and this is reflected in
the high isolation rate for these pathogens reported for
poultry products sold in major supermarket outlets.
For example, in the US, 69% of chickens bought from
a local supermarket were found to be contaminated
with C. jejuni (Willis and Murray, 1997) and levels of
contamination may vary between 102 and 105 CFU
per carcass (Jacobs-Reitsma, 2000). Given that C.
jejuni has a reported infective dose of just 500 CFU,
in some instances (Black et al., 1988), it is perhaps not
surprising that epidemiological studies have revealed
a strong association between Campylobacter infection
and the handling and eating of raw or undercooked
poultry (Friedman et al., 2000). Accordingly, in most
industrialised nations, the main infective route for C.
jejuni to man is considered to be through the con-
sumption of undercooked poultry. Foods tainted by
cross-contamination may also represent a significant
source of infection since campylobacters have been
found to contaminate multiple sites within domestic
kitchens following the preparation of raw chicken
(Cogan et al., 1999). Consequently, once poultry
harbouring these pathogens is introduced into the
kitchen, it has the potential to serve as a focal point
for gross contamination.
2.3. The nature of the association with poultry and
physiological adaptation to this host
Many domestic and wild animals such as poultry,
swine, sheep, cattle, dogs and cats carry campylo-
bacters in their gastrointestinal tracts without display-
ing any of the overt symptoms associated with the
disease in humans (Blaser et al., 1980b). Consequently,
the gastrointestinal tract of certain warm-blooded ani-
mals is thought to be the natural habitat and environ-
mental reservoir of Campylobacter species. In
particular, birds, and especially poultry, are regarded
as the primary reservoir for C. jejuni and the organism is
generally considered to be a commensal in these hosts.
When poultry is inoculated with campylobacters
experimentally, colonisation is found largely in the
ceca, large intestine and cloaca and is generally
restricted to the intestinal mucous layer in the crypts
180 S.F. Park / International Journal of Food Microbiology 74 (2002) 177–188
of the intestinal epithelium at these locations (Beery et
al., 1988). This represents a highly specialised envi-
ronment but it is now evident that C. jejuni has
evolved specialised strategies that allow it to exploit
this restricted ecological niche. For example, the
optimal growth temperature of the organism (42
C)
mirrors that of the avian gut and this differs consid-
erably from that encountered in the mammalian gut
(37
C). It has long been recognised that motility is
necessary for the intestinal colonisation of animals by
campylobacters since nonmotile mutants are incapable
of establishing infection (Morooka et al., 1985).
Indeed, it would seem that the mechanism of motility
has evolved specifically to enable campylobacters to
colonise competitively the mucous layer of the gastro-
intestinal tract of animals. In this context, the polar
flagellum and the spiral shape of Campylobacter
species endow the cells with a characteristic rapid
darting corkscrew-like motility. This features enables
campylobacters to remain motile in mucous, a highly
viscous environment which rapidly paralyses other
motile rod-shaped bacteria (Ferrero and Lee, 1988;
Shigematsu et al., 1998). In addition, chemotactic
mechanisms also attune campylobacters to a life in
this environment since the organisms are attracted
towards mucin and more specifically fucose, a con-
stituent of mucin (Hugdahl et al., 1988). Conse-
quently, any colonising organisms would be able to
readily associate with intestinal mucus. The impor-
tance of this mechanism in colonisation is exemplified
by the fact that fully motile but nonchemotatic
mutants do not colonise the intestines of animal
models (Takata et al., 1992).
The ability of C. jejuni to become established in
the gastrointestinal tract of chickens is believed to
involve binding of the bacterium to its surface cells.
The outer membrane protein CadF, which facilitates
the binding of campylobacters to fibronectin, is
thought to be responsible for this since a deficient
mutant is incapable of colonising the cecum of newly
hatched chicks (Ziprin et al., 1999). Other facets of
the physiology of campylobacters also point to the
fact that the organism has evolved to occupy the
mucous layer of the gastrointestinal tract. Firstly, their
microaerophilic nature is probably a reflection of the
concentration of oxygen encountered in this niche.
Secondly, competition for essential nutrients amongst
the bacterial community within the gastrointestinal
tract is likely to be intense and it appears that
campylobacters have evolved mechanisms to allow
them to compete successfully in this environment.
Iron is such an essential nutrient, which will have
limited availability within the gut. As a consequence,
campylobacters have evolved mechanisms to acquire
iron from both the host and the gastrointestinal flora.
For example, the organisms are able to utilise the host-
derived iron compounds haemin and haemoglobin
(Pickett et al., 1992). Siderophores are high-affinity
iron compounds synthesised by a variety of patho-
genic bacteria, which enable the pathogen to compete
for this nutrient when it is limiting or withheld by host
iron binding proteins. Whilst some strains of Campy-
lobacter may produce siderophores (Field et al.,
1986), intriguingly others do not, yet have transport
systems which enable them to scavenge siderophores,
such as enterochelin, that have been generated by
other gastrointestinal bacteria (Baig et al., 1986;
Richardson and Park, 1995).
3. Physiological mechanisms influencing the
survival of campylobacters in foods and the
environment
3.1. The response to low temperature
Campylobacters are unable to grow below 30
C
and, consequently, in moderate climates will not
actually multiply during handling or storage at room
temperature. Nevertheless, temperature impacts dra-
matically on the survival of campylobacters in food
and, generally, survival is greater at temperatures
below room temperature. Consequently, the response
of these organisms to low temperatures has been
studied in some detail and unlike other microorgan-
isms, which show a gradual reduction in growth rate
near the minimal growth temperature, C. jejuni shows
a dramatic and sudden growth rate decline near the
lower temperature limit (Hazeleger et al., 1998). What
actually limits the growth of campylobacters at low
temperatures is not known at present. However, whilst
many bacteria produce characteristic cold shock pro-
teins and these are associated with their ability to
replicate at temperatures below the optimum growth
temperature (Phadtare et al., 1999), an analysis of the
C. jejuni genome sequence (Parkhill et al., 2000)
 S.F. Park / International Journal of Food Microbiology 74 (2002) 177–188
indicates that campylobacters do not produce this type
of cold shock protein. This, in part, may explain the
failure of these pathogens to grow below 30
C.
Although incapable of replication at temperatures
normally associated with food storage, C. jejuni is
metabolically active at temperatures far below its
minimal growth temperature and is able to perform
respiration and generate ATP at temperatures as low
as 4
C. Furthermore, whilst replication at this temper-
ature is not possible, the organism is still fully motile
and thus retains the capacity to move towards favour-
able environments (Hazeleger et al., 1998). At even
lower temperatures, viability is rapidly lost and al-
though campylobacters can still be isolated from
frozen meats and poultry products (Fernandez and
Pison, 1996), freezing significantly reduces their sur-
vival (Humphrey and Cruickshank, 1985). Whilst
several factors, including ice nucleation and dehydra-
tion, have been implicated in the freeze-induced injury
of bacterial cells, more recently oxidative stress has
been shown to contribute to the freeze –thaw induced
killing of campylobacters (Stead and Park, 2000).
3.2. The response to elevated temperatures
Although thermophilic in growth requirement,
campylobacters are sensitive to heat and readily in-
activated by pasteurization treatments and domestic
cooking processes. The physiological events that take
place during adaptation to elevated temperature are
well documented from studies with other bacteria but
far from resolved for campylobacters. Bacterial cells
exposed to temperatures above that which is optimal
for growth generally respond by eliciting a heat shock
response involving the synthesis of proteins able to
act as ATP-dependent proteases. Since these have
roles in the degradation or stabilization of abnormal
proteins, this response is considered to be an impor-
tant homeostatic mechanism that enables bacterial
cells to survive a heating and a variety of environ-
mental stresses (Arsene et al., 2000). At least 24
proteins are preferentially synthesized by C. jejuni
immediately following heat shock (Konkel et al.,
1998) and some have been identified as GroELS,
DnaJ, DnaK and Lon protease (Konkel et al., 1998;
Thies et al., 1998, 1999a,b). An analysis of the C.
jejuni genome sequence reveals the presence of a
number of additional heat shock proteins, for example
181
HrcA, GrpE, and HspR (Parkhill et al., 2000). The
recent finding, that dnaJ mutants are severely retarded
in growth at 46
C and also unable to colonize
chickens suggests that the heat shock response plays
an important role in both thermotolerance and colo-
nisation (Konkel et al., 1998).
Whilst it is clear that campylobacters are able to
elicit a heat shock response similar to that observed in
other bacteria, the regulatory mechanisms governing
this response have not yet been studied in detail. From
an analysis of the genome sequence (Parkhill et al.,
2000), it is clear that the Escherichia coli heat shock
regulatory s-factor s32, sB and CtsR, the regulators of
Bacillus subtilis Class II and Class III heat shock
genes, are all absent from C. jejuni. There are, how-
ever, potentially three alternative regulatory systems
controlling the induction of the heat shock response in
C. jejuni. The RacRS regulon, previously character-
ized as a two component regulatory system, is
required for the differential expression of proteins at
37 and 42
C (Bras et al., 1999). Furthermore, since
the genome sequence has also revealed the presence
of orthologues of HrcA and HspR, negative regulators
of the heat shock response in B. subtilis (Schulz and
Schumann, 1996) and Streptomyces coelicolor (Bucca
et al., 1997), respectively, these proteins are also
likely to regulate some aspects of the heat shock
response in C. jejuni. Putative consensus recognition
sequences for HrcA binding have been identified
upstream of the groESL and dnaK operons of C.
jejuni (Thies et al., 1999a,b) providing further support
for a regulatory role for the HcrA orthologue.
3.3. The response to stationary phase and starvation
In other bacterial species, entry into the stationary
phase and/or starvation is accompanied by profound
structural and physiological changes that result in
increased resistance to heat shock, oxidative, osmotic
and acid stress (Rees et al., 1995). For many foodborne
pathogens, this adaptive process has an important
bearing on the ability of the organisms to survive the
physical challenges encountered during food process-
ing. The central regulator for many of these stationary
phase induced changes in a number of Gram-negative
bacteria is the s-factor RpoS, which, accordingly, is
critical for the survival of the bacterial cell in stationary
phase and following exposure to many types of envi-
182 S.F. Park / International Journal of Food Microbiology 74 (2002) 177–188
ronmental stress (Loewen et al., 1998). A reflection of
the importance of RpoS in regulating the response of
bacteria to stationary phase and stress is its widespread
occurrence in a diverse range of bacterial species.
Accordingly, to date, RpoS homologues have been
found in most Enterobacteriaceae, Pseudomonas spe-
cies, Vibrio species and Legionella pneumophila. An
analysis of the C. jejuni NCTC 11168 genome
sequence (Parkhill et al., 2000), however, indicates
that RpoS is absent from this organism and this raises
the possibility that, unlike the situation observed in
other Gram-negative bacteria, campylobacters do not
elicit an RpoS-mediated phenotypic stationary phase
response. Support for this contention comes from the
recent observation that stationary phase cultures of C.
jejuni are actually more sensitive to mild heat stress
and oxidative stress than those containing exponential
phase cells (Kelly et al., 2001). Furthermore, in view
of the increased sensitivity of cells from this growth
phase (Kelly et al., 2001), it seems unlikely that there
is an alternative regulator responsible for generating
stationary phase resistance, at least in the strains of C.
jejuni studied to date.
In the absence of a recognizable phenotypic
response to stationary phase, it is possible that some,
if not all strains, of campylobacters have evolved an
alternative strategy to promote survival that involves
genetic variation. When cultures containing aging
cells of E. coli have been studied over prolonged
periods, the populations of surviving cells have been
shown to be highly dynamic (Finkel and Kolter,
1999). In this situation, mutation in a small subpo-
pulation of cells gives rise to alleles able to confer a
competitive advantage in the prevailing environment.
Subsequently, the culture is taken over by the indi-
viduals which posses the advantageous mutations. In
particular, mutants of increased fitness and which
have a growth advantage in stationary phase have
been associated with loss of function of both RpoS
(Zambrano et al., 1993) and Lrp, the global regulator
(Zinser and Kolter, 1999). Although C. jejuni lacks
both RpoS and Lrp (Parkhill et al., 2000), a similar
process, which results in the evolution of fitter
mutants, may operate in this species. In this context,
fluctuating changes in the heat resistance of aging
cultures of C. jejuni have been associated with the
emergence of new subpopulations expressing a
growth advantage in the stationary phase (Kelly et
al., 2001). Although the nature of the genetic varia-
tion in these cells is not known at present, the
prolonged incubation of campylobacters in stationary
phase has been shown to result in the generation
variant of cell types with altered motility (Park et al.,
2000) and decreased ability to from cocci (Kelly et
al., 2001). Thus, in the absence of a phenotypic
stationary phase response, cultures of C. jejuni in
this growth phase may represent dynamic populations
of variant cell types and for some Campylobacter
strains at least, this may offer an alternative mecha-
nism for promoting continued survival.
An analysis of the genome of C. jejuni gives some
insight into the mechanisms that may govern the
generation such genetic variation. The genome of this
organism is unusual in that it contains as many as 25
homopolymeric tracts (Parkhill et al., 2000). Since
these stretches of single base residues are hot spots
for frameshift mutation, their presence allows gene
expression to be turned on and off by high-frequency
mutation (Saunders et al., 1998, 2000). In this context,
high-frequency mutation at a homopolymeric tract in
the flhA gene of C. coli has been shown to result in the
accumulation of nonmotile variants during prolonged
exposure to stationary phase (Park et al., 2000). Thus,
a generalized mechanism that allowed high-frequency
mutation at such sites distributed around the genome
could explain the formation of the variant cell types in
aging populations of campylobacters.
3.4. The response to oxidative stress
Exposure to oxygen, whilst inevitable for bacterial
pathogens, leads to the formation of reactive oxygen
intermediates (ROIs), such as superoxide radicals. If
these highly reactive agents are not neutralized, then
lethal damage to nucleic acids, proteins and mem-
branes may ensue. Consequently, as a response
against distinct ROIs excesses, many prokaryotic cells
are able induce the synthesis of anti-oxidant enzymes.
The paradigms established in E. coli are the soxRS
regulon, which coordinates the induction of at least 12
genes in response to superoxide or nitric oxide stress
in E. coli (Demple, 1996) and the oxyR regulon,
which coordinates the response of the cell to peroxide
(Storz et al., 1990). Although it is possible to grow
campylobacters in the presence of air under certain
conditions (Jones et al., 1993), the organisms are
 S.F. Park / International Journal of Food Microbiology 74 (2002) 177–188
generally considered to be microaerophilic implying
an inherent sensitivity towards oxygen and its reduc-
tion products. Consequently, cellular defences against
the damaging effects of oxidative stress play an
important role in the survival of these bacteria during
exposure to air.
A number of enzymes, such as superoxide dis-
mutase (SOD) (Purdy and Park, 1994; Pesci et al.,
1994; Purdy et al., 1999), alkyl hydroperoxide reduc-
tase (Ahp) (Baillon et al., 1999), and catalase (KatA)
(Grant and Park, 1995), play roles in the oxidative
defence system of campylobacters. The deleterious
effects of exposure to superoxide radicals are coun-
teracted by the activity of SOD and both C. jejuni
and C. coli possesses a single iron cofactored SOD
(Purdy and Park, 1994; Pesci et al., 1994). This
enzyme has been shown to play a key role in the
defence against oxidative stress and aerotolerance
(Purdy and Park, 1994; Purdy et al., 1999). SOD-
deficient Campylobacter mutants are also less able to
survive in milk, on poultry meat, and to survive
freezing (Purdy et al., 1999; Stead and Park, 2000),
indicating that SOD is an important determinant in
the ability of campylobacters to survive in food.
Furthermore, since mutants lacking this enzyme are
also less able to colonise animal models (Purdy et al.,
1999) and less able to invade mammalian cell in vitro
(Pesci et al., 1994), SOD may also play an important
role during infection.
The key regulators of oxidative stress defence
enzymes in E. coli and S. typhimurium, namely SoxRS
and OxyR, are not present in C. jejuni (Parkhill et al.,
2000), thus the recognition and response to oxidative
stress in this organisms is not mediated by these
archetypal mechanisms. However, an alternative reg-
ulator termed PerR, which has also been identified as a
negative regulator of the peroxide responsive regulon
in B. subtilis (Bsat et al., 1998), mediates at least part
of the response to oxidative stress response in campy-
lobacters since it has been shown to regulate both
AhpC and KatA expression (van Vliet et al., 1999).
3.5. The role of viable nonculturable stages in
survival
As a consequence of environmental stress, certain
bacteria are believed to enter a viable nonculturable
(VNC) state. This novel concept of a bacterium that
183
remains infectious but that can no longer be cultured
by conventional means, was first proposed by Colwell
et al. (Roszak et al., 1984) following a study on the
survival of Salmonella in aquatic systems. In this
state, the bacterium whilst retaining metabolic activity
is not capable of replication on culture medium but
under as yet undefined conditions may revert to full
viability. Clearly, if such a form existed for campylo-
bacters, then it would have important implications for
the environmental transmission of campylobacters
and for detection. A VNC form of C. jejuni was first
reported by Rollins and Colwell (1986) and since
then, there has been continuous debate as to whether a
VNC form for campylobacters actually exists. Given
the fastidious nature of Campylobacter, the loss of
culturability in this organism is relatively easy to in-
duce and occurs following exposure to oxygen,
changes in temperature, and starvation. The viability
of the VNC stage has been largely attributed to the
ability of this form to modify chemical indicators of
viability (Cappelier et al., 1997; Tholozan et al., 1999)
or to the longevity of certain macromolecules follow-
ing the loss of culturability (Lazaro et al., 1999).
Recovery or reversion of the VNC form has been
reported by a number of groups using different animal
models (Saha et al., 1991; Jones et al., 1991; Pearson
et al., 1993) and, more recently, a factor in embryo-
nated eggs has been shown to induce recovery of the
VNC form (Cappelier et al., 1999). In contrast, a
number of studies have failed to induce the recovery
of VNC cells of C. jejuni in animal models (Beumer
et al., 1992; Medema et al., 1992) and these results
have cast doubts on the existence of VNC form.
Recently, however, Tholozan et al. (1999) have dem-
onstrated that only a limited number of isolates are
able to form the VNC stage and, in view of this, it is
possible that the conflicting conclusions regarding the
existence of a VNC form may simply be due to strain
differences.
3.6. The role of coccoid cells in Campylobacter
survival
The decline in viability and loss of culturability that
occurs following exposure of campylobacters to cer-
tain unfavourable environments is often associated
with a change in cell morphology from a spiral rod-
like form into a coccoid form (Buck et al., 1983;
184 S.F. Park / International Journal of Food Microbiology 74 (2002) 177–188
Moran and Upton, 1987). These observations have
given rise to speculation that the coccoid form is in fact
the dormant VNC stage of C. jejuni. However, a
number of studies have suggested that the coccoid
stage is merely a degenerative form that contains de-
creased levels of nucleic acids and peptides and also
lacks cellular integrity (Moran and Upton, 1987;
Beumer et al., 1992; Boucher et al., 1994). Indeed,
mutants that form cocci at dramatically reduced rates
show no overall difference in survival, lending further
support to the notion that the coccoid form is not viable
(Kelly et al., 2001). However, the conclusion that all
coccoid forms are degenerate may be too simplistic
since different types of cocci may form in response to
different temperatures (Hazeleger et al., 1995). Never-
theless, since the formation of cocci is not prevented
by the inhibition of protein synthesis or DNA repli-
cation, whatever the role of the cocci, the process must
be passive rather than an active one requiring de novo
protein synthesis (Hazeleger et al., 1995). More
recently, it has been suggested that the actual VNC
stage is to be found amongst the spiral rod-like
population (Lazaro et al., 1999).
3.7. The response to osmotic stress
Campylobacters are much less tolerant of osmotic
stress than other bacterial foodborne pathogens
(Doyle and Roman, 1982) and this may be a reflec-
tion of their limited capacity to respond to osmotic
stress. Long-term resistance to osmotic stress in other
bacteria has been correlated with mechanisms for the
synthesis or transport of compatible solutes (Kempf
and Bremer, 1998). It is clear from an analysis of the
C. jejuni genome sequence (Parkhill et al., 2000) that
whilst this organism may possess an orthologue of
ProP, a low affinity transporter for proline and glycine
betaine (Cairney et al., 1985), it does not possess any
previously characterised high-affinity transporters for
known compatible solutes such as the ProU system
for betaine transport (Stirling et al., 1989). In addi-
tion, campylobacters would also appear to lack the
capacity to synthesise compatible solutes by known
pathways since they lack the osmoregulatory betaine
(Lamark et al., 1991) and trehalose (Strom and
Kaasen, 1993) biosynthetic pathways seen in other
bacteria. In conclusion, the limited capacity for the
accumulation of compatible solutes may explain the
apparent sensitivity of campylobacters to osmotic
stress.
3.8. Quorum sensing
Quorum sensing, or the control of gene expression
in response to cell density, allows individual bacteria
of numerous species to communicate and coordinate
actions through the production and detection of ex-
tracellular signalling compounds (Bassler, 1999).
Such systems, which allow cell –cell communication,
also play important roles in virulence and the forma-
tion of complex communities of bacteria. Whilst the
genome sequence of C. jejuni does not contain any
gene predicted to encode an acyl homoserine lactone
synthase and, thus, the organism is unlikely to pro-
duce acyl homoserine lactone based signalling mole-
cules, it does contain an orthologue of LuxS. Since
this protein is necessary for the production of a second
class of signalling compounds involved in the quo-
rum-sensing system 2 of a number of bacteria (Surette
et al., 1999), it is likely that C. jejuni too is able to
generate this type of extracellular signalling molecule.
A similar quorum-sensing system pathway has
recently been identified in Helicobacter pylori (For-
syth and Cover, 2000; Joyce et al., 2000) and it has
been postulated that it may play a role in limiting
growth in certain environments. It may also play a
similar role in C. jejuni given the close phylogenetic
relationship between these two groups of organisms.
4. The pathogenesis of Campylobacter infections
Infection with C. jejuni or C. coli can induce a
spectrum of disease symptoms and the pathogenesis
reflects both the susceptibility of the host and the
virulence of the infecting strain. Notably, whilst
infection in developing countries tend to result in
watery diarrhoea, in developed countries, the out-
come of infection is usually acute inflammatory
enteritis. The mechanisms by which campylobacters
induce disease are not clearly understood but on the
basis of experimental evidence, at least two mecha-
nisms for gastrointestinal illness have been postu-
lated: (i) intestinal adherence and toxin production;
(ii) bacterial invasion and proliferation with the in-
testinal mucosa.
 S.F. Park / International Journal of Food Microbiology 74 (2002) 177–188
4.1. Strain-dependent variation in virulence
C. jejuni strains make at least one cytotoxin, the
cytolethal distending toxin (CDT) (Pickett, 2000).
Though the genes encoding this protein seem to be
universally present in this species (Pickett et al.,
1996), the role of CDT in C. jejuni pathogenesis has
not yet been determined empirically. However, the
protein has been shown to cause cultured eukaryotic
cells to become blocked in the G2 phase of the cell
cycle (Whitehouse et al., 1998). If the toxin is
similarly active on rapidly dividing and differentiating
cells within the crypts of the intestine, it could
potentially lead to loss of function or erosion of the
epithelial layer and thereby generate the symptoms of
diarrhoea. Since certain strains still retain some toxi-
genic activity when CDT-negative mutants have been
analysed (Pickett et al., 1996; Purdy et al., 2000), it is
possible that additional toxigenic activities are present
in some strains of C. jejuni. Consequently, it is
apparent that different strains may manifest different
potentials to cause disease. In this context, the effi-
ciency with which campylobacters invade cultured
human cells also varies greatly (Everest et al., 1992;
Harvey et al., 1999) and again this implies strain-
specific differences in virulence. Further emphasis on
strain-dependent variations in virulence can be de-
rived from a recent study which has shown that the
possession of certain plasmids by a small subset of
strains is correlated with increased virulence (Bacon
et al., 2000). Conversely, it is possible that certain
strains of C. jejuni or C. coli may not actually be
capable of causing disease in humans since the dis-
tribution of genotypes from poultry and humans are
not necessarily the same (Korolik et al., 1995; Clow et
al., 1998).
4.2. Genetic heterogeneity
From the above discussion, it is apparent that differ-
ent strains of campylobacters may have very different
abilities to cause disease and this implies that strains
can have important differences in genetic content. In
this context, the publication of the genome sequence
for one strain of C. jejuni, namely NCTC 11168 (Park-
hill et al., 2000), has provided a reference point for
comparing the genetic content of campylobacters
strains. Whilst chromosome heterogeneity in enteric
185
bacteria has resulted from acquisition and deletion of
large segments of DNA with changes in gene order or
small changes being rare (Ochman and Bergthorsson,
1998), already striking differences in the content,
positions and arrangements of mapped genes in strains
of C. jejuni have been characterised (Wassenaar et al.,
2000). The high degree of plasticity in terms of genetic
content and gene order resembles that of H. pylori
(Jiang et al., 1996).
5. Conclusion and perspectives
Campylobacteriosis, being one of the most com-
mon manifestations of bacterial foodborne disease,
has significant social and economic consequences
worldwide. Campylobacters are widespread in warm-
blooded animals used for food production and, con-
sequently, the contamination of meat products, espe-
cially poultry, is a significant risk factor. Whilst there
is an urgent need to address the problem caused by
these organisms, even today after the publication of
the complete genome sequence for C. jejuni NCTC
11168 (Parkhill et al., 2000), the development of
control strategies is hampered by a lack of under-
standing of the physiology and virulence of these
pathogens. However, from the information that we
have derived for these pathogens already, it is clear
that the organisms do not obey many of the physio-
logical paradigms established for model organisms
such as E. coli and B. subtilis (Table 1). The unusual
sensitivity of these organisms is a striking feature
compared to other foodborne pathogens and seems to
reflect an apparent lack of adaptive mechanisms and
a minimal capacity for recognising and responding to
environmental stress. Nevertheless, it is a sobering
thought that, as we start a new millenium, such an
apparently sensitive organism is able to persist in the
food chain and in doing so remains the most common
cause of bacterial foodborne illness.
Acknowledgements
I had the honour to be Gordon’s first ever PhD
student back in 1985. He proved to be a great inspiration
to me and it is with a great deal of fondness that I
remember him.
186 S.F. Park / International Journal of Food Microbiology 74 (2002) 177–188
The author is grateful to the Ministry of Agricul-
ture Fisheries and Food, UK and the Biotechnology
and Biological Sciences Research Council, UK for
funding aspects of the work described here. He would
also like to thank Martin Adams for commenting on
the manuscript.
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