MI NI R E V I E W

Pasteurella multocida pathogenesis: 125years after Pasteur

Marina Harper, John D. Boyce & Ben Adler
Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Department of Microbiology,
Monash University, Melbourne, Australia
Correspondence: Ben Adler, Department of
Microbiology, Monash University, Melbourne
3800, Australia. Tel.: 16 139 905 4815;
fax: 16 139 905 4811;
e-mail: ben.adler@med.monash.edu.au
Received 20 July 2006; revised 15 August 2006;
accepted 15 August 2006.
First published online 11 September 2006.
DOI:10.1111/j.1574-6968.2006.00442.x
Editor: Ian Henderson
Keywords
Pasteurella multocida ; pathogenesis; fowl
cholera; virulence factors.
Abstract
Pasteurella multocida was rst shown to be the causative agent of fowl cholera by
Louis Pasteur in 1881. Since then, this Gram-negative bacterium has been
identied as the causative agent of many other economically important diseases
in a wide range of hosts. The mechanisms by which these bacteria can invade the
mucosa, evade innate immunity and cause systemic disease are slowly being
elucidated. Key virulence factors identied to date include capsule and lipopoly-
saccharide. The capsule is clearly involved in bacterial avoidance of phagocytosis
and resistance to complement, while complete lipopolysaccharide is critical for
bacterial survival in the host. A number of other virulence factors have been
identied by both directed and random mutagenesis, including Pasteurella
multocida toxin (PMT), putative surface adhesins and iron acquisition proteins.
However, it is likely that many key virulence factors are yet to be identied,
including those required for initial attachment and invasion of host cells and for
persistence in a relatively nutrient poor and hostile environment.
Introduction
It has been over 125 years since Louis Pasteur rst identied
that a bacterium was the causative agent of fowl cholera. In
seminal experiments, he also showed that repeated passage of
the bacteria produced an attenuated strain incapable of
causing disease, but the inoculation of birds with this strain
could elicit a protective immune response (Pasteur, 1880,
1881). In this review, we aim to outline the progress that has
been made in understanding this highly versatile pathogen.
Indeed, many of the molecular determinants for virulence are
now identied and understood and we can begin to piece
together many of the steps required for successful infection.
The species Pasteurella multocida is subdivided into four
subspecies that include the type strain, multocida, and three
others, gallicida, septica and the recently described tigris
(Capitini et al., 2002). This review will consider only the
type strain, subspecies multocida. Pasteurella multocida can
cause disease in a wide range of animal species and is the
causative agent of numerous, economically important dis-
eases, including avian fowl cholera, bovine haemorrhagic
septicaemia, enzoonotic pneumonia and swine atrophic
rhinitis (De Alwis, 1992). Pasteurella multocida strains are
classied into serogroups (A, B, D, E and F) based on
capsule antigens and further classied into 16 serotypes
(116) based primarily on lipopolysaccharide antigens using
the Heddleston scheme (Carter, 1955; Heddleston et al.,
1972).
Fowl cholera is a serious disease of poultry and can
present in either acute or chronic forms. The majority of
acute fowl cholera cases are caused by serogroup A strains of
P. multocida. Obvious clinical signs of acute fowl cholera
may not occur until very late in the infection and include
depression, rufed feathers, fever, anorexia, mucous dis-
charge from the mouth, diarrhoea and an increased respira-
tory rate (Rhoades & Rimler, 1989).
Haemorrhagic septicaemia, predominantly caused by
serotypes B and E strains of P. multocida, is an acute disease
that affects cattle and buffalo and is characterized by
oedematous swelling of the head and neck, and swollen
haemorrhagic lymph nodes (Carter & De Alwis, 1989).
Atrophic rhinitis in pigs is caused by strains of P. multocida
that express P. multocida toxin (PMT), and typically belong
to serogroup D. In pigs, the most obvious symptoms include
the shortening and twisting of the snout, dark tear staining
and pneumonia (Chanter & Rutter, 1989). Atrophic rhinitis
rarely causes death, but it is economically important as it
signicantly reduces the growth rate of the infected pigs.
FEMS Microbiol Lett 265 (2006) 110 c 2006 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
Pasteurella multocida can be a primary or secondary agent
involved in pneumonia in cattle (predominantly caused by
serotype A:1), pigs and, occasionally, sheep (Gilmour, 1978;
Chanter & Rutter, 1989; Frank, 1989). Pasteurella multocida
can also infect rabbits resulting in rhinitis (snufes) and
pneumonia (Manning et al., 1989). Although relatively un-
common, human infections have been observed in a range of
sites, commonly following cat or dog bites (Weber et al., 1984).
Of all the diseases caused by P. multocida, fowl cholera is
probably best understood. In birds, it is widely believed that
P. multocida enters the host through tissues of the respira-
tory tract. Adhesion of P. multocida to turkey air sac
macrophages has been demonstrated, and virulent P. multo-
cida inoculated into the upper respiratory tract or trachea of
turkeys can be subsequently detected in internal organs
between 6 and 12 h postinoculation (Rhoades & Rimler,
1990; Matsumoto et al., 1991; Pruimboom et al., 1996,
1999). The mechanisms by which P. multocida invades from
the lungs into the bloodstream are poorly understood,
although a study using heterophil-depleted chickens experi-
mentally infected with P. multocida showed that heterophils
may play a dual role. Initially, recruitment of heterophils
into the lungs led to tissue damage and invasion, but as the
infection progressed, heterophils limited the infection by
promoting clearance of the bacteria from the lungs and
spleen (Bojesen et al., 2004).
Although it has been generally accepted that fowl cholera
is a septicaemic infection, bacteria can only be isolated in
large numbers from the blood of birds very late in infection,
and it has been proposed that this late re-emergence of
blood-borne bacteria is due to the rupture of liver and
spleen phagocytes (Pabs-Garnon & Soltys, 1971). In the
terminal stages of fowl cholera, death is probably caused by
massive bacteraemia and endotoxic shock (Carter, 1967;
Rhoades & Rimler, 1984).
The rst systemic host defence used against most invad-
ing bacteria involves the innate immune system and includes
phagocytosis and bactericidal properties of serum compo-
nents such as complement. However, P. multocida has
mechanisms to evade this system, including the presence of
a capsule (Boyce & Adler, 2000; Chung et al., 2001). Active
immunity against P. multocida infection is mainly humoral;
vaccination of birds with killed P. multocida stimulates
protection against homologous challenge, and opsonization
studies in mice have shown that bactericidal antibodies are
produced (Wijewardana & Sutherland, 1990).
Virulence factors
Capsule
Pasteurella multocida can be classied by serological meth-
ods into ve capsule groups designated A, B, D, E and F. The
composition and structure of the capsular material found in
P. multocida serotypes A, D and F are very similar to
mammalian glycosaminoglycans and consist mainly of hya-
luronan, heparosan and unsulphated chondroitin, respec-
tively (Pandit & Smith, 1993; Rimler, 1994; DeAngelis, 1996;
DeAngelis & Padgett-McCue, 2000). The genes required for
the synthesis and transport of these capsular types are
encoded within a single region on the genome (Townsend
et al., 2001). However, recently, in type A, D and F strains, an
additional gene encoding a heparosan synthase was identi-
ed outside of the known capsule biosynthesis region. The
synthase encoded by this gene, renamed hssB (formerly
pgla), is transcribed 10-fold less than the synthase within
the capsule operon, uses a different acceptor and gives rise to
smaller molecular weight polymer products. It was pro-
posed that the expression of this gene may give rise to
capsular variation (Deangelis & White, 2004).
In general, strains that possess a capsule are more virulent
than their acapsular variants (Heddleston et al., 1964; Snipes
et al., 1987; Tsuji & Matsumoto, 1989). The important role
of capsule in the pathogenesis of P. multocida has been
clearly demonstrated as genetically dened, acapsular mu-
tants constructed from both serogroup A and B strains were
strongly attenuated in mice (Boyce & Adler, 2000; Chung
et al., 2001). The serogroup A acapsular mutant was also
shown to be avirulent in chickens and was unable to
establish growth in chicken muscle (Chung et al., 2001).
Interestingly, despite its apparent lack of persistence, vacci-
nation of chickens with high doses of this acapsular mutant
stimulated protective immunity (Chung et al., 2005).
It is widely accepted that capsule plays a signicant role in
resistance to phagocytosis, and this has been demonstrated
in vitro by Harmon et al. (1991) and others, who have
correlated sensitivity to phagocytosis with the presence and
thickness of the bacterial capsule (Truscott & Hirsh, 1988;
Harmon et al., 1991; Pruimboom et al., 1996). Moreover,
studies using murine macrophages clearly demonstrated
that a genetically dened acapsular serotype B mutant was
more susceptible to uptake than its wild-type parent (Boyce
& Adler, 2000). Resistance to complement-mediated lysis
is clearly important for virulence, and experiments on
P. multocida type A strains have shown that serum resistance
correlates with the possession of a capsule (Snipes & Hirsh,
1986; Hansen & Hirsh, 1989). A genetically dened acapsu-
lar mutant was no longer serum resistant in normal avian
serum compared with the serotype A wild-type parent and
complemented mutant (Chung et al., 2001). In contrast, a
genetically dened, acapsular mutant of a serotype B strain
showed no reduction in serum resistance in either bovine or
murine serum compared with the parent strain (Boyce &
Adler, 2000). The basis for this difference between capsular
types remains unknown. However, despite this evidence
suggesting no loss of serum resistance, the serotype B
FEMS Microbiol Lett 265 (2006) 110 c 2006 Federation of European Microbiological Societies
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2 M. Harper et al.
acapsular mutant was strongly attenuated in mice and had
increased sensitivity to phagocytosis by murine macro-
phages (Boyce & Adler, 2000).
Lipopolysaccharide
Pasteurella multocida lipopolysaccharide plays a critical role
in the pathogenesis of disease. It stimulates humoral im-
munity and is considered to be a protective antigen. Mono-
clonal antibodies raised against the lipopolysaccharide from
a serotype A strain were bactericidal and protected mice
against homologous challenge (Wijewardana et al., 1990). In
addition, an opsonic monoclonal antibody against lipopo-
lysaccharide from a serotype B strain of P. multocida
partially protected mice against P. multocida infection
(Ramdani & Adler, 1991).
There are conicting reports as to the endotoxic proper-
ties of lipopolysaccharide isolated from P. multocida. Intra-
venous inoculation of lipopolysaccharide from serotype B:2
stains could reproduce clinical signs of haemorrhagic septi-
caemia in buffalo (Horadagoda et al., 2002), but the
endotoxic properties of lipopolysaccharide from serotype A
strains is less clear. Studies have indicated that chicken
embryos and mice are highly susceptible, but that turkey
poults are relatively resistant (Ganeld et al., 1976; Rhoades
& Rimler, 1987; Mendes et al., 1994).
It is clear that P. multocida requires a complete lipopoly-
saccharide structure in order to replicate in vivo and cause
disease. In a recent study using signature-tagged mutagen-
esis, a mutant attenuated in mice and chickens had an
insertional inactivation of the gene waaQ
PM
(encoding a
putative heptosyl transferase) required for the addition of
heptose to lipopolysaccharide (Harper et al., 2004). Using
mass spectrometry and nuclear magnetic resonance, it was
demonstrated that the predominant lipopolysaccharide gly-
coforms extracted from this mutant were severely truncated.
Complementation experiments demonstrated that provid-
ing a functional waaQ
PM
gene in trans restored both the
lipopolysaccharide structure and growth in mice to wild-
type levels (Harper et al., 2004).
A galE mutant of P. multocida had signicantly reduced
viability in mice (Fernandez de Henestrosa et al., 1997).
Included in the role of galE in bacteria is the epimerization
of UDP-glucose to UDP-galactose before lipopolysaccharide
assembly, and this mutant probably expressed an altered
lipopolysaccharide, although the structural analysis of the
lipopolysaccharide was not reported (Fernandez de Henes-
trosa et al., 1997).
The complete lipopolysaccharide structure of strains
VP161 and X73 belonging to Heddleston serotype 1 and
PM70, a Heddleston serotype 3 strain, have been deter-
mined and all possess a structure similar to the lipopolysac-
charide or lipo-oligosaccharide (LOS) of Neisseria spp. and
Haemophilus spp. The lipopolysaccharide from the P. mul-
tocida strains had highly conserved inner cores with a tri-
heptose unit linked via a Kdo residue to lipid A, but there
were signicant variations in the outer core between the
three different strains (St Michael et al., 2005a, b, c). Inter-
estingly P. multocida lipopolysaccharide isolated from the
two Heddleston type I strains contains terminal phospho-
choline residues, which in other bacteria plays a key role in
bacterial adhesion to, and invasion of, host cells by binding
directly to the platelet-activating factor (PAF) receptor
(Cundell et al., 1995; Schenkein et al., 2000; Swords et al.,
2000; Serino & Virji, 2002). Although the role of phospho-
choline residues on the lipopolysaccharide of P. multocida
remains unknown, it has been shown in the bovine model
that lipopolysaccharide from P. multocida assists in adhesion
to neutrophils and transmigration through endothelial cells
(Galdiero et al., 2000).
In addition to phosphocholine residues, all the P. multo-
cida strains studied to date have phosphoethaolamine
residues attached to various sites on their lipopolysacchar-
ide. Notably, in addition to phosphocholine residues, the
X73 strain has phosphoethaolamine residues attached to
each of the terminal galactose sugars (St Michael et al.,
2005a). In other Gram-negative bacteria, phosphoethaola-
mine is added to a number of sites within the inner core of
lipopolysaccharide by specic transferases, and in Neisseria
meningitidis the expression and position of these residues
affects the ability of the bacteria to resist the innate immune
response (Ram et al., 2003). A clear role for phosphoethao-
lamine in P. multocida has not been dened.
Fimbriae and adhesins
There are many genes, including ptfA, mA, p1, p2, hsf_1
and hsf_2 on the P. multocida genome that encode proteins
similar to mbriae or brils in other bacteria.
It is likely that mbriae play a role in the surface adhesion,
as mbriae have been observed on some P. multocida
serotype A strains that were able to adhere to mucosal
epithelium, but not on the surface of those strains unable
to adhere (Glorioso et al., 1982; Rebers et al., 1988; Isaacson
& Trigo, 1995; Ruffolo et al., 1997). Type IV mbriae (pili)
have been isolated and characterized from P. multocida
serotypes A, B and D (Ruffolo et al., 1997) and are often
associated with virulence in other bacteria because of their
role in attachment to host cell surfaces. The subunit gene,
ptfA, has been isolated and sequenced from a number of
strains and the predicted protein sequences showed signi-
cant variation between strains (Doughty et al., 2000).
However, the role of mbrial structures in P. multocida
virulence is still unproven.
The P. multocida Pm70 genome contains a region encod-
ing proteins with signicant similarity to the Flp pilin locus
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3 Pasteurella multocida pathogenesis
in Actinobacillus actinomycetemcomitans, encoding a re-
cently described type IV mbrial subfamily (Kachlany et al.,
2001b; May et al., 2001). This locus encodes proteins
predicted to be the Flp pilin subunits and the proteins
required for the pilin assembly. Despite the lack of physical
evidence for Flp pili in P. multocida, there is evidence
through STM studies in mice that the products of these
genes are required for virulence. Two genes, p1, encoding a
Flp pilin subunit and tadD, predicted to encode a compo-
nent of the secretion apparatus required for Flp pilin
assembly, have been inactivated in two independent STM
studies using transposon mutagenesis, and both mutants
were signicantly attenuated in mice (Fuller et al., 2000;
May et al., 2001; Kachlany et al., 2001a, b; Harper et al.,
2003).
Two P. multocida genes, pfhaB1 and pfhaB2, share sig-
nicant similarity with a class of genes that encode lamen-
tous haemagglutinins, which in Bordetella pertussis play a
major role in the colonization of the upper respiratory tract
(Kimura et al., 1990; Mooi et al., 1992). Mutation of these
genes in P. multocida resulted in signicantly reduced
virulence in mice (Fuller et al., 2000). More recently, a
pfhaB2 mutant was constructed in a fowl cholera strain,
P1059, and shown to be highly attenuated in turkeys when
administered intranasally, but only moderately attenuated
when given intravenously, suggesting that pfhaB2 has a
signicant role in initial colonization or invasion (Tatum
et al., 2005).
Toxins
In general, most P. multocida strains that cause fowl cholera,
haemorrhagic septicaemia or pneumonia are not known to
express any toxins. The dermonecrotic toxin, PMT, ex-
pressed mainly by serogroup D strains, is the only toxin
identied to date and is responsible for the clinical and
pathological signs of atrophic rhinitis (Foged et al., 1987;
Rimler & Rhoades, 1989). Both puried native and recom-
binant PMT toxin can be used to experimentally induce
clinical signs of disease (Foged et al., 1987; Lax & Chanter,
1990).
PMT acts intracellularly by modulating the Ga
q
subunit
in the phospholipase C signal transduction pathway (Mur-
phy & Rozengurt, 1992; Wilson et al., 1997). In pigs, this
leads to atrophy of nasal turbinates where bone resorption
occurs due to uncontrolled proliferation of osteoclasts, and
regeneration of bone is prevented by the inhibition of
osteoblasts (Sterner-Kock et al., 1995; Mullan & Lax, 1998).
PMT is also a potent mitogen, inducing many cellular effects
including rearrangements in the actin cytoskeleton (Zywietz
et al., 2001). Like cholera and pertussis toxins, PMTactivates
dendritic cells to mature cells but, unlike the other toxins, it
is a poor adjuvant and appears to suppress the antibody
response (Bagley et al., 2005). It has been proposed that
PMT blocks chemotaxis-induced migration of dendritic
cells to regional lymph nodes and might, therefore, in a
natural infection, limit the development of an adaptive
immune response (Blocker et al., 2006).
The PMT toxin gene resides on a lysogenic bacteriophage
belonging to the Siphoviridae family. As the PMT toxin has
no signal sequence and no known mechanism of export, it
has been suggested that the lytic phase of the bacteriophage
may mediate the release of the toxin (Pullinger et al., 2004).
The toxin is an effective immunogen; a toxoid developed by
deletion mutagenesis of the cloned PMT toxin gene was
found to protect mice and their offspring against challenge
with puried PMT (Petersen et al., 1991). Similarly, a
genetically modied PMT toxin, where there were two key
amino acid substitutions, led to a nontoxigenic protein that
protected pigs against experimental challenge with the wild-
type strain (To et al., 2005).
Iron regulated and iron acquisition proteins
Iron is an essential element which must be acquired by
bacteria in order to survive. Because of its inherent toxicity,
the level of free iron available in vivo is very limited and
P. multocida, like other bacterial species, has developed
multiple mechanisms for iron uptake. Sequence analysis of
P. multocida PM70 revealed that a relatively large proportion
of the genome (over 2.5%) encodes 53 proteins with
similarity to proteins involved in iron uptake or acquisition
(May et al., 2001).
Comparisons of P. multocida grown in iron-rich, iron-
depleted media or in vivo has demonstrated that many high
molecular weight outer membrane proteins are regulated by
iron levels and have therefore been called iron-regulated
outer membrane proteins (IROMPs) (Snipes et al., 1988;
Choi-Kim et al., 1991). Pasteurella multocida grown under
iron-limited conditions also induces a stronger protective
response in mice compared with the same strain grown
under iron-replete conditions (Kennett et al., 1993), and it is
thought that IROMPs may, therefore, play a signicant role
in cross-protective immunity (Glisson et al., 1993; Ruffolo
et al., 1998). However, analysis of IROMPs using a proteo-
mics approach identied only one protein, PM0805, that
was up-regulated and only one, OmpW, that was down-
regulated under low-iron conditions (Boyce et al., 2006).
Transferrin receptors utilized by bacterial species in the
Pasteurellaceae and Neisseriaceae families usually consist of
two iron binding receptors TbpA and TbpB (Gray-Owen &
Schryvers, 1996), but recent evidence suggests that the
transferrin receptor in bovine strains of P. multocida is
composed of only a single protein TbpA (Ogunnariwo &
Schryvers, 2001). However, this receptor may not be present
in all P. multocida strains; a recent PCR and DNA
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4 M. Harper et al.
hybridization study found that the tbpA gene is present only
in some bovine and ovine clinical isolates (Ewers et al.,
2006). Iron acquisition proteins are believed to play a role in
the disease process; serogroup A mutants with inactivated
ExbB, ExbD, TonB, or HgbA proteins are attenuated in mice
(Fuller et al., 2000; Bosch et al., 2002a). ExbB, ExbD and
TonB are part of the TonB transport complex, required to
transport and provide energy for iron sequestration, and
HgbA is predicted to be a haemoglobin-binding protein
required for the acquisition of iron from host proteins
(Bosch et al., 2002b).
Sialic acid metabolism
Sialidases are produced by some bacterial species and act to
remove sialic acid from host glycosylated proteins and lipids
for use as a carbon source. These enzymes may also enhance
bacterial virulence by unmasking key host receptors and/or
reducing the effectiveness of host defences such as mucin.
Most P. multocida strains produce sialidase and both cell
bound and extracellular sialidases have been reported in
P. multocida (Scharmann et al., 1970; Drzeniek et al., 1972;
White et al., 1995). Bacterial sialidase is produced in vivo in
goats after transthoracic challenge with either P. multocida
or M. haemolytica (Straus & Purdy, 1994; Straus et al., 1996).
Passive protection of mice against P. multocida A:3 homo-
logous challenge has been demonstrated using rabbit anti-
sera raised against partially puried sialidase, although there
was some difculty in removing anti-LPS antibodies from
the serum before administration into mice (Ifeanyi & Bailie,
1992), thus raising the question about the specicity of the
protective antibodies.
Two sialidases, NanH and NanB, have been cloned and
characterized from a fowl cholera isolate of P. multocida
(Mizan et al., 2000). These sialidases differed in their
specicity, with both able to utilize 2,3
0
sialyl lactose, but
only NanB able to fully utilize 2,6
0
sialyl lactose. It was
proposed that the presence of two sialidases with slightly
different specicities would enhance the metabolic capacity
of P. multocida in the host (Mizan et al., 2000).
In addition, there is increasing evidence to suggest that
P. multocida is capable of scavenging sialic acid from the
environment for both the sialylation of cell components and
for nutrients via a catabolic breakdown pathway (Steenber-
gen et al., 2005). Furthermore, the uptake, but not catabo-
lism, of sialic acid was shown to be essential for virulence in
mice (Steenbergen et al., 2005). Two genes, pm0188 and
pm0508, encoding sialic acid transferases, have been identi-
ed in the P. multocida genome. Interestingly, the product of
pm0188 has been shown to be a multifunctional enzyme
capable of four functions. It exhibits transferase activity
linking sialic acid to galactose with either 2,3 or 2,6 linkages
with varying activity. In lower, more acidic pH conditions, it
can function both as a sialidase capable of cleaving 2,3 sialyl
linkages, but not 2,6 linkages, and as a trans sialidase,
transferring 2,3 linked sialyl groups to another galactose
residue (Yu et al., 2005). An unequivocal role in pathogen-
esis has not yet been demonstrated.
Hyaluronidase
Although the role of hyaluronidase in pathogenesis has not
been determined, it is present in many of the serotype B
strains of P. multocida that cause bovine haemorrhagic
septicaemia. A study of 74 P. multocida strains representing
all capsular serotypes found that only the type B strains,
isolated from haemorrhagic septicaemia infections, pro-
duced hyaluronidase (Carter & Chengappa, 1980). Another
study of 176 strains of P. multocida representing different
serotypes also found hyaluronidase activity conned to
serotype B, but more specically B:2, and it was suggested
that a test for hyaluronidase activity could be used to
presumptively identify B:2 strains (Rimler & Rhoades,
1994).
Outer membrane proteins
Early studies on the P. multocida outer membrane showed
that a 37 kDa protein was among ve identied as possible
protective immunogens based rstly on radioimmunopre-
cipitation results using protective immune rabbit sera, and
secondly on their location in the outer membrane (Lu et al.,
1988). Monoclonal antibodies raised against the 37 kDa
protein were able to passively protect rabbits and mice
against infection with P. multocida with strong protection
afforded against homologous strains, and some limited
protection against heterologous strains (Lu et al., 1991).
A protein of similar molecular mass (39 kDa) was identi-
ed in the P. multocida A:3 strain P1059; its expression was
shown to correlate with the presence and amount of capsule
present on the cell (Borrathybay et al., 2003b; Ali et al.,
2004a). Pasteurella multocida can adhere to, and invade,
chicken embryo broblasts, and this adherence was inhib-
ited by both monoclonal and polyclonal antibodies raised
against the 39 kDa protein (Borrathybay et al., 2003a; Al-haj
Ali et al., 2004; Ali et al., 2004a, b). Passive immunization of
mice with a monoclonal antibody against the 39 kDa protein
or active immunization with afnity puried 39 kDa pro-
tein, demonstrated that antibodies raised against this pro-
tein were cross-protective against serovars A:1 and A:3 (Ali
et al., 2004a, b). The actual identity of this 39 kDa protein
was not reported, but recently a 39 kDa protein which can
stimulate cross-serotype protection (Rimler, 2001) was iso-
lated from outer membrane protein extracts of the same A:3
strain, P1059, used in the above studies. This protein was
identied as PlpB (Pasteurella lipoprotein B), using peptide
mass ngerprinting (Tabatabai & Zehr, 2004) and is
FEMS Microbiol Lett 265 (2006) 110 c 2006 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
5 Pasteurella multocida pathogenesis
predicted to be an ABC transport protein required for the
uptake of methionine into the cell (Merlin et al., 2002).
One of the major outer membrane proteins of P. multo-
cida is OmpH. Antibodies raised against this protein pro-
vide some protection against disease. Monoclonal
antibodies specic for OmpH passively protect mice against
P. multocida challenge (Marandi & Mittal, 1997) and
vaccination with the native, but not recombinant, OmpH
protein elicits protective immunity in birds against homo-
logous challenge (Luo et al., 1997). In addition, antibodies
raised to an OmpH synthetic peptide, Cyclic-L2, provided
partial protection in chickens against homologous challenge
(Luo et al., 1999).
Recent studies examining the ability of P. multocida to
bind host extracellular matrix proteins have shown that the
bacteria can adhere to bronectin and collagen type IX.
Proteins identied as possible adhesins include OmpA,
Oma87, Pm1069 and the iron related proteins, Tbp (trans-
ferrin binding protein) and the putative TonB receptor
HgbA (Dabo et al., 2005).
OmpA, a b-barrel, ion channel protein, has been speci-
cally identied as having a direct role in adhesion. Homo-
logs of this protein are important adhesins in Escherichia
coli, Haemophilus inuenzae and other bacteria. Notably,
recombinant P. multocida OmpA binds to bovine kidney
cells and interacts with host extracellular matrix molecules
heparin and bronectin (Dabo et al., 2003).
Concluding remarks
Pasteurella multocida is capable of causing disease in a wide
range of animals and birds. There is a clear correlation
between capsular type and the disease, with serotypes A and
F typically associated with fowl cholera, serotypes B and E
with haemorrhagic septicaemia in cattle, and serotype D
strains expressing PMT toxin with atrophic rhinitis in swine.
What is unclear is whether the expression of a particular
type of lipopolysaccharide or the type and amount of
proteins presented on the bacterial surface also contribute
to the disease specicity. Other virulence factors such as
neuraminidases, iron sequestering proteins and metabolic
enzymes play key roles in acquiring and utilizing substrates
for growth within the host, often a relatively nutrient poor
and hostile environment.
There has been little progress in understanding exactly
how P. multocida invades mucosal surfaces to gain access to
the blood and how the host responds to the infection.
However, signicant advances have been made in identify-
ing bacterial factors critical to P. multocida pathogenesis. It
is known that capsule and lipopolysaccharide are essential
for normal disease progression in fowl cholera and there is
some progress in understanding the bacterial response to the
in vivo environment (Boyce et al., 2002, 2004) and identify-
ing bacterial factors required for disease progression (Fuller
et al., 2000, Harper et al., 2003).
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