Treatment of plague: promising alternatives to
Andrey P. Anisimov1and Kingsley K. Amoako2
Andrey P. Anisimov
1Laboratory for Plague Microbiology, Department of Infectious Diseases, State Research
Center for Applied Microbiology and Biotechnology, 142279 Obolensk, Serpukhov District,
Moscow Region, Russia
2Canadian Food Inspection Agency, Animal Diseases Research Institute, P.O. 640, Township
Road 9-1, Lethbridge, AB T1J 3Z4, Canada
possible use of Yersinia pestis as a biological weapon by terrorists. The septicaemic and
pneumonic forms are always lethal if untreated. Attempts to treat this deadly disease date back to
the era of global pandemics, when various methods were explored. The successful isolation of the
plague pathogen led to the beginning of more scientific approaches to the treatment and cure
of plague. This subsequently led to specific antibiotic prophylaxis and therapy for Y. pestis. The use
of antibiotics such as tetracycline and streptomycin for the treatment of plague has been embraced
by the World Health Organization Expert Committee on Plague as the ‘gold standard’ treatment.
However, concerns regarding the development of antibiotic-resistant Y. pestis strains have led to
the exploration of alternatives to antibiotics. Several investigators have looked into the use of
alternatives, such as immunotherapy, non-pathogen-specific immunomodulatory therapy, phage
therapy, bacteriocin therapy, and treatment with inhibitors of virulence factors. The alternative
therapies reported in this review should be further investigated by comprehensive studies of their
clinical application for the treatment of plague.
As a Gram-negative bacterium, the causative agent of
plague, Yersinia pestis (Yersin, 1894), has been the cause of
three pandemics (Achtman et al., 1999; Drancourt et al.,
2004; Guiyoule et al., 1994; Raoult et al., 2000), and has led
to the deaths of millions of people, the devastation of cities
and villages, and the collapse of governments and civiliza-
tions (Zietz & Dunkelberg, 2004). At the present time, the
circulation of Y. pestis has been detected within the
populations of more than 200 species of wild rodent
inhabiting natural plague foci on all continents, except for
Australia and Antarctica, and the transmission of plague is
provided for by a minimum of 80 species of flea. Plague
epizootics, during which the pathogen spreads through new
territories, alternate with a decrease in epizootic activity.
When natural foci of infection are investigated during
periods between epizootics, no antibodies to Y. pestis are
detected in the animals, and the plague microbe is not
detected by bacteriological
Morbidity in humans is noted, as a rule, when epizootics
become acute, and is a consequence of bites of fleas, direct
contact with infected animal tissues, the consumption of
insufficiently cooked meat products, or the inhalation of
aerosolized respiratory excreta of animals or patients with
the pneumonic form of infection (Anisimov, 2002a, b;
Anisimov etal.,2004;Aparin& Golubinskii,1989;Brubaker,
1991; Butler, 1983; Dennis et al., 1999; Domaradskii, 1993,
1998;Gage & Kosoy,2005;Hinnebusch,2003;Inglesby etal.,
2000; Lien-Teh et al., 1936; Naumov & Samoilova, 1992;
Nikolaev, 1972; Perry & Fetherston, 1997; Pollitzer, 1954).
Plague remains a serious problem for international public
health. Small outbreaks of plague continue to occur
throughout the world, and at least 2000 cases of plague
are reported annually (Gage & Kosoy, 2005). Plague has
recently been recognized as a reemerging disease, and Y.
pestis, if used by the aerosol route of exposure as a
bioterrorism agent, could cause mass casualties (Gage &
Kosoy, 2005; Inglesby et al., 2000). According to World
Health Organization (WHO) data, if 50 kg of the plague
pathogen was released as an aerosol over a city with a
population of 5 million, 150000 people might fall ill with
pneumonic plague, 36000 of whom would die (WHO,
being pursued to deal with potential infection. Com-
mercially available human plague vaccines are based on
either a live, attenuated strain or a killed, whole-cell
preparation. The live, attenuated vaccine is produced in
Abbreviations: DIC, diffuse intravascular coagulation; WHO, World
46697 G 2006 SGMPrinted in Great Britain1461
Journal of Medical Microbiology (2006), 55, 1461–1475
the former Soviet Union, and is based on Y. pestis strain EV,
line NIIEG. This strain is attenuated due to deletion of the
102 kbpgm locus that includes thehms locus responsiblefor
the ability to store haemin, and a cluster of genes needed for
production of the siderophore-based yersiniabactin biosyn-
thetic/transport systems. The parental wild-type strain was
isolated in Madagascar. The second vaccine is a formalin-
fixed virulent Y. pestis strain 195/P (originally isolated in
India) that was developed in the USA, although at present it
is manufactured only in Australia. Both these types of
vaccines have unacceptable side effects when used (Meyer,
1970; Naumov et al., 1992). A number of subunit-based
vaccines are currently under development and/or at
different stages of preclinical/clinical trials. These offer the
advantage of employing a defined antigen that possesses the
ability to elicit high-level protection, and they are also less
reactogenic than the currently used whole-cell vaccines
(Anisimov et al., 2004; Williamson, 2001; Williamson et al.,
2005). The main limitation of the prevention of plague by
vaccination is that protection is delayed for at least 1 week
after immunization, and this time may be crucial with
respect to the lethal outcome of the disease (Butler, 1983;
Dennis et al., 1999; Domaradskii, 1993, 1998; Inglesby et al.,
2000; Lien-Teh et al., 1936; Naumov & Samoilova, 1992;
Nikolaev, 1972; Perry & Fetherston, 1997; Pollitzer, 1954;
Rudnev, 1940). As a consequence, antibiotics are employed
for the early initiation of prophylaxis and therapy of plague.
The overwhelming majority of Y. pestis natural isolates are
susceptible in vitro and in vivo to antimicrobials such as
tetracycline, doxycycline, ciprofloxacin, streptomycin, gen-
tamicin, chloramphenicol, fluoroquinolones, sulphona-
mides, and trimethoprim-sulfamethoxazole (Domaradskii,
recovery of natural drug-resistant isolates of Y. pestis has
been explained by the relative rarity of cases of human
plague at the present time and by the acute nature of the
disease (Domaradskii, 1993). However, a ‘natural’ strain
with resistance to multiple antibiotics, including all of those
recommended for plague prophylaxis and treatment, was
isolated in 1995 in the Ambalavao district of Madagascar
from a 16-year-old boy. The Y. pestis strain 17/95 was
resistant to ampicillin, chloramphenicol, kanamycin, strep-
tomycin, spectinomycin, sulfonamides, tetracycline and
minocycline. The resistance genes were carried by a plasmid
that could conjugate with high frequency to other Y. pestis
strains in vitro (Galimand et al., 1997) or in fleas
(Hinnebusch et al., 2002). The possibility of the rise of
the ease of generation of such strains under laboratory
conditions (Hinnebusch et al., 2002; Hurtle et al., 2003), the
potential use of such strains for bioterrorist attack, together
with the rapidity and high lethality of the disease (Butler,
1983; Dennis et al., 1999; Domaradskii, 1993, 1998; Inglesby
et al., 2000; Lien-Teh et al., 1936; Naumov & Samoilova,
1992; Nikolaev, 1972; Perry & Fetherston, 1997; Pollitzer,
1954; Rudnev, 1940), are evidence of the necessity for a
search for novel antimicrobial alternatives to antibiotics.
Here, we will briefly review the existing methods, as well as
promising current strategies under investigation for the
treatment of plague.
Pathogenesis and virulence factors
For constantcirculation in natural foci, the plague pathogen
must penetrate into the host organism, counteract the
protective bactericidal systems of the rodent, and reproduce
to ensure bacteraemia, essential for further transmission of
the infection by fleas to a new host. In the case of a human
pneumonic plague outbreak, the bacteria must also over-
come host innate immunity to develop pneumonia with
abundant exhalation of Y. pestis, causing plague pneumonia
in naı ¨ve persons. Each of these stages in the cyclic existence
of Y. pestis is supported by numerous factors of the plague
genes (Table 1), which may exert an influence, jointly or
individually, upon variousstagesoftheinfectiousprocessor
transmission. The removal of any one of these components
may or may not render the organism avirulent. However,
only in aggregate do these factors ensure survival of Y. pestis
in the host organism, no matter how significant or
insignificant their individual effect might be (Anisimov
et al., 2004; Brubaker, 1991; Perry & Fetherston, 1997).
The main pathogenicity factor of Yersinia resides in the
complex traits encoded by the plasmid pCad (also termed
essential for the manifestation of virulence (Portnoy &
Falkow, 1981). It is considered as the Yop virulon: the
system that permits extracellular bacteria to disarm the cells
involved in the host immune response, disrupt their
binding, and induce their apoptosis by injection of bacterial
effector proteins. This system consists of the Yop proteins
and the apparatus of their type III secretion, called Ysc. The
can be divided into two groups according to their functions.
Some of them are intracellular effectors (YopE, YopH,
YpkA/YopO, YopP/YopJ, YopM, YopT), whereas others
(YopB, YopD, LcrV) form the translocation apparatus,
which is unfolded on the surface of the bacterium to deliver
the effectors into eukaryotic cells through the plasma
membrane. The secretion of Yops proteins is triggered by
contact with eukaryotic cells. In the absence of attachment,
yersiniae do not release Yops from the bacterial cell. The
adhesion mechanism is not yet known, but it seems that
close contact with eukaryotic membrane lipids alone might
blocked at different levels by proteins of the virulon,
including YopN, TyeA and LcrG, which cover the bacterial
secretory channel, presumably in the form of a trap door.
The precise functioning of the system also requires several
chaperones, called Syc proteins, that assist Yops to be
secreted by the injectisome. Each of these chaperones serves
only one Yop, and they do not leave the bacterial cytosol.
Transcription of the genes is controlled by the temperature
and activity of the secretion apparatus (Cornelis, 2002;
Viboud & Bliska, 2005).
1462Journal of Medical Microbiology 55
A. P. Anisimov and K. K. Amoako
Table 1. Selected factors ensuring survival of Y. pestis in the host organism
Compiled from Anisimov, 2002a, b, Anisimov et al., 2004; Brubaker, 1991; Oyston et al., 2000; Perry & Fetherston, 1997; Robinson et al.,
2005; Sing et al., 2002; Sodhi et al., 2004. ND, Not determined.
Bacterial factorFunction or activity Reported decrease of virulence
in knock-outs (by order of magnitude)
Dramatic (>)Moderate (4–2) Low (2–0)
Low-calcium response (LCR)
type III secretion (T3S)
System permitting extracellular yersiniae
to counteract the non-specific
immune response by an impairment
of phagocytic and signalling activity
of macrophages and induction of apoptosis
of phagocytic cells (delivery of toxic
bacterial proteins, Yops, from extracellularly located
bacteria into the eukaryotic cell cytosol)
Yop translocator; inhibition of chemotaxis
of neutrophils; suppression
of the synthesis of c-interferon and tumour
necrosis factor a: cytokines necessary
for non-specific activation of professional
phagocytes and the formation
of productive granulomas, by stimulation
of interleukin (IL)-10 production;
a repressor of the cytokines indicated above;
inhibition of LPS-induced
production of IL-1b in macrophages; competition
with LPS for toll-like receptor 2 binding
Antiphagocytic; actin depolymerization;
inactivation of Rho proteins
Antiphagocytic; protein tyrosine phosphatase; induction
of apoptosis; inhibition of lymphocyte proliferation
Disruption of thrombin interaction
with thrombocytes and hindering
of their aggregation, essential
for the formation of a blood clot
Down-regulation of the inflammatory
response of macrophages, epithelial
and endothelial cells by blocking the mitogen-activated
protein kinase and nuclear factor-kB pathways
Antiphagocytic; inactivation of Rho proteins;
depolymerization of actin stress fibres
Antiphagocytic; inactivation of Rho proteins;
autophosphorylating serine/threonine kinase
Formation of the external needle of the
T3S system; participation in virulence
protein secretion, in translocation
of virulence proteins across eukaryotic
membranes and in the cell contact-
and calcium-dependent regulation of T3S
Alternative treatment of plague
Infective doses of 10 bacteria or less are sufficient to cause
lethal infection in naı ¨ve rodents and primates via the
(Anisimov et al., 2004; Brubaker, 1991; Perry & Fetherston,
1997). LD50values in the case of the respiratory and oral
routes of infection increase to 102–104c.f.u. (Anisimov,
2002a;Anisimovetal.,2004; Ehrenkranz & Meyer,1955) and
105–109c.f.u. (Anisimov, 2002a), respectively.
Y. pestis is primarily a rodent pathogen, and is usually
transmitted to another mammalian host by fleas, following
the bacterium is initially susceptible to phagocytosis and
killing by neutrophils (Cavanaugh & Randall, 1959) and
CD11c+cells (Bosio et al., 2005), but it may survive
and multiply within macrophages. Released bacteria are
resistant to capture by neutrophils and begin an unchecked
propagation (Cavanaugh & Randall, 1959). The bacteria
where local replication causes a suppurative lymphadenitis
(bubo). If the lymphatic system becomes overwhelmed,
septicaemia results, with Y. pestis spreading to other organs.
The LPS of Y. pestis causes the development of endotoxic
shock peculiar to other Gram-negative infections (Butler,
1983; Dmitrovskii, 1994; Van Amersfoort et al., 2003). After
the development of highly contagious plague pneumonia,
the disease spreads in the air in droplets (Lien-Teh, 1926;
Lien-Teh et al., 1936; Rudnev, 1940).
There are three main primary forms of human plague,
bubonic, septicaemic and pneumonic. Complications such
as secondary septicaemic plague, secondary pneumonic
Plasminogen activator (Pla) Spreading factor that promotes generalization
of infection, possesses
proteolytic properties and determines
the fibrinolytic (37uC) and plasmocoagulase
(28uC) activities of the plague pathogen;
post-translational degradation of Yop proteins;
adhesive and invasive activity
Antiphagocytic; adhesive activity
Antiphagocytic; adhesive activity
pH 6 antigen (PsaA)
fraction I (F1; Caf1)
Adhesive activity; resistance to bactericidal
action of normal sera
Development of toxic shock
(lethal effect on mice and rats);
reinforcement of endotoxic shock in mammals
Development of endotoxic shock;
resistance to the action
of bactericidal cationic peptides
and normal sera; adhesive activity
Yersinia ‘murine’ toxin (Ymt)
Haemin storage (Hms)
Purine biosynthetic enzymes
Siderophore-dependent iron-transport system+
Adsorption of haemin on microbial cell surface
De novo synthesis of purines
DNA adenine methylation
Activation of resistance to innate immune defences
*More than one + indicates the existence of conflicting data reported by different researchers.
Table 1. cont.
Bacterial factorFunction or activity Reported decrease of virulence
in knock-outs (by order of magnitude)
Dramatic (>)Moderate (4–2)Low (2–0)
1464Journal of Medical Microbiology 55
A. P. Anisimov and K. K. Amoako
plague, plague meningitis, plague endophthalmitis and
multiple lymph node involvement result from bacteraemic
dissemination of the pathogen (Butler, 1983; Dennis et al.,
1999; Lien-Teh et al., 1936; Naumov & Samoilova, 1992;
Nikolaev, 1972; Pollitzer, 1954; Rudnev, 1940). Septicaemia
may be followed by digital gangrene (Kuberski et al., 2003).
Irrespective of clinical form, the mean incubation period is
3–6 days, but may decrease to 1–2 days in patients with
primary septicaemic or pneumonic plague, and increase in
vaccinated people. All of the clinical forms may be
characterized by sudden onset of illness, malaise, chills
and temperature increase up to 39–40uC, headache,
myalgia, insomnia, indistinct speech, wobbly walk, and
sometimes vomiting. In the case of serious illness, patients
are delirious, and violent and aggressive. Attempts to make
an escape from a patient care institution may be considered
as a sign of developing meningitis. In extremely severe cases,
a profound prostration and cyanosis can be observed.
while untreated septicaemic and pneumonic forms of the
disease are always lethal (Albizo & Surgalla, 1970; Butler,
1983; Dennis et al., 1999; Dmitrovskii, 1994; Kool, 2005;
Krishna & Chitkara, 2003; Lien-Teh, 1926; Lien-Teh et al.,
1954; Rudnev, 1940).
open skin lesion with plague-infected material. Sometimes,
a vesicle, pustule or ulcer develops at the inoculation site. Y.
pestis spreads via the lymphatic vessels to the regional lymph
nodes, causing inflammation and swelling in one or several
nodes: buboes (‘bubo’ is derived from the Greek ‘boubon’,
groin).Buboes areusuallyno greaterthan 5 cm in diameter,
extremelytender,erythematous, and surrounded bya boggy
haemorrhagic area. Buboes typically arise in the inguinal
and femoral regions, but also occur in other regional lymph
node sites, including popliteal, axillary, supraclavicular,
cervical, post-auricular, pharyngeal and other sites. Deeper
nodes (such as intrabdominal or intrathoracic nodes) may
also be involved through the lymphatic or haematogenous
spread of Y. pestis. Initial symptoms include malaise, high
fever, and one or more painful lymph nodes. Pulse rate is
increased to 110–140 min21. Blood pressure is low, usually
about 100/60 mm Hg, due to extreme vasodilatation.
Circulatory collapse, haemorrhage and peripheral throm-
bosis are the terminal events (Butler, 1983; Dennis et al.,
1999; Lien-Teh et al., 1936; Naumov & Samoilova, 1992;
Nikolaev, 1972; Pollitzer, 1954; Rudnev, 1940).
Septicaemic plague may occur primarily as a result of
infection with massive doses of the pathogen, or when the
bacillus is deposited in the vasculature, bypassing the
lymphatics. In this case, bacteria proliferate in the body
without producing a bubo. Secondary septicaemic plague is
a complication of haematogenous dissemination of bubonic
plague. The presenting signs and symptoms of primary
septicaemic plague are essentially the same as those of any
Gram-negative septicaemia: fever, chills, nausea, vomiting
and diarrhoea. Later, purpura, disseminated intravascular
coagulation, and acral cyanosis and necrosis may be seen.
Other symptoms include abdominal pain and digital
gangrene (Albizo & Surgalla, 1970; Butler, 1983; Dennis
et al., 1999; Dmitrovskii, 1994; Lien-Teh et al., 1936;
Rudnev, 1940; Van Amersfoort et al., 2003).
Pneumonic plague is rare, but is the most dangerous and
fatal form of the disease, and is spread via respiratory
droplets. It can develop as a secondary complication of
septicaemic plague or result from the inhalation of
infectious respiratory excreta of humans or animals with
the pneumonic form of infection. The onset of pneumonic
plague is acute and fulminant, with high fever, chills,
headache, malaise, myalgia and productive cough (with
sputum that may be clear, bloody or purulent) within 24 h
of the onset of symptoms. Buboes on the neck are rare, but
are a symptom of pneumonic plague. Nausea, diarrhoea,
vomiting and abdominal pain may also accompany the
disease. The pneumonia progresses rapidly, resulting in
dyspnoea, stridor and cyanosis. The disease rapidly engulfs
the lungs and haemorrhages develop, filling them with fluid
(a haemorrhagic pneumonia). The terminal events are
respiratory failure, circulatory collapse, and bleeding
diathesis (Albizo & Surgalla, 1970; Butler, 1983; Dennis
et al., 1999; Dmitrovskii, 1994; Kool, 2005; Krishna &
Chitkara, 2003; Lien-Teh, 1926; Lien-Teh et al., 1936;
Naumov & Samoilova, 1992; Nikolaev, 1972; Pollitzer, 1954;
Methods of plague treatment
Until the nineteenth century, the treatment of plague was
based on mysticism and superstition. Such ‘remedies’ as
magic and talismans, mixtures of bird and animal blood,
tablets made from rattlesnake meat, and even material
squeezed from fresh horse dung, were widely used
(Afanas’ev & Vaks, 1903). Later, methods such as
phlebotomy, emetics, purgatives and diaphoretics were
also applied to plague treatment (Rudnev, 1940). The
isolation of the plague pathogen, Y. pestis, in 1894 (Yersin,
1894) made possible scientific approaches to the cure of
plague-infected patients. The local application of antiseptics
such as iodine, mercuric chloride, carbolic acid or quinine,
together with the incision or even searing of bubos, were
promising in some cases, as were attempts to surmount
severe systemic disease by the use of the same remedies,
specific bacteriophages or animal hyperimmune sera (Lien-
Teh et al., 1936; Rudnev, 1940); however, real success in
plague therapy was observed when sulfanilamides (Carman,
1938) and then streptomycin (Hornibrook, 1946) became
Alternative treatment of plague
Antibiotic prophylaxis and therapy
Currently, antibiotics are the cornerstone of plague
treatment. The antibiotic prophylaxis and therapy for Y.
on Plague (1970), focuses on the use of tetracycline,
streptomycin, and chloramphenicol for eradication of the
organism. More recently, the US Working Group on
Civilian Biodefence has added gentamicin, doxycycline
and ciprofloxacin to this list (Inglesby et al., 2000).
Chloramphenicol is optional for the treatment of plague
meningitis (Becker et al., 1987). Aminoglycosides (strepto-
mycin, kanamycin, tobramycin, gentamicin and amikacin)
and cephalosporins (ceftriaxone and ceftazidim) are
recommended for the treatment of plague caused by F1-
negative Y. pestis strains that are resistant to doxycycline,
ampicillin and cefoperazone in vivo. Studies in mice suggest
that an increase in the daily doses of less-efficient drugs such
as cefotaxime, cefoperazone, sulbactam/ampicillin, azthreo-
nam, ciprofloxacin and rifampicin, along with prolongation
of the treatment course for up to 7 days, make it possible to
increase the protective effects to 80–100% (Anisimov et al.,
2004; Ryzhko et al., 1998). Furthermore, studies using
ciprofloxacin, doxycycline and the newer fluoroquinolones
gatifloxacin and moxifloxacin have shown an increase in the
survival of mice presenting with pneumonic plague (Byrne
et al., 1998; Russell et al., 1998; Steward et al., 2004).
It is recommended that antibiotic therapy be started as early
as possible. A delay in antibiotic therapy will result in an
increase in bacterial biomass, and in a more harmful
subsequent inflammatory response caused by endotoxin
release induced by both lytic and non-lytic antimicrobials
(Nau & Eiffert, 2002). During the first few hours of
antibiotic treatment, patients should be monitored closely,
because shock may develop after the start of antibiotic
application due to bacteriolysis, with the subsequent release
of large amounts of endotoxin (Jacobs et al., 1990). Those in
contact with pneumonic plague patients and persons who
have been exposed to aerosols should receive doxycycline,
ciprofloxacin or chloramphenicol as post-exposure pro-
phylaxis (Inglesby et al., 2000). The recent increase in
multidrug-resistant strains (Galimand et al., 1997; Wong
et al., 2000) has led to renewed efforts to find alternatives to
use the serum of vaccinated rabbits to cure infected ani-
mals (Yersin et al., 1895). In 1896, Yersin was able to cure
several patients in Asia with a horse serum (Yersin, 1897).
However, the experiences of other researchers with the
use of plague serum were conflicting. The horse, mule or
bull sera were produced in different laboratories with the
use of different immunization schemes involving killed or
live bacteria of different strains. In the course of treat-
ment, patients were injected subcutaneously or intrave-
nously with up to 1000 ml immune serum (200–500 ml
for one subcutaneous or intramuscular injection, and
A. Yersin and others were the first to
50–100 ml for one intravenous injection). In the case of
bubonic plague, the reported death rate in treated (13%)
and untreated (64%) patients differed significantly. In
patients with septicaemic or pneumonic plague, treatment
did not cause a detectable decrease in mortality. The
sooner treatment was started the better the result. Even in
patients that succumbed to infection, an up to twofold
increase in time to death was usually reported. The dan-
gers of serum sickness and anaphylactic shock frequently
induced by serum therapy were believed to be less signifi-
cant than that of septic shock (Lien-Teh et al., 1936;
Pollitzer, 1954; Rudnev, 1940). In 1970, the WHO Expert
Committee on Plague recommended the continuation of
further development of plague antitoxic sera that might
be used for the treatment of plague patients with severe
toxicosis (WHO, 1970).
body preparations were introduced into clinical practice
for preventing and treating infectious diseases. In contrast
to older remedies based on animal sera, these specific
immunoglobulins contained antibodies derived from
immunized human donors, and so had minimal side
effects. Although human-specific globulins lack the toxici-
ties associated with animal sera, they have several limita-
tions, such as high cost, low availability, and the potential
to transmit infectious disease (Buchwald & Pirofski, 2003;
Casadevall, 2002; 2005; Keller & Stiehm, 2000).
Beginning in the 1960s, separate anti-
Hybridoma technology, introduced in 1975 (Kohler &
Milstein, 1975), provides a method for the unlimited
production of homogeneous mAbs. The construction of
mouse–human chimeric or humanized mAbs (Morrison,
1992), completely human mAbs (Kang et al., 1991) from
hybridomas or combinatorial libraries, and recombinant
human polyclonal antibodies (Bregenholt & Haurum,
2004), makes it possible to reduce the immunogenicity of
rodent mAbs in humans. These approaches provide the
possibility of raising relevant antibodies against protective
antigens only, and even against protective epitopes of
In the case of Y. pestis, several antigens have been shown to
capsular antigen (Meyer et al., 1974; Simpson et al., 1990),
LcrV or simply V antigen (Leary et al., 1995; Motin et al.,
1994; Une & Brubaker, 1984), YopD (Andrews et al., 1999),
and type III secretion system needle complex protein, YscF
found for the F1 (Sabhnani & Rao, 2000; Sabhnani et al.,
2003; Zav’yalov et al., 1995) and V (Hill et al., 1997)
antigens. Passive administration of antibodies against target
antigens protects macrophages from Y. pestis-induced cell
death, promotes phagocytosis (Cowan et al., 2005;
Philipovskiy et al., 2005; Weeks et al., 2002), and protects
animals against both bubonic and pneumonic plague
(Anderson et al., 1997; Friedlander et al., 1995; Green
et al., 1999; Hill et al., 2006; Motin et al., 1994; Roggenkamp
1466 Journal of Medical Microbiology 55
A. P. Anisimov and K. K. Amoako
et al., 1997; Une & Brubaker, 1984; Williamson et al., 2005).
Importantly, therapy based on a single antibody against a
single antigen or epitope will be ineffective in the case of
infection with a virulent strain lacking the antigen or
expressing a different serological variant of the antigen
(Anisimovet al.,2004;Friedlander etal.,1995;Roggenkamp
et al., 1997).
pestis is known to efficiently overcome the innate immune
system of many mammals. However, it has been shown
that neutrophils (Cavanaugh & Randall, 1959) and
CD11c+cells (Bosio et al., 2005), which represent the
initial line of host defence against invading pathogens,
play an important role in suppressing the initial replica-
tion and dissemination of inhaled Y. pestis. Recent studies
(Liles, 2001) conducted in vitro and in vivo have shown
that granulocyte colony-stimulating factor, granulocyte-
macrophage colony-stimulating factor and interferon-c
can augment the functional antimicrobial activities of neu-
trophils. Studies conducted in animal models have shown
the potential use of each of these cytokines for the treat-
ment of bacterial infections. We can speculate that such
adjunctive treatment may be useful for plague therapy.
Y. pestis mediates septic shock, which contributes signifi-
cantly to host death (Butler, 1983; Dmitrovskii, 1994).
Sepsis and the systemic inflammatory response syndrome
are accompanied by the inability to regulate the inflamma-
tory response (Van Amersfoort et al., 2003). The most
potent class of cholesterol-lowering drugs, statins, has been
shown to also possess cholesterol-independent effects,
including diverse immunomodulatory and anti-inflamma-
tory properties (Almog, 2003). Recent studies have
demonstrated that simvastatin (Merx et al., 2004) and
cerivastatin (Ando et al., 2000) pretreatment profoundly
improves survival in a murine model of sepsis. Another
retrospective study has shown that statin therapy reduces
both overall and attributable mortality in patients with
bacteraemia (Liappis et al., 2001). The lipid profiles of the
statin-pretreated patients were considerably higher than
those of the no-statin group, and it has been suggested that
the medicinal efficacy is a result of the attenuation of the
intensity of the inflammatory response due to binding of
endotoxins by increased amounts of lipids (Almog et al.,
Several other immune response modifiers that target
different stages of innate immunity and might be useful
for plague therapy have recently been reviewed (Amlie-
Lefond et al., 2005; Masihi, 2000), but only one, glutoxim, a
sulfur-containing hexapeptide with an immunomodulatory
an animal model of plague (Zhemchugov, 2004). When
injected into mice (12?5 mg per animal) 6 h before
challenge with 10 LD50of the virulent Y. pestis strain 231,
it protected half of the animals from death. Glutoxim has
also been shown to protect mice from tularaemia and
melioidosis. However, the data thus far are inconclusive, as
they were obtained in isolated experiments that employed a
minimal number of laboratory animals.
Bacteriophages seem to be good candidates for antibacterial
therapy: they often possess high species specificity, they
are non-toxic to eukaryotes, and they kill the target
bacteria that they infect and within which they multiply.
After the discovery of bacteriophages by Twort in 1915, and
independently by d’Herelle in 1917, a number of researchers
and physicians were overenthusiastic in the use of
bacteriophagesfor the therapy
(Skurnik & Strauch, 2006; Sulakvelidze, 2005; Summers,
1999, 2001). With respect to plague, in 1925, d’Herelle used
a highly virulent anti-plague phage that had been isolated in
1920 in Indo-China from rat faeces to treat four cases of
1925). All the patients had laboratory-diagnosed bubonic
plague with very serious clinical signs. d’Herelle treated all
four with anti-plague phage preparations by single/double
several hours of injection, the patients felt better, a 2uC
average fall in temperature was recorded, and severe pain in
the buboes decreased. All four patients recovered in what
was considered a remarkable fashion. On the basis of this
work, a number of attempts to confirm the efficacy of the
phage therapy of plague both in animal models and in
clinical trials were performed (d’Herelle, 1925; Flu, 1929;
Fonquernie, 1932; Lien-Teh et al., 1936; Naidu & Avari,
1932; Rudnev 1940). However, a poor understanding of the
mechanisms of phage–bacterial interactions, including
lysogeny and phage DNA restriction, and poorly designed
and executed experiments and clinical trials, together with
the use of undefined phages in the form of non-purified
phage preparations, led to conflicting results (Skurnik &
Strauch, 2006; Sulakvelidze, 2005; Summers, 1999, 2001).
of bacterial disease
Bacteriophages have received renewed attention as possible
agents against bacterial pathogens. Evidence from several
recent trials designed and executed in accordance with good
laboratory practice (GLP) regulations indicates that phage
therapy can be effective, although the efficacy of the phage
aerosol spray, etc.) and/or frequency of phage application
(Skurnik & Strauch, 2006; Sulakvelidze, 2005; Summers,
1999, 2001). Numerous obstacles to the use of phage as
antimicrobials for clinical practice remain. Among them are
the issue of phage resistance, and the possibility of phage-
mediated transfer of undesirable genetic material to
bacterial hosts. Therapy based on the simultaneous use of
several phages with known genetic sequences and targeting
different bacterial receptors can help in overcoming these
obstacles.Currently, the genomes of several Y. pestis-specific
phages have been sequenced (Filippov et al., 2005; Garcia
et al., 2003), and they could be candidates for the revival of
plague phage therapy.
Alternative treatment of plague
A phage-encoded peptidoglycan-degrading activity is res-
ponsible for the cell-wall-hydrolysing action of bacterio-
phages. At least four types of these enzymes, endolysins, are
responsible for this activity in different phages (Young,
1992). Taking into account that if a sufficiently high phage
dose is given, phages are able to control infection through a
non-proliferative lytic mechanism (Berchieri et al., 1991;
Goode et al., 2003), the therapeutic use of endolysins in a
controlled fashion seems advantageous in comparison with
the uncontrollable increase of the live active agent.
Bacteriocins, bacterially produced antimicrobial peptides,
range from the well-studied, narrow spectrum, high-
molecular-mass colicins produced by Escherichia coli and
the short polypeptide lantibiotics of lactic acid bacteria to
the relatively unknown halocins produced almost universally
by halobacteria. Purified bacteriocins could be used for the
reduction or elimination of certain pathogens (Braude &
Siemienski, 1965; Riley & Wertz, 2002). It has been shown in
assays for potency that purified colicins V and K have similar
inhibitory activities on a per weight basis to those of the
therapeutic antibiotics kanamycin, streptomycin and oxyte-
by Lactococcus lactis) and mutacin B-Ny266 (produced by
Streptococcus mutans) are as active as vancomycin and
oxacillin against most strains tested (Bacillus, Enterococcus,
Lactococcus, Listeria, Mycobacterium, Pediococcus, Stap-
hylococcus, Bordetella, Clostridium,
Propionibacterium, Streptococcus and Micrococcus). Fur-
thermore, mutacin B-Ny266 remains active against strains
Meira et al., 2000).
Intraperitoneal injections of mutacin B-Ny266 have been
used for the treatment of mice infected with Staphylococcus
aureus. While there was 100% mortality in the control
group of mice, no mortality was observed in the mice
injected with vancomycin or mutacin B-Ny266 (Mota-
Meira et al., 2005). Lacticin 3147, a broad-spectrum
bacteriocin produced by the food-grade organism L. lactis,
reduced the incidence of mastitis after experimental
challenge with Streptococcus dysgalactiae in non-lactating
dairy cows (Ryan et al., 1999). Local injections of
staphylococcin A-1262a were used to treat 50 patients
with a variety of staphylococcal lesions. Complete recovery
was observed in 42 of the patients (Lachowicz, 1965). The
streptococcal bacteriocin tomicide was used for protection
of white mice from staphylococcal infection. Tomicide,
administered in the maximum dose admissible for mice,
ensured the protection of up to two-thirds of the total
number of mice. A single oral administration of the
preparation immediately after infection protected one-
third of the surviving mice from local staphylococcal
infection (Blinkova et al., 2003). The pronounced prophy-
lactic effect of tomicide, manifested by a reliable decrease of
morbidity in respiratory streptococcal infection among
children in a test group in comparison with controls, has
been reported (Briko & Zhuravlev, 2004). Enterocoliticin, a
phage-tail-like bacteriocin, has been administered as an
antimicrobial compound by the oral route for the treatment
of BALB/c mice infected with Yersinia enterocolitica, the
nearest relative of Y. pestis. The increase in the number of Y.
enterocolitica c.f.u. in animals was retarded at time points
shortly after the application of enterocoliticin, indicating
that the bacteriocin was effective during the early phase of
infection (Damasko et al., 2005). A purified class IIa
bacteriocin, secreted by Paenibacillus polymyxa NRRL-B-
30509, has been incorporated into chicken feed, and
dramatically reduced both intestinal levels and the fre-
quency of chicken colonization by Campylobacter jejuni
(Stern et al., 2005). The same bacteriocin has been shown to
Eruslanov, personal communication) in doses similar to
those recommended by the WHO Expert Committee on
Plague (WHO, 1970) for antibiotics. The above studies
suggest that there is a potential therapeutic effect associated
with bacteriocins. When contemplating the clinical use of
bacteriocins, one important consideration is their possible
pathological effects. In early studies with partially purified
bacteriocins (Montgomerie et al., 1973; Tagg & McGiven,
1972; Turnowsky et al., 1973) or strain pairs differing in
their expression (Brubaker et al., 1965; Burrows, 1965;
Smith, 1974), the data showed their potential toxicity, and
also a relationship between the carriage of bacteriocinogenic
factors and the virulence of certain strains. However, studies
with purified substances have in many cases failed to
confirm toxicity (Braude & Siemienski, 1965; Tagg et al.,
1976). Although intraperitoneal injection of 10 mg mutacin
B-Ny266 kg21did not apparently affect the health of mice,
these results will have to be confirmed with more relevant
toxicity tests (Mota-Meira et al., 2005). The investigation of
the in vitro cytotoxicities of two bacteriocins, gallidermin
(Staphylococcus gallinarum) and nisin A, in comparison
with those of antimicrobial peptides of eukaryotic origin,
magainin I, magainin II and melittin, indicated that
gallidermin was the least cytotoxic antimicrobial peptide,
followed by nisin A, magainin I, magainin II and melittin.
Nisin caused haemolysis, but at concentrations which were
1000-fold higher than those required for antimicrobial
activity. Gallidermin shows the most promise as a
therapeutic agent, with relatively low cytotoxicity and
potent antimicrobial activities (Maher & McClean, 2006).
In considering the potential toxicity of bacteriocins, the
well-known toxicity of antibiotics such as quinolones,
doxycycline, streptomycin and gentamicin, and the possible
problems associated with massive use of antimicrobial
agents for prophylaxis or therapy during a bioterrorist
attack, should be noted (Navas, 2002).
Inhibitors of virulence factors
Virulence refers to the ability of an organism to establish an
infection and cause disease. Many steps are involved in the
infection process, including adherence, invasion and the
evasion of host defences (Finlay & Falkow, 1997). Microbial
1468Journal of Medical Microbiology 55
A. P. Anisimov and K. K. Amoako
their inhibition, by definition, should interfere with the
process of infection rather than with bacterial viability.
to be cross-resistant to existing therapies, or to induce
resistance themselves. Bacterial virulence may therefore offer
(Alksne, 2002; Y. M. Lee et al., 2003; Marra, 2004).
A necessary step in the successful colonization and,
ultimately, production of disease by microbial pathogens
is the ability to adhere to host surfaces (Finlay & Falkow,
1997), in many cases involving oligosaccharides located
on the host cell surface and bacterial adhesins. The terminal
di- or trisaccharide units of these oligosaccharides may be
used to inhibit these interactions, preventing attachment
and therefore disease. The validity of this approach has been
unequivocally demonstrated in experiments performed in a
wide variety of animals, from mice to monkeys, and also in
humans (Ofek et al., 2003).
Y. pestis expresses a range of adhesins, including pH 6
Kienle et al., 1992; Parkhill et al., 2001; Payne et al., 1998).
pH 6 antigen binds to several human immunoglobulin G
1996). It is also able to bind to gangliotetraosylceramide,
gangliotriaosylceramide and lactosylceramide, and also to
attach to hydroxylated galactosylceramide. Recombinant
pH 6 antigen, present on the surface of intact E. coli cells,
exception of binding to non-hydroxylated galactosylcera-
mide. The observed binding patterns indicate that the
presence of b1-linked galactosyl residues in glycosphingo-
lipids is the minimum requirement for binding of the pH 6
antigen. The glycosphingolipids recognized by the pH 6
antigen are common and may be found on a range of host
cell types (Payne et al., 1998). In fact, pH 6 antigen
preparations are able to agglutinate human, rabbit, guinea
pig and murine erythrocytes (Bichowsky-Slomnicki & Ben-
Efraim, 1963). Studies that are currently in progress in the
Laboratory for Plague Microbiology, Department of
Infectious Diseases, State Research Center for Applied
Microbiologyand Biotechnology, indicatethat pH 6 antigen
is capable of promoting the adhesion of macrophage-like
eukaryotic cells to each other and to plastic surfaces, and the
formation of cell monolayers. The high-molecular-weight
capsular antigen F1 possesses haemagglutinating activity on
account of its ability to bind specifically to D-galactosamine-
HCl and glucuronic acid (Anisimov, 2002b). An analysis of
the complete genome of Y. pestis has revealed the presence of
eight more gene clusters similar to the operons psa and caf1,
each of which is potentially capable of promoting the
expression of the pilus adhesins (Parkhill et al., 2001).
Transfer of the pla locus, which encodes the production of
the plasminogen activator Pla, to E. coli cells imparted
adhesive activity to the latter with respect to a number of
eukaryoticcells(Kienleetal.,1992),on account oftheability
of Pla to bind to the mammalian extracellular matrix
(La ¨hteenma ¨ki et al., 1998). Y. pestis S-layer protein at a
concentration of 8–16 mg ml21agglutinated rabbit erythro-
cytes; this agglutination was inhibited by 0?1 M sugars:
rhamnose (fourfold) and dulcitol (eightfold) (Diatlov &
Antonova, 1999). Until recently it was customarily con-
sidered that the plague pathogen had lost the ability to
synthesize adhesin/invasin Ail on account of the insertion of
IS285 (Brubaker, 2004); however, in the genome of the Y.
pestis virulent strain CO92, this gene is intact (Parkhill et al.,
possess twohomologuesto the ErwiniaHecAadhesin (Rojas
an adhesin (Straley, 1993).
Y. pestis, as a species associated with pneumonic infections,
adheres more efficiently to an alveolar epithelial A549 cell
line than enteric bacteria, including enteric yersiniae. The
plague pathogen demonstrates a restricted tropism for
oligosaccharides compared with environmental and oppor-
tunistic bacteria. It has been shown that the compound with
the greatest anti-adhesion activity toward A549 cells is p-
nitrophenol (Thomas & Brooks, 2004). As an alternative to
antibiotics, the inhibition of attachment can be mediated
through the use of oligosaccharide receptor mimics. In a
more recent report, Thomas & Brooks (2006) have
demonstrated that the attachment of Y. pestis strain GB to
respiratory epithelial cell lines is reduced by 55–65% after
pre-treatment of the cell lines with tunicamycin (an
inhibitor of the biosynthesis and processing of N-linked
oligosaccharides, produced by Streptomyces lysosuperificus).
This further demonstrates the potential of oligosaccharides
as anti-adhesion therapeutics. Other generic attachment
inhibitors include polymeric saccharides (dextran and
4GlcNAc and Galb1-3GlcNAc (Thomas & Brooks, 2004).
It is possible that mixtures of such compounds may serve as
a novel class of therapeutics for respiratory tract infections,
including pneumonic plague.
into the cytosol of the eukaryotic target cell seems to be the
main pathogenicity factor of Yersinia. Inhibitors specifically
targeting type III secretion are attracting attention (Chen
et al., 2003; K. Lee et al.; 2003, 2005; Kauppi et al., 2003a,b;
Nordfelth et al., 2005; Xie et al.,2004).The majority of them
target YopH, protein tyrosine phosphatase (Chen et al.,
2003; K. Lee et al., 2003, 2005; Xie et al., 2004) or YopE, a
GTPase-activating protein (Kauppi et al., 2003b). Among
such inhibitors are compounds that belong to a class of
acylated hydrazones of different salicylaldehydes (Nordfelth
et al., 2005), monoanionic squaric acids (Xie et al., 2004),
peptidic a-ketocarboxylic acids, and sulfonamides (Chen
et al., 2003). A eukaryotic cell model that mimics in vivo
conditions has shown that some of the inhibitors attenuate
the pathogen to the advantage of the host cell.
Alternative treatment of plague
Iron is a necessary nutrient for all pro- and eukaryotic cells,
and at physiological pH values, iron salts (Fe3+) form an
almost-insoluble ferric hydroxide, Fe(OH)3. To assimilate
the negligible portion of the iron that is still present in the
dissolved state, both in the mammalian organism and in
micro-organisms, special iron-binding molecules, side-
rophores, are synthesized. Bacterial siderophores have a
critical roleinthecompetitionbetweenparasite andhostfor
iron acquisition (Braun, 2001; Finlay & Falkow, 1997).
Therefore, the Y. pestis siderophore yersiniabactin, as well as
its receptor Psn (Perry & Fetherston, 1997), are promising
treat plague. An inhibitor of the domain salicylation enzymes
required for siderophore biosynthesis in Y. pestis, the
arylic acyl adenylate analogue 59-O-[N-(salicyl)-sulfamoyl]
adenosine, has recently been designed, synthesized, and
shown to inhibit yersiniabactin biosynthesis and the growth
of Y. pestis under iron-limiting conditions (Ferreras et al.,
2005). More recently, a set of newly synthesized aryl
sulfamoyl adenosine derivatives has also been shown to
inhibit yersiniabactin biosynthesis in vitro (Miethke et al.,
Other possible targets for inhibiting Y. pestis virulence are
quorum sensing (Suga & Smith, 2003), the two-component
that govern virulence, and/or the enzymes for the
biosynthesis of the LPS that is believed to determine
antimicrobial-cationic-peptide (Anisimov et al., 2005;
Bengoechea et al., 1998) and serum resistance (Anisimov
et al., 2005; Porat et al., 1995).
Severe cases of plague are characterized by shock and
extensive diffuse intravascular coagulation (DIC), two
interrelated processes that have common causal mechan-
isms and reinforce each other (Hardaway, 1982). The
standard treatment of the pathophysiological changes
accompanying endotoxic shock and DIC consists of
administration of fluid and vasopressors to restore blood
pressure and organ blood flow, and oxygenation (Cohen &
1991; Wheeler & Bernard, 1999).
Very important to the management of shock is early fluid
resuscitation and the immediate start of mechanical
ventilation (Carcillo et al., 1991). In addition to extensive
capillary leakage, severe plague cases are characterized by
severe cardiac depression (Albizo & Surgalla, 1970; Butler,
1983; Dennis et al., 1999; Dmitrovskii, 1994; Lien-Teh et al.,
1954; Rudnev, 1940; Van Amersfoort et al., 2003).
Consequently, pulmonary congestion may develop early,
and this limits the amount of fluid that can be administered.
In general, inotropic and vasopressive support is needed
from an early stage. Dobutamine is preferred for its
beneficial effects on cardiac function and peripheral
oxygenation (Vincent et al., 1990; Winslow et al., 1973).
As for the anti-DIC therapy, currently the only undoubtedly
successful treatment is anti-shock therapy. Bleeding due
to DIC should probably be treated with replacement
therapy: platelets for thrombocytopenia, cryoprecipitate
for hypofibrinogenaemia and fresh frozen plasma for
decreased coagulation factors (Jacobson & Young, 1986).
DIC may cause severe distal necrosis (Welty et al., 1985),
and ifgangrenehas completely
plastic surgery or amputation may be needed (Kuberski
et al., 2003). In the case of evolving gangrene, in a patient
with good peripheral blood supply and no bleeding
diathesis, sympathetic blockade to preserve peripheral feet
tissues has been shown to be successful (Kuberski et al.,
The treatment dynamics of plague are of critical interest
because of the high human mortality rate of the disease, and
current threat for use in bioterrorism. Even though
antibiotics such as ciprofloxacin, doxycycline and the
newer fluoroquinolones have shown an increase in survival
in mice presenting with pneumonic plague, there has
recently been a worrying increase in multidrug-resistant Y.
pestis strains. This has necessitated the need to look at
alternatives to antibiotics as treatment regimens for plague.
This review has highlighted some of the promising non-
Thus, a novel treatment mechanism of pneumonic plague
infection may be via inhibiting adhesion of Y. pestis to the
respiratory tract. Recent progress in the use of short-chain
oligosaccharides as potential anti-adhesion therapeutics,
and also a set of newly synthesized aryl sulfamoyl adenosine
these receptor mimics potential alternatives to antibiotics.
Although hopes remain high that these alternative strategies
of plague treatment, alone or as part of combination
therapies, will provide a valuable new line of defence against
multdrug-resistant Y. pestis strains, they remain a long way
from clinical practice. The alternative therapies reported in
this review should be investigated by comprehensive studies
of their clinical applications as a form of preparedness
against any possible bioterrorist attack involving the use of
antibiotic-resistant Y. pestis.
This work was partially funded by US Civilian Research and
Development Foundation (CRDF) grant RBO-11012-MO-01 (DOE/
LAB agreement 325786-A-K6) and by the International Science and
Technology Center (ISTC) grant 2927.
Achtman, M., Zurth, K., Morelli, G., Torrea, G., Guiyoule, A. &
Carniel, E. (1999). Yersinia pestis, the cause of plague, is a recently
emerged clone of Yersinia pseudotuberculosis. Proc Natl Acad Sci U S
A 96, 14043–14048.
1470Journal of Medical Microbiology 55
A. P. Anisimov and K. K. Amoako
Afanas’ev, M. I. & Vaks, P. B. (1903). Human Plague. St Petersburg,
Russia: Modern Medicine and Hygiene Press (in Russian).
Albizo, J. M. & Surgalla, M. J. (1970). Isolation and biological
characterization of Pasteurella pestis endotoxin. Infect Immun 2,
Alksne, L. E. (2002). Virulence as a target for antimicrobial
chemotherapy. Expert Opin Investig Drugs 11, 1149–1159.
Almog, Y. (2003). Statins, inflammation, and sepsis: hypothesis.
Chest 124, 740–743.
Almog, Y., Shefer, A., Novack, V., Maimon, N., Barski, L., Eizinger,
M., Friger, M., Zeller, L. & Danon, A. (2004). Prior statin therapy is
associated with a decreased rate of severe sepsis. Circulation 110,
Amlie-Lefond, C., Paz, D. A., Connelly, M. P., Huffnagle, G. B., Dunn,
K. S., Whelan, N. T. & Whelan, H. T. (2005). Innate immunity for
biodefense: a strategy whose time has come. J Allergy Clin Immunol
Anderson, G. W., Worsham, P. L., Bolt, C., Andrews, G. P., Welkos,
S., Friedlander, A. M. & Burans, J. P. (1997). Protection of mice from
fatal bubonic and pneumonic plague by passive immunization with
monoclonal antibodies against the F1 protein of Yersinia pestis. Am
J Trop Med 56, 471–473.
Ando, H., Takamura, T., Ota, T., Nagai, Y. & Kobayashi, K. (2000).
Cerivastatin improves survival of mice with lipopolysaccharide-
induced sepsis. J Pharmacol Exp Ther 294, 1043–1046.
Andrews, G. P., Strachan, S. T., Benner, G. E., Sample, A. K.,
Anderson, G. W., Jr, Adamovicz, J. J., Welkos, S. L., Pullen, J. K. &
Friedlander, A. M. (1999). Protective efficacy of recombinant Yersinia
outer proteins against bubonic plague caused by encapsulated and
nonencapsulated Yersinia pestis. Infect Immun 67, 1533–1537.
Anisimov, A. P. (2002a). Factors of Yersinia pestis proving circulation
and persistence of plague pathogen in ecosystems of natural foci.
Communication 2. Mol Gen Mikrobiol Virusol 4, 3–11 (in Russian).
Anisimov, A. P. (2002b). Yersinia pestis factors, assuring circulation
and maintenance of the plague pathogen in natural foci ecosystems.
Report 1. Mol Gen Mikrobiol Virusol 3, 3–23 (in Russian).
Anisimov, A. P., Lindler, L. E. & Pier, G. B. (2004). Intraspecific
diversity of Yersinia pestis. Clin Microbiol Rev 17, 434–464 (erratum
Anisimov, A. P., Dentovskaya, S. V., Titareva, G. M. & 9 other
authors (2005). Intraspecies and temperature-dependent variations
in susceptibility of Yersinia pestis to bactericidal action of serum and
polymyxin B. Infect Immun 73, 7324–7331.
Aparin, G. P. & Golubinskii, E. P. (1989). Plague Microbiology
Manual. Irkutsk, USSR: Irkutsk State University (in Russian).
Becker, T. M., Poland, J. D., Quan, T. J., White, M. E., Mann, J. M. &
Barnes, A. M. (1987). Plague meningitis – a retrospective analysis of
cases reported in the United States, 1970–1979. West J Med 147,
Bengoechea, J.-A., Lindner, B., Seydel, U., Dı ´az, R. & Moriyo ´n, I.
(1998). Yersinia pseudotuberculosis and Yersinia pestis are more
resistant to bactericidal cationic peptides than Yersinia enterocolitica.
Microbiology 144, 1509–1515.
Berchieri, A. J., Lovell, M. A. & Barrow, P. A. (1991). The activity in
the chicken alimentary tract of bacteriophages lytic for Salmonella
typhimurium. Res Microbiol 142, 541–549.
Bichowsky-Slomnicki, L. & Ben-Efraim, S. (1963). Biological
activities in extracts of Pasteurella pestis and their relation to the
‘pH 6 antigen’. J Bacteriol 86, 101–111.
Blinkova, L. P., Butova, L. G., Sergeev, V. V., Elkina, S. I., Al’tshuler,
M. L. & Kalina, N. G. (2003). Effectiveness of the oral administration
of tomicide in experimental infection. Zh Mikrobiol Epidemiol
Immunobiol 1, 74–77 (in Russian).
Bosio, C. M., Goodyear, A. W. & Dow, S. W. (2005). Early interaction
of Yersinia pestis with APCs in the lung. J Immunol 175, 6750–6756.
resistance to infection by Gram-negative bacteria. I. The effect of colicin
on bactericidal power of blood. J Clin Invest 44, 849–859.
Braun, V. (2001). Iron uptake mechanisms and their regulation in
pathogenic bacteria. Int J Med Microbiol 291, 67–79.
Bregenholt, S. & Haurum, J. (2004). Pathogen-specific recombinant
human polyclonal antibodies: biodefence applications. Expert Opin
Biol Ther 4, 387–396.
Briko, N. I. & Zhuravlev, M. V. (2004). Use of tomicid in prophylaxis
of respiratory streptococcal infection in the organized groups of
children of pre-school age. Zh Mikrobiol Epidemiol Immunobiol 4,
17–20 (in Russian).
Brubaker, R. R. (1991). Factors promoting acute and chronic disease
caused by yersiniae. Clin Microbiol Rev 4, 309–324.
Brubaker, R. R. (2004). The recent emergence of plague: a process of
felonious evolution. Microb Ecol 47, 293–299.
role of pesticin I and iron in experimental plague. Science 149, 422–424.
Buchwald, U. K. & Pirofski, L. (2003). Immune therapy for infectious
diseases at the dawn of the 21st century: the past, present and future
role of antibody therapy, therapeutic vaccination and biological
response modifiers. Curr Pharm Des 9, 945–968.
Burrows, T. W. (1965). A possible role for pesticin in virulence of
Pasteurella pestis. Zentbl Bakteriol Parasitenkd Infektkr Hyg Abt 1 Orig
Reihe A 196, 315–317.
Butler, T. (1983). Plague and Other Yersinia Infections. New York:
Byrne, W. R., Welkos, S. L., Pitt, M. L. & 7 other authors (1998).
Antibiotic treatment of experimental pneumonic plague in mice.
Antimicrob Agents Chemother 42, 675–681.
Carcillo, J. A., Davis, A. L. & Zaritsky, A. (1991). Role of early fluid
resuscitation in pediatric septic shock. JAMA (J Am Med Assoc) 266,
Carman, J. A. (1938). Prontosil in the treatment of oriental plague.
East Afr Med J 14, 362–366.
Casadevall, A. (2002). Passive antibody administration (immediate
immunity) as a specific defense against biological weapons. Emerg
Infect Dis 8, 833–841.
Casadevall, A. (2005). Antibody-based defense strategies against
biological weapons. ASM News 71, 28–33.
Cavanaugh, D. C. & Randall, R. (1959). The role of multiplication of
Pasteurella pestis in mononuclear phagocytes in the pathogenesis of
fleaborne plague. J Immunol 83, 348–363.
Chen, Y. T., Xie, J. & Seto, C. T. (2003). Peptidic a-ketocarboxylic
acids and sulphonamides as inhibitors of protein tyrosine phospha-
tases. J Org Chem 68, 4123–4125.
Cohen, J. & Glauser, M. P. (1991). Septic shock: treatment. Lancet
Cornelis, G. R. (2002). Yersinia type III secretion: send in the
effectors. J Cell Biol 158, 401–408.
Cowan, C., Philipovskiy, A. V., Wulff-Strobel, C. R., Ye, Z. & Straley,
S. C. (2005). Anti-LcrV antibody inhibits delivery of Yops by
Yersinia pestis KIM5 by directly promoting phagocytosis. Infect
Immun 73, 6127–6137.
Damasko, C., Konietzny, A., Kaspar, H., Appel, B., Dersch, P. &
Strauch, E. (2005). Studies of the efficacy of enterocoliticin, a
Alternative treatment of plague
phage-tail like bacteriocin, as antimicrobial agent against Yersinia
enterocolitica serotype O3 in a cell culture system and in mice. J Vet
Med B Infect Dis Vet Public Health 52, 171–179.
Dennis, D. T., Gratz, N., Poland, J. D. & Tikhomirov, E. (1999). Plague
Manual: Epidemiology, Distribution, Surveillance and Control. Geneva:
World Health Organization.
d’Herelle, F. (1925). Essai de traitement de la peste bubonique par le
bacteriophage. La Presse Medicale 84, 1393–1394 (in French).
Diatlov, I. A. & Antonova, O. A. (1999). The detection and
characteristics of the Yersinia pestis antigen exhibiting the properties
of S-layer proteins. Zh Mikrobiol Epidemiol Immunobiol 4, 90–91 (in
Dmitrovskii, V. G. (1994). Toxic component of pathogenesis of
plague infectious process: infective toxic shock. In Prophylaxis and
Means of Prevention of Plague, pp. 15–16. Edited by V. M. Stepanov.
Almaty, Kazakhstan: Scientific-Manufacturing Association of the
Plague-Control Establishments (in Russian).
Domaradskii, I. V. (1993). Plague: Contemporary State, Assumptions,
Problems. Saratov, Russia: Saratov Medical Institute Press (in Russian).
Domaradskii, I. V. (1998). Plague. Moscow: Meditsina Press (in
Drancourt, M., Roux, V., Dang, L. V. & 7 other authors (2004).
Genotyping, Orientalis-like Yersinia pestis, and plague pandemics.
Emerg Infect Dis 10, 1585–1592.
Ehrenkranz, N. F. & Meyer, K. F. (1955). Studies on immunization
against plague, VIII: study of three immunizing preparations in
protecting primates against pneumonic plague. J Infect Dis 96, 138–144.
Ferreras, J. A., Ryu, J. S., Lello, F. D., Tan, D. S. & Quadri, L. E. (2005).
tuberculosis and Yersinia pestis. Nat Chem Biol 1, 29–32.
Filippov, A. A., Elliott, J. M., Bobrov, A. G., Kirillina, O. A., Motin, V. L.,
Chain, P. S. & Garcia, E. (2005). Description of the genomic
nucleotide sequence of the plague diagnostic bacteriophage, L-413C.
The Problems of Particularly Dangerous Infections (Saratov) 90, 49–52
Fimiani, V., Cavallaro, A., Ainis, T., Baranovskaia, G., Ketlinskaya, O.
& Kozhemyakin, L. (2002). Immunomodulatory effect of glutoxim
on some activities of isolated human neutrophils and in whole
blood. Immunopharmacol Immunotoxicol 24, 627–638.
Finlay, B. B. & Falkow, S. (1997). Common themes in microbial
pathogenicity revisited. Microbiol Mol Biol Rev 61, 136–169.
Flu, P. C. (1929). Antipest bakteriophag und die prophylaxe und
therapie der experimentellen pest. Zentbl Bakteriol I Orig 113, 468–
473 (in German).
Fonquernie, I. (1932). Essais de traitement de la peste par le
bacteriophage. Bull Sol Pathol Exot 25, 677 (in French).
Frean, J., Klugman, K. P., Arntzen, L. & Bukofzer, S. (2003).
Susceptibility of Yersinia pestis to novel and conventional anti-
microbial agents. J Antimicrob Chemother 52, 294–296.
Friedlander, A. M., Welkos, S. L., Worsham, P. L., Andrews, G. P.,
Heath, D. G., Anderson, G. W., Jr, Pitt, M. L., Estep, J. & Davis, K.
(1995). Relationship between virulence and immunity as revealed in
recent studies of the F1 capsule of Yersinia pestis. Clin Infect Dis 21
(Suppl. 2), S178–S181.
Gage, K. L. & Kosoy, M. Y. (2005). Natural history of plague:
perspectives from more than a century of research. Annu Rev
Entomol 50, 505–528.
Galimand, M., Guiyoule, A., Gerbaud, G., Rasoamanana, B.,
Chanteau, S., Carniel, E. & Courvalin, P. (1997). Multiple antibiotic
resistance in Yersinia pestis mediated by a self-transferable plasmid. N
Engl J Med 337, 677–680.
Garcia, E., Elliott, J. M., Ramanculov, E., Chain, P. S., Chu, M. C. &
Molineux, I. J. (2003). The genome sequence of Yersinia pestis
bacteriophage wA1122 reveals an intimate history with the coliphage
T3 and T7 genomes. J Bacteriol 185, 5248–5262.
Goode, D., Allen, V. M. & Barrow, P. A. (2003). Reduction of
experimental Salmonella and Campylobacter contamination of
chicken skin by application of lytic bacteriophages. Appl Environ
Microbiol 69, 5032–5036.
Green, M., Rogers, D., Russell, P., Stagg, A. J., Bell, D. L., Eley, S. M.,
Titball, R. W. & Williamson, E. D. (1999). The SCID/Beige mouse as a
model to investigate protection against Yersinia pestis. FEMS
Immunol Med Microbiol 23, 107–113.
Guiyoule, A., Grimont, F., Iteman, I., Grimont, P. D., Lefe `vre, M. &
Carniel, E. (1994). Plague pandemics investigated by ribotyping of
Yersinia pestis strains. J Clin Microbiol 32, 634–641.
Hardaway, R. M. (1982). Pathology and pathophysiology of
Shock, Anoxia and Ischaemia, pp. 186–197. Edited by R. A. Cowley
& B. F. Trump. Baltimore, MD: Williams & Wilkins.
Hill, J., Leary, S. E. C., Griffin, K. F., Williamson, E. D. & Titball, R. W.
(1997). Regions of Yersinia pestis V antigen that contribute to
protection against plague identified by passive and active immuniza-
tion. Infect Immun 65, 4476–4482.
Hill, J., Eyles, J. E., Elvin, S. J., Healey, G. D., Lukaszewski, R. A. &
Titball, R. W. (2006). Administration of antibody to the lung protects
mice against pneumonic plague. Infect Immun 74, 3068–3070.
Hinnebusch, B. J. (2003). Transmission factors: Yersinia pestis genes
Hinnebusch, B. J., Rosso, M. L., Schwan, T. G. & Carniel, E. (2002).
High-frequency conjugative transfer of antibiotic resistance genes to
Yersinia pestis in the flea midgut. Mol Microbiol 46, 349–354.
Hornibrook, J. W. (1946). Streptomycin in experimental plague. Publ
Health Rep 61, 535–538.
Hurtle, W., Lindler, L., Fan, W., Shoemaker, D., Henchal, E. &
Norwood, D. (2003). Detection and identification of ciprofloxacin-
resistant Yersinia pestis by denaturing high-performance liquid
chromatography. J Clin Microbiol 41, 3273–3283.
Inglesby, T. V., Dennis, D. T., Henderson, D. A. & 16 other authors
(2000). Plague as a biological weapon: medical and public health
management. JAMA (J Am Med Assoc) 283, 2281–2290.
Jacobs, R. F., Sowell, M. K., Moss, M. M. & Fiser, D. H. (1990). Septic
shock in children: bacterial etiologies and temporal relationships.
Pediatr Infect Dis J 9, 196–200.
Jacobson, M. A. & Young, L. S. (1986). New developments in the
treatment of Gram-negative bacteremia. West J Med 144, 185–194.
Kang, A. S., Burton, D. R. & Lerner, R. A. (1991). Combinatorial
immunoglobulin libraries in phage. Methods: Companion Methods
Enzymol 2, 111–118.
Kauppi, A. M., Nordfelth, R., Hagglund, U., Wolf-Watz, H. &
Elofsson, M. (2003a). Salicylanilides are potent inhibitors of type
III secretion in Yersinia. Adv Exp Med Biol 529, 97–100.
Kauppi, A. M., Nordfelth, R., Uvell, H., Wolf-Watz, H. & Elofsson, M.
(2003b). Targeting bacterial virulence: inhibitors of type III secretion
in Yersinia. Chem Biol 10, 241–249.
Keller, M. A. & Stiehm, E. R. (2000). Passive immunity in prevention
and treatment of infectious diseases. Clin Microbiol Rev 13, 602–614.
Kienle, Z., Emody, L., Svanborg, C. & O’Toole, P. W. (1992).
Adhesive properties conferred by the plasminogen activator of
Yersinia pestis. J Gen Microbiol 138, 1679–1687.
Kohler, G. & Milstein, C. (1975). Continuous cultures of fused cells
secreting antibody of predefined specificity. Nature 256, 495–497.
1472Journal of Medical Microbiology 55
A. P. Anisimov and K. K. Amoako
Kool, J. L. (2005). Risk of person-to-person transmission of
pneumonic plague. Clin Infect Dis 40, 1166–1172.
Krishna, G. & Chitkara, R. K. (2003). Pneumonic plague. Semin
Respir Infect 18, 159–167.
Kuberski, T., Robinson, L. & Schurgin, A. (2003). A case of plague
successfully treated with ciprofloxacin and sympathetic blockade for
treatment of gangrene. Clin Infect Dis 36, 521–523.
Lachowicz, T. (1965). Investigations on staphylococcins. Zentbl
Bakteriol Parasitenkd Infektkr Hyg Abt 1 Orig Reihe A 196, 340–351.
La ¨hteenma ¨ki, K., Virkola, R., Sare ´n, A., Emo ¨dy, L. & Korhonen, T. K.
(1998). Expression of plasminogen activator Pla of Yersinia pestis
enhances bacterial attachment to the mammalian extracellular
matrix. Infect Immun 66, 5755–5762.
Leary, S. E. C., Williamson, E. D., Griffin, K. F., Russell, P., Eley, S. M.
& Titball, R. W. (1995). Active immunization with recombinant V
antigen from Yersinia pestis protects mice against plague. Infect
Immun 63, 2854–2858.
Lee, K., Gao, Y., Yao, Z. J., Phan, J., Wu, L., Liang, J., Waugh, D. S.,
Zhang, Z. Y. & Burke, T. R., Jr (2003). Tripeptide inhibitors of
Yersinia protein-tyrosine phosphatase. Bioorg Med Chem Lett 13,
Lee, Y. M., Almqvist, F. & Hultgren, S. J. (2003). Targeting virulence
for antimicrobial chemotherapy. Curr Opin Pharmacol 3, 513–519.
Lee, K., Boovanahalli, S. K., Nam, K. Y. & 9 other authors (2005).
Synthesisof tripeptidesas potent
phosphatase inhibitors. Bioorg Med Chem Lett 15, 4037–4042.
Liappis, A. P., Kan, V. L., Rochester, C. G. & Simon, G. L. (2001). The
effect of statins on mortality in patients with bacteremia. Clin Infect
Dis 33, 1352–1357.
Lien-Teh, W. (1926). A Treatise on Pneumonic Plague. League of
Nations, Health Organisation. Printed by Berger-Levrault.
Lien-Teh, W., Chun, J. W. H., Pollitzer, R. & Wu, C. Y. (1936). Plague:
a Manual for Medical & Public Health Workers. Shanghai.
Liles, W. C. (2001). Immunomodulatory approaches to augment
phagocyte-mediated host defense for treatment of infectious diseases.
Semin Respir Infect 16, 11–17.
Maher, S. & McClean, S. (2006). Investigation of the cytotoxicity of
eukaryotic and prokaryotic antimicrobial peptides in intestinal
epithelial cells in vitro. Biochem Pharmacol 71, 1289–1298.
Marra, A. (2004). Can virulence factors be viable antibacterial targets?
Expert Rev Anti Infect Ther 2, 61–72.
Masihi, K. N. (2000). Immunomodulatory agents for prophylaxis and
therapy of infections. Int J Antimicrob Agents 14, 181–191.
Matson, J. S., Durick, K. A., Bradley, D. S. & Nilles, M. L. (2005).
Immunization of mice with YscF provides protection from Yersinia
pestis infections. BMC Microbiol 5, 38.
McGeachie, J. (1970). An in vitro comparison of colicines K and V
and some therapeutic antibiotics. Zentbl Bakteriol Parasitenkd
Infektkr Hyg Abt 1 Orig Reihe A 215, 245–251.
Merx, M. W., Liehn, E. A., Janssens, U., Lutticken, R., Schrader, J.,
Hanrath, P. & Weber, C. (2004). HMG-CoA reductase inhibitor
simvastatin profoundly improves survival in a murine model of
sepsis. Circulation 109, 2560–2565.
Meyer, K. F. (1970). Effectiveness of live or killed plague vaccines in
man. Bull W H O 42, 653–666.
Meyer, K. F., Hightower, J. A. & McCrumb, F. R. (1974). Plague
immunization. VI. Vaccination with the fraction I antigen of Yersinia
pestis. J Infect Dis 129 (Suppl.), S41–S45.
Miethke, M., Bisseret, P., Beckering, C. L., Vignard, D., Eustache, J.
& Marahiel, M. A. (2006). Inhibition of aryl acid adenylation domains
involved in bacterial siderophore synthesis. FEBS J 273, 409–419.
Montgomerie, J. Z., Kalmanson, G. M., Harwick, H. J. & Guze, L. B.
(1973). Relation between bacteriocin production and virulence of
Streptococcus faecalis var. liquefaciens. Proc Soc Exp Biol Med 144,
Morrison, S. L. (1992). In vitro antibodies: strategies for production
and application. Annu Rev Immunol 10, 239–265.
Mota-Meira, M., LaPointe, G., Lacroix, C. & Lavoie, M. C. (2000).
MICs of mutacin B-Ny266, nisin A, vancomycin, and oxacillin
against bacterial pathogens. Antimicrob Agents Chemother 44, 24–29.
Mota-Meira, M., Morency, H. & Lavoie, M. C. (2005). In vivo activity
of mutacin B-Ny266. J Antimicrob Chemother 56, 869–871.
Motin, V. L., Nakajima, R., Smirnov, G. B. & Brubaker, R. R. (1994).
Passive immunity to yersiniae mediated by anti-recombinant V antigen
and protein A-V antigen fusion peptide. Infect Immun 62, 4192–4201.
Naidu, B. P. B. & Avari, G. R. (1932). Bacteriophage in the treatment
of plague. Ind J Med Res 19, 737–748.
Nau, R. & Eiffert, H. (2002). Modulation of release of proinflamma-
tory bacterial compounds by antibacterials: potential impact on
course of inflammation and outcome in sepsis and meningitis. Clin
Microbiol Rev 15, 95–110.
Naumov, A. V. & Samoilova, L. V. (1992). Manual on Plague
Prophylaxis. Saratov, Russia: Russian Research Anti-Plague Institute
‘Microbe’ (in Russian).
Naumov, A. V., Ledvanov, M. Yu. & Drozdov, I. G. (1992). Plague
Immunology. Saratov, Russia: Russian Research Anti-Plague Institute
‘Microbe’ (in Russian).
Navas, E. (2002). Problems associated with potential massive use of
antimicrobial agents as prophylaxis or therapy of a bioterrorist
attack. Clin Microbiol Infect 8, 534–539.
Nikolaev, N. I. (1972). Manual on Plague Prophylaxis. Saratov, USSR:
All-Union Research Anti-Plague Institute ‘Microbe’ (in Russian).
Nordfelth, R., Kauppi, A. M., Norberg, H. A., Wolf-Watz, H. &
Elofsson, M. (2005). Small-molecule inhibitors specifically targeting
type III secretion. Infect Immun 73, 3104–3114.
Ofek, I., Hasty, D. L. & Sharon, N. (2003). Anti-adhesion therapy of
bacterial diseases: prospects and problems. FEMS Immunol Med
Microbiol 38, 181–191.
Oyston, P. C. F., Dorrell, N., Williams, K., Li, S.-R., Green, M., Titball,
R. W. & Wren, B. W. (2000). The response regulator PhoP is
important for survival under conditions of macrophage-induced
stress and virulence in Yersinia pestis. Infect Immun 68, 3419–3425.
Parkhill, J., Wren, B. W., Thomson, N. R. & 32 other authors (2001).
Genome sequence of Yersinia pestis, the causative agent of plague.
Nature 413, 523–527.
Payne, D., Tatham, D., Williamson, E. D. & Titball, R. W. (1998). The
pH 6 antigen of Yersinia pestis binds to b1-linked galactosyl residues
in glycosphingolipids. Infect Immun 66, 4545–4548.
Perry, R. D. & Fetherston, J. D. (1997). Yersinia pestis – etiologic
agent of plague. Clin Microbiol Rev 10, 35–66.
Philipovskiy, A. V., Cowan, C., Wulff-Strobel, C. R., Burnett, S. H.,
Kerschen, E. J., Cohen, D. A., Kaplan, A. M. & Straley, S. C. (2005).
Antibody against V antigen prevents Yop-dependent growth of
Yersinia pestis. Infect Immun 73, 1532–1542.
Pollitzer, R. (1954). Plague. W H O Monogr Ser 22, 1–698.
Porat, R., McCabe, W. R. & Brubaker, R. R. (1995). Lipopolysaccharide-
associated resistance to killing of yersiniae by complement. J Endotoxin
Res 2, 91–97.
Portnoy, D. A. & Falkow, S. (1981). Virulence-associated plasmids from
Yersinia enterocolitica and Yersinia pestis. J Bacteriol 148, 877–883.
Rackow, E. C. & Astiz, M. E. (1991). Pathophysiology and treatment
of septic shock. JAMA (J Am Med Assoc) 266, 548–554.
Alternative treatment of plague
Raoult, D., Aboudharam, G., Crubezy, E., Larrouy, G., Ludes, B. &
Drancourt, M. (2000). Molecular indentification by ‘suicide PCR’ of
Yersinia pestis as the agent of medieval Black Death. Proc Natl Acad
Sci U S A 97, 12800–12803.
Riley, M. A. & Wertz, J. E. (2002). Bacteriocins: evolution, ecology,
and application. Annu Rev Microbiol 56, 117–137.
Robinson, V. L., Oyston, P. C. & Titball, R. W. (2005). A dam mutant
of Yersinia pestis is attenuated and induces protection against plague.
FEMS Microbiol Lett 252, 251–256.
Roggenkamp, A., Geiger, A. M., Leitritz, L., Kessler, A. &
Heesemann, J. (1997). Passive immunity
Yersinia spp. mediated by anti-recombinant V antigen is dependent
on polymorphism of V antigen. Infect Immun 65, 446–451.
Rojas, C. M., Ham, J. H., Deng, W. L., Doyle, J. J. & Collmer, A. (2002).
HecA, a member of a class of adhesins produced by diverse pathogenic
bacteria, contributes to the attachment, aggregation, epidermal cell
killing, and virulence phenotypes of Erwinia chrysanthemi EC16 on
Rudnev, G. P. (1940). Clinical Picture of Plague. Moscow, Leningrad,
Russia: Medgiz (in Russian).
Russell, P., Eley, S. M., Green, M. & 8 other authors (1998). Efficacy
of doxycycline and ciprofloxacin against experimental Yersinia pestis
infection. J Antimicrob Chemother 41, 301–305.
Ryan, M. P., Flynn, J., Hill, C., Ross, R. P. & Meaney, W. J. (1999). The
natural food grade inhibitor, lacticin 3147, reduced the incidence of
mastitis after experimental challenge with Streptococcus dysgalactiae
in nonlactating dairy cows. J Dairy Sci 82, 2625–2631.
Ryzhko, I. V., Samokhodkina, E.D.,Tsuraeva,R. I., Shcherbaniuk, A. I.
& Tsetskhladze, N. S. (1998). Characteristics of etiotropic therapy of
plague infection induced by atypical strains of F12phenotype plague
microbe. Antibiot Khimioter 43, 24–28 (in Russian).
Sabhnani, L. & Rao, D. N. (2000). Identification of immunodominant
epitope of F1 antigen of Yersinia pestis. FEMS Immunol Med
Microbiol 27, 155–162.
Sabhnani, L., Manocha, M., Sridevi, K., Shashikiran, D., Rayanade,
R. & Rao, D. N. (2003). Developing subunit immunogens using B and
T cell epitopes and their constructs derived from the F1 antigen of
Yersinia pestis using novel delivery vehicles. FEMS Immunol Med
Microbiol 38, 215–229.
Simpson, W. J., Thomas, R. E. & Schwan, T. G. (1990). Recombinant
capsular antigen (fraction 1) from Yersinia pestis induces a protective
antibody response in BALB/c mice. Am J Trop Med Hyg 43, 389–396.
Sing, A., Rost, D., Tvardovaskaia, N., Roggenkamp, A., Wiedemann,
A., Kirschning, C. J., Aepfelbacher, M. & Heesemann, J. (2002).
Yersinia V-antigen exploits toll-like receptor 2 and CD14 for
interleukin 10-mediated immunosuppression. J Exp Med 196,
Skurnik, M. & Strauch, E. (2006). Phage therapy: facts and fiction.
Int J Med Microbiol 296, 5–14.
Smith, H. W. (1974). A search for transmissible pathogenic characters
in invasive strains of Escherichia coli: the discovery of a plasmid-
controlled toxin and a plasmid-controlled lethal character closely
associated, or identical, with colicin V. J Gen Microbiol 83, 95–111.
Sodhi, A., Sharma, R. K., Batra, H. V. & Tuteja, U. (2004).
Mechanism of rLcrV and rYopB mediated immunosuppression in
murine peritoneal macrophages. Mol Immunol 41, 767–774.
Stern, N. J., Svetoch, E. A., Eruslanov, B. V., Kovalev, Y. N.,
Volodina, L. I., Perelygin, V. V., Mitsevich, E. V., Mitsevich, I. P. &
Levchuk, V. P. (2005). Paenibacillus polymyxa purified bacteriocin to
control Campylobacter jejuni in chickens. J Food Prot 68, 1450–1453.
Steward, J., Lever, M. S., Russell, P., Beedham, R. J., Staga, A. J.,
Taylor, R. R. & Brooks, T. J. G. (2004). Efficacy of the latest
fluoroquinolones against experimental Yersinia pestis. Int J Antimicrob
Agents 24, 609–612.
Straley, S. C. (1993). Adhesins in Yersinia pestis. Trends Microbiol 1,
Suga, H. & Smith, K. M. (2003). Molecular mechanisms of bacterial
quorum sensing as a new drug target. Curr Opin Chem Biol 7, 586–591.
Sulakvelidze, A. (2005). Phage therapy: an attractive option for
dealing with antibiotic-resistant bacterial infections. Drug Discov
Today 10, 807–809.
Summers, W. C. (1999). Felix d’Herelle and the Origins of Molecular
Biology. New Haven, CT: Yale University Press.
Summers, W. C. (2001). Bacteriophage therapy. Annu Rev Microbiol
Tagg, J. R. & McGiven, A. R. (1972). Some possible autoimmune
mechanisms in rheumatic carditis. Lancet 2, 686–688.
Tagg, J. R., Dajani, A. S. & Wannamaker, L. W. (1976). Bacteriocins
of Gram-positive bacteria. Bacteriol Rev 40, 722–756.
Thomas, R. & Brooks, T. (2004). Common oligosaccharide moieties
inhibit the adherence of typical and atypical respiratory pathogens.
J Med Microbiol 53, 833–840.
Thomas, R. & Brooks, T. (2006). Attachment of Yersinia pestis to
human respiratory cell lines is inhibited by certain oligosaccharides.
J Med Microbiol 55, 309–315.
Turnowsky, F., Drews, J., Eich, F. & Hogenauer, G. (1973). In vitro
inactivation of ascites ribosomes by colicin E3. Biochem Biophys Res
Commun 52, 327–334.
Une, T. & Brubaker, R. R. (1984). Roles of V antigen in promoting
virulence and immunity in yersiniae. J Immunol 133, 2226–2230.
Van Amersfoort, E. S., Van Berkel, T. J. & Kuiper, J. (2003).
Receptors, mediators, and mechanisms involved in bacterial sepsis
and septic shock. Clin Microbiol Rev 16, 379–414.
Viboud, G. I. & Bliska, J. B. (2005). Yersinia outer proteins: role in
modulation of host cell signaling responses and pathogenesis. Annu
Rev Microbiol 59, 69–89.
Vincent, J.-L., Roman, A. & Kahn, R. J. (1990). Dobutamine
administration in septic shock: addition to a standard protocol.
Crit Care Med 18, 689–693.
Weeks, S., Hill, J., Friedlander, A. & Welkos, S. (2002). Anti-V
antigen antibody protects macrophages from Yersinia pestis-induced
cell death and promotes phagocytosis. Microb Pathog 32, 227–237.
Welty, T. K., Grabman, J., Kompare, E., Wood, G., Welty, E., Van
Duzen, J., Rudd, P. & Poland, J. (1985). Nineteen cases of plague in
Arizona: a spectrum including ecthyma gangrenosum due to plague
and plague in pregnancy. West J Med 142, 641–646.
Wheeler, A. P. & Bernard, G. R. (1999). Treating patients with severe
sepsis. N Engl J Med 340, 207–214.
Williamson, E. D. (2001). Plague vaccine research and development.
J Appl Microbiol 91, 606–608.
Williamson, E. D., Flick-Smith, H. C., Lebutt, C. & 7 other authors
(2005). Human immune response to a plague vaccine comprising
recombinant F1 and V antigens. Infect Immun 73, 3598–3608.
Winfield, M. D., Latifi, T. & Groisman, E. A. (2005). Transcriptional
regulation of the 4-amino-4-deoxy-L-arabinose biosynthetic genes in
Yersinia pestis. J Biol Chem 280, 14765–14772.
Winslow, E. J., Loeb, H. S., Rahimtoola, S. H., Kamath, S. & Gunnar,
R. M. (1973). Hemodynamic studies and results of therapy in 50
patients with bacteremic shock. Am J Med 54, 421–432.
Wong, J. D., Baresh, J. R., Sandfort, R. F. & Janda, J. M. (2000).
Susceptibilities of Yersinia pestis strains to 12 antimicrobial agents.
Antimicrob Agents Chemother 44, 1995–1996.
1474Journal of Medical Microbiology 55
A. P. Anisimov and K. K. Amoako
WHO (1970). Health Aspects of Chemical and Biological Weapons: Download full-text
Report of a WHO Group of Consultants. Geneva: World Health
WHO Expert Committee on Plague (1970). Fourth report. World
Health Organ Tech Rep Ser 447, 1–25.
Xie, J., Comeau, A. B. & Seto, C. T. (2004). Squaric acids: a new
motif for designing inhibitors of protein tyrosine phosphatases. Org
Lett 6, 83–86.
Yersin, A. (1894). La peste bubonique a ` Hong-Kong. Ann Inst
Pasteur 8, 662–667 (in French).
Yersin, A. (1897). Sur la peste bubonique (se ´rothe ´rapie). Ann Inst
Pasteur 11, 81–93 (in French).
Yersin, A., Calmette, A. & Borrel, A. (1895). La peste bubonique
(deuxie ´me note). Ann Inst Pasteur 9, 589–592 (in French).
Young, R. (1992). Bacteriophage lysis: mechanism and regulation.
Microbiol Rev 56, 430–481.
Zav’yalov, V., Denesyuk, A., Zav’yalova, G. & Korpela, T. (1995).
Molecular modeling of the steric structure of the envelope F1 antigen
of Yersinia pestis. Immunol Lett 45, 19–22.
Zav’yalov, V. P., Abramov, V. M., Cherepanov, P. G., Spirina, G. V.,
Chernovskaya, T. V., Vasiliev, A. M. & Zav’yalov, G. A. (1996). pH6
antigen (PsaA protein) of Yersinia pestis, a novel bacterial Fc-
receptor. FEMS Immunol Med Microbiol 14, 53–57.
Zhemchugov, V. Ye. (2004). How We Developed Chemical Vaccines:
Notes about Today’s ‘Microbe Hunters’. Moscow: Nauka (in Russian).
Zietz, B. P. & Dunkelberg, H. (2004). The history of the plague and
the research on the causative agent Yersinia pestis. Int J Hyg Environ
Health 207, 165–178.
Alternative treatment of plague