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Review |
1 Laboratory for Plague Microbiology, Department of Infectious Diseases, State Research Center for Applied Microbiology and Biotechnology, 142279 Obolensk, Serpukhov District, Moscow Region, Russia
2 Canadian Food Inspection Agency, Animal Diseases Research Institute, P.O. 640, Township Road 9-1, Lethbridge, AB T1J 3Z4, Canada
Correspondence
Andrey P. Anisimov
anisimov{at}obolensk.org
Abbreviations: DIC, diffuse intravascular coagulation; WHO, World Health Organization.
Overview
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 civilizations (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 and biological methods. 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 et al., 2004; Aparin & Golubinskii, 1989; Brubaker, 1991; Butler, 1983; Dennis et al., 1999; Domaradskii, 1993, 1998; Gage & Kosoy, 2005; Hinnebusch, 2003; Inglesby et al., 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, 150 000 people might fall ill with pneumonic plague, 36 000 of whom would die (WHO, 1970).
Immunization against plague is one of the major approaches being pursued to deal with potential infection. Commercially 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 the former Soviet Union, and is based on Y. pestis strain EV, line NIIEG. This strain is attenuated due to deletion of the 102 kb pgm locus that includes the hms locus responsible for the ability to store haemin, and a cluster of genes needed for production of the siderophore-based yersiniabactin biosynthetic/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, gentamicin, chloramphenicol, fluoroquinolones, sulphonamides, and trimethoprim-sulfamethoxazole (Domaradskii, 1993; Frean et al., 2003; Inglesby et al., 2000). The infrequent 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, streptomycin, 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 such multidrug-resistant strains in the natural environment, 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 constant circulation 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 overcome host innate immunity to develop pneumonia with abundant exhalation of Y. pestis, causing plague pneumonia in naïve persons. Each of these stages in the cyclic existence of Y. pestis is supported by numerous factors of the plague pathogen, including pathogenicity factors and housekeeping genes (Table 1
), which may exert an influence, jointly or individually, upon various stages of the infectious process or 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).
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Infective doses of 10 bacteria or less are sufficient to cause lethal infection in naïve rodents and primates via the intradermal, subcutaneous and intravenous routes (Anisimov et al., 2004; Brubaker, 1991; Perry & Fetherston, 1997). LD50 values in the case of the respiratory and oral routes of infection increase to 102–104 c.f.u. (Anisimov, 2002a; Anisimov et al., 2004; Ehrenkranz & Meyer, 1955) and 105–109 c.f.u. (Anisimov, 2002a), respectively.
Y. pestis is primarily a rodent pathogen, and is usually transmitted to another mammalian host by fleas, following the death of the rodent. After being introduced into the host, 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 then spread from the initial flea-bite site to the lymph nodes, 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).
Clinical manifestations
There are three main primary forms of human plague, bubonic, septicaemic and pneumonic. Complications such as secondary septicaemic plague, secondary pneumonic 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 39–40 °C, 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.
Fatality for untreated bubonic plague varies from 40 to 60 %, 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., 1936; Naumov & Samoilova, 1992; Nikolaev, 1972; Pollitzer, 1954; Rudnev, 1940).
Bubonic plague Bubonic plague results from a flea bite or direct contact of an 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 are usually no greater than 5 cm in diameter, extremely tender, erythematous, and surrounded by a 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 min–1. Blood pressure is low, usually about 100/60 mm Hg, due to extreme vasodilatation. Circulatory collapse, haemorrhage and peripheral thrombosis 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 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; Naumov & Samoilova, 1992; Nikolaev, 1972; Pollitzer, 1954; Rudnev, 1940; Van Amersfoort et al., 2003).
Pneumonic plague 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; Rudnev, 1940).
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 available.
Antibiotic prophylaxis and therapy Currently, antibiotics are the cornerstone of plague treatment. The antibiotic prophylaxis and therapy for Y. pestis infection, as suggested by the WHO Expert Committee 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 (streptomycin, 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, azthreonam, 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 prophylaxis (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 antibiotics.
Immunotherapy
Serum therapy.
A. Yersin and others were the first to use the serum of vaccinated rabbits to cure infected animals (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 treatment, patients were injected subcutaneously or intravenously with up to 1000 ml immune serum (200–500 ml for one subcutaneous or intramuscular injection, and 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 dangers of serum sickness and anaphylactic shock frequently induced by serum therapy were believed to be less significant 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).
Antibody therapy.
Beginning in the 1960s, separate antibody 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 toxicities associated with animal sera, they have several limitations, such as high cost, low availability, and the potential to transmit infectious disease (Buchwald & Pirofski, 2003; Casadevall, 2002; 2005; Keller & Stiehm, 2000).
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 protective antigens.
In the case of Y. pestis, several antigens have been shown to be able to produce protective immunity. Among them are F1 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 (Matson et al., 2005). Immunodominant epitopes have been 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 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 (Anisimov et al., 2004; Friedlander et al., 1995; Roggenkamp et al., 1997).
Non-pathogen-specific immunomodulatory therapy.
Y. 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 replication 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-
can augment the functional antimicrobial activities of neutrophils. Studies conducted in animal models have shown the potential use of each of these cytokines for the treatment of bacterial infections. We can speculate that such adjunctive treatment may be useful for plague therapy.
Y. pestis mediates septic shock, which contributes significantly to host death (Butler, 1983; Dmitrovskii, 1994). Sepsis and the systemic inflammatory response syndrome are accompanied by the inability to regulate the inflammatory 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-inflammatory 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., 2004).
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 effect on lymphocytes (Fimiani et al., 2002), has been used in an animal model of plague (Zhemchugov, 2004). When injected into mice (12.5 mg per animal) 6 h before challenge with 10 LD50 of 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.
Phage therapy 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 bacteriophages for the therapy of bacterial disease (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 bubonic plague as the first bacteriophage therapy (d'Herelle, 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 direct injection of phage (0.5–1 ml) into the buboes. Within several hours of injection, the patients felt better, a 2 °C 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).
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 treatment depends greatly on the route (oral, intramuscular, 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.
A phage-encoded peptidoglycan-degrading activity is responsible for the cell-wall-hydrolysing action of bacteriophages. 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.
Bacteriocin therapy 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 oxytetracycline (McGeachie, 1970). Bacteriocins nisin A (produced 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, Staphylococcus, Bordetella, Clostridium, Peptostreptococcus, Propionibacterium, Streptococcus and Micrococcus). Furthermore, mutacin B-Ny266 remains active against strains that are resistant to nisin A, oxacillin and vancomycin (Mota-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 prophylactic effect of tomicide, manifested by a reliable decrease of group A streptococcal carrier state, as well as by a decrease in 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 frequency of chicken colonization by Campylobacter jejuni (Stern et al., 2005). The same bacteriocin has been shown to inhibit the growth of Y. pestis in vitro (E. A. Svetoch and B. V. 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 kg–1 did 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 factors involved in the process of virulence are unique, in that their inhibition, by definition, should interfere with the process of infection rather than with bacterial viability. Inhibitors of such targets would be unlikely to affect host cells, to be cross-resistant to existing therapies, or to induce resistance themselves. Bacterial virulence may therefore offer unique opportunities to inhibit the establishment of infection or alter its course as a method of antimicrobial chemotherapy (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 (PsaA), F1 (Caf1), Pla and S-layer protein (Anisimov, 2002b; Kienle et al., 1992; Parkhill et al., 2001; Payne et al., 1998). pH 6 antigen binds to several human immunoglobulin G subclasses by acting as a bacterial Fc receptor (Zav'yalov et al., 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, possesses the same specificity as the purified antigen, with the exception of binding to non-hydroxylated galactosylceramide. The observed binding patterns indicate that the presence of ß1-linked galactosyl residues in glycosphingolipids 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 Microbiology and Biotechnology, indicate that 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 eukaryotic cells (Kienle et al., 1992), on account of the ability of Pla to bind to the mammalian extracellular matrix (Lähteenmäki et al., 1998). Y. pestis S-layer protein at a concentration of 8–16 µg ml–1 agglutinated rabbit erythrocytes; this agglutination was inhibited by 0.1 M sugars: rhamnose (fourfold) and dulcitol (eightfold) (Diatlov & Antonova, 1999). Until recently it was customarily considered 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., 2001). More recently, the Y. pestis genome has been shown to possess two homologues to the Erwinia HecA adhesin (Rojas et al., 2002). Y. pestis lipopolysaccharide is also reported to be 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 opportunistic 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 the murine monocyte cell line J774A.1 and a range of human 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 heparin), GalNAcß1-4Gal, GalNAcß1-3Gal, Galß1-4GlcNAc and Galß1-3GlcNAc (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.
The Ysc-Yop-‘type III’ weaponry delivering effector proteins 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 
-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.
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, siderophores, are synthesized. Bacterial siderophores have a critical role in the competition between parasite and host for iron acquisition (Braun, 2001; Finlay & Falkow, 1997). Therefore, the Y. pestis siderophore yersiniabactin, as well as its receptor Psn (Perry & Fetherston, 1997), are promising targets for the development of new antimicrobial inhibitors to treat plague. An inhibitor of the domain salicylation enzymes required for siderophore biosynthesis in Y. pestis, the arylic acyl adenylate analogue 5'-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., 2006).
Other possible targets for inhibiting Y. pestis virulence are quorum sensing (Suga & Smith, 2003), the two-component regulatory systems (Oyston et al., 2000; Winfield et al., 2005) 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).
Symptomatic treatment Severe cases of plague are characterized by shock and extensive diffuse intravascular coagulation (DIC), two interrelated processes that have common causal mechanisms 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 & Glauser, 1991; Naumov & Samoilova, 1992; Rackow & Astiz, 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., 1936; Naumov & Samoilova, 1992; Nikolaev, 1972; Pollitzer, 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 if gangrene has completely demarcated then 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., 2003).
Concluding remarks
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-antibiotic therapeutic strategies that can be explored further. 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 derivatives as inhibitors of yersiniabactin biosynthesis, make 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.
ACKNOWLEDGEMENTS
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.
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