Medical Countermeasures, Protection and Treatment, against the Brucella species
John W. Cherwonogrodzky*
Defence Scientist, BioTechnology Section, Defence Research and Development Canada Suffield, PO Box 4000 Station Main Medicine Hat, AB, Canada
- *Corresponding Author:
- John W. Cherwonogrodzky
Defence Scientist, BioTechnology Section
Defence Research and Development Canada Suffield
PO Box 4000 Station Main Medicine Hat, AB, Canada
E-mail: [email protected]
Received Date: December 26, 2012; Accepted Date: February 15, 2013; Published Date: February 18, 2013
Citation: Cherwonogrodzky JW (2013) Medical Countermeasures, Protection and Treatment, against the Brucella species. J Bioterr Biodef S3:012. doi: 10.4172/2157-2526.S3-012
Copyright: © 2013 Cherwonogrodzky JW. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The Brucella species are easily grown, highly infectious to humans by the aerosol route and resistant to harsh environments. These traits have contributed to these being part of the biological weapons programs in the United States (1943-1969), former Soviet Union (1920s-1990s), and Iraq (1973-1991). Brucella species also continue to be an agricultural and public health concern, afflicting about 10% of the livestock and about 500,000 people in developing countries. Although it is generally assumed that infections can be readily cleared with aggressive antibiotic therapy, relapses occur and recent PCR results on the sera of former brucellosis patients suggest that the infections are never totally eliminated. However, within this decade there is likely to be several successes for improved medical countermeasures (protection and treatment) against this bacterium, spurred by recent advances for subunit vaccines, immunomodulators, anti-Brucella antibodies, serum surrogate markers, and liposomal delivery of therapeutics. These discoveries are exciting but perhaps the greatest contribution will be indirect. The new concepts and approaches to improve medical countermeasures against the Brucella species may in turn also apply to several other pathogens equally difficult to protect against or treat.
The Brucella is gram-negative non-motile, non-sporulating, noncapsulated bacteria that appear as cocci or short rods, either singly, in pairs or short chains depending on how these are cultured. These do not secrete toxins nor enzymes such as proteases . These differ from other pathogenic bacteria by having two chromosomes [2,3], the ability to utilize erythritol, a sugar found in some fruits but also in animal reproductive tracts [4,5], an extensive collection of virulence factors [6,7], and their ability to be facultative intracellular parasites . For many years there has been a debate as to whether there are different species of Brucella within different hosts (e.g. B. abortus for cattle, B. melitensis for goats, B. suis for swine) , or a single zoonotic species (B. melitensis) with several variants or biovars . With the recent discovery of Brucella with more varied genetic sequences, different metabolic profiles and antigens (e.g. B. ceti and B. pinnipedialis of marine mammals , B. microti from voles , B. inopinata from humans ), an international taxonomic committee has recommended that the Brucella family be divided into species, rather than B. melitensis biovars .
The Brucella species are zoonotic infectious agents, with people usually acquiring these from infected animals or their products . Although we tend to think of it as a modern disease, skeletal evidence suggests that 1.5-2.8 million years ago Australopithecus africanus had brucellosis  from meat in their diet . Although the bacteria are zoonotic, these vary in their virulence for animals and humans. As an example, B. ovisis highly pathogenic for sheep but seldom causes illness in people . For those species that are highly pathogenic for humans (e.g. B. abortus, B. melitensis and B. suis), these have a low attack rate , seldom kill (the mortality rate being between 2-4% [19,20] ) and half of those infected will not show symptoms of illness . The incubation period in the host is variable, usually taking about 3 weeks before the onset of symptoms ; but in rare instances it might take several decades . The species are minimally contagious. Although there may be transmission from the mother to the fetus  or the breast-feeding baby , exposure to infected blood  or by sexual contact , these aren’t spread by patient respiration or touch . Infections of Brucella, including difficult cases of neurobrucellosis where the blood-brain barrier plays a role , can be treated with common antibiotics  and incidences of brucellosis rarely occur in developed countries .
Although the noted characteristics may suggest that it is of little concern as a threat, it is far from innocuous. Within livestock, wildlife and marine mammals, these will cause malaise, weight loss and abortions [31-33]. Humans are exceptionally sensitive to several Brucella species, suffering daily high undulating fever (from normal to 40°C), night sweats, incapacitation, muscle/joint aches, arthritis, bone deformities, headaches, swollen spleen/liver, and inflammation of the reproductive tract [22,34]. Hematological complications such as anemia and leukopenia frequently arise in brucellosis but subside rapidly with successful antibiotic therapy . Neurobrucellosis is very rare for patients that have been infected by land Brucella species [22,36] but more frequent for those exposed to marine Brucella species . Often the involvement of the bacterium in neural infection and psychosis is discovered in hind-sight from positive blood tests for Brucella [38,39]. Unlike mice which are naturally resistant to Brucella with an ID50 of about 10,000 colony forming units (cfu) , humans may become infected with as little as 10 cfu . Humans are also susceptible to most routes of infection, be these by finger-prick, contaminated skin, oral ingestion of contaminated dairy products or inhalation of aerosols . For the latter, there have been incidences where those in a laboratory became infected when one person inoculated a plate on a bench top rather than using the biosafety cabinet . In another example, 45 students in a classroom on the second and third floors of a university building became infected (with one death) because of researchers working with Brucella in the basement . Brucella are also the most frequent cause of laboratory-acquired bacterial infections . Although it does not form a spore or protective capsule, Brucella is exceptionally tough in the environment, lasting 8 months in manure, 18 months in frozen milk, 6 months in cheddar cheese and 3 months in drinking water [18,43]. Part of this resilience may be due to its surface lipids . The author has found a yellow wax, about 1% of the cell’s dry weight, which when removed with organic solvents makes the cell more readily degraded by lysozyme and protease (Cherwonogrodzky JW, unreported findings) . The bacterium also protects itself from degradation within the mammalian cell by creating a protective brucellosome , and by having components, such as lipopolysaccharide (LPS), that are 10,000- fold less toxic than the LPS of Escherichia coli  and do not activate cellular defences . Rather than being harmless, the Brucella spp. is sophisticated facultative parasites that use several mechanisms to persist within the host.
The bacterium can be easily grown, bulk-produced, and was one of the first infectious agents to be weaponized by the USA  and the former Soviet Union . The risk increases further when one notes that there is a deficiency of medical countermeasures against this bacterium. There are currently no vaccines or antibody to protect humans , even aggressive antibiotic treatment of infections may result in relapses once these are discontinued , and a patient thought to have cleared the bacterium may have it resurface decades later .
Additional cause for concern stem from its ubiquitous nature. It occurs throughout the world, notably in politically unstable countries, and it is the most common zoonotic disease in the world . In light of Brucella’s stability, availability, virulence and the inadequate medical countermeasures to protect or treat casualties, these species are very real biological threats to civilian populations and national security [52-54]. The following review offers insights into what can be done for now, and the new developments that will soon defend us from Brucella.
Antibiotics: As vaccines do not exist to protect people from Brucella, potentially one can take antibiotics as a measure to prevent infection, similar to the military using anti-malarial drugs to protect soldiers going into a malaria-endemic area  or using antibiotics to treat combat-related injuries . However, this approach is impractical to protect against an unlikely illness such as brucellosis. Antibiotic use is more practical as a medical countermeasure after infection, and this will be reviewed in the next section.
Anti-Brucella antibodies: There is substantial evidence that mouse monoclonal antibodies, directed against the outer membrane proteins [57,58], LPS [59,60] and polysaccharide (PS) [61,62] of Brucella, are protective in the mouse model against brucellosis. The latter antibodies provided the best protection against smooth species; to which humans are sensitive [63,64]. To date no approved antibodies are available for human use. As one cannot predict who will be exposed to Brucella, or when, if ever, the use of anti-Brucella antibodies to protect the military or civilians is an impractical countermeasure.
Vaccines against Brucella species:
a) Killed cells as vaccine candidates: In 1897, Sir Almoth Wright (UK) vaccinated himself with heat-killed B. melitensis cells, then a few weeks later infected himself with viable cells. The intent was to apply basic principles of vaccination to develop a vaccine against Brucella. It didn’t work. He became debilitated for several weeks with high fevers, emotional outbursts and hallucinations . Studies in France by Taylor et al.  also showed that killed Brucella cells did not protect animals or people from brucellosis. Kolmer et al.  found that, although killed cells greatly increased serum agglutinin (anti-Brucella antibody levels), only 8 of 29 adults had sera that could protect mice from B. abortus or B. melitensis challenge . The inconsistent results, erythema, swelling and excessive local pain to recipients made the approach of using killed cells as vaccines fall into disfavor.
b) Live attenuated cells as vaccine: There have been several successful trials in which live attenuated Brucella strains have been used in animals or people to prevent brucellosis. As the sheer number of these is beyond the scope of this review, and as far more capable experts have addressed this topic [68-72], only a few examples will be discussed to outline the different approaches.
The attenuated Brucella abortus strain 19 vaccine had a major impact on the control of brucellosis in animals and to a lesser extent in humans. In 1923, an isolate recovered from the milk of a Jersey cow was subcultured by J.M. Buck and left at room temperature for a year . These cultures were tested in guinea pigs, and it was found that the culture in the 19th tube, hence its strain designation, had lost its virulence. From the 1930s, this strain has been used throughout the world to protect livestock, especially cattle from B. abortus. A derivative of this strain, B. abortus 19-BA  has been used in the former Soviet Union to vaccinate people in high risk occupations. Unfortunately, strain 19retained some of its virulence and on occasion caused brucellosis in people . Other live attenuated strains, such as B. abortus RB51, have been developed that were less severe but the same issues of residual virulence arose [76,77].
There have been several other attempts to genetically manipulate Brucella strains to create defective mutants that will both enhance protection of laboratory or farm animals against brucellosis and avoid illness caused by the vaccine itself. Researchers have investigated bacterial structural proteins, enzymes, the synthetic pathway for carbohydrates and LPS, the synthesis of key nucleotides, acquisition of essential metals, stress adaptation, metabolism of substrates, efflux of toxic compounds, and components that manipulate the host mammalian cell [78-140]. There have also been the transfers of Brucella structural or virulence components into less harmful bacteria to create protective recombinants [141-148]. With hundreds of mutants and recombinants created by manipulating several diverse structural or physiological pathways of different species of Brucella, there is a need to compare these so as to determine the best strain for protection without ill effects.
c) Subunit components as vaccine candidates: It has been discussed that killed Brucella cells are not protective, while live attenuated strains do offer protection in livestock or laboratory animals from brucellosis. To date, the lesson learned from the development of such vaccines has been that only “rough” living strains (those lacking PS on their cell surface, on agar plates their colonies have a rough surface) have been effective while “smooth” strains (those coated with sugars) were ineffective. As surface proteins would be exposed on the former and masked on the latter, these outer membrane proteins (Omps) have been investigated since the 1980s as virulence factors and vaccine candidates . Most of the Omps did not play a role for either , but a few Omps did show vaccine potential, notably Omp25 and 31 [151-153], the latter being a haemin-binding protein . In the mouse model, a DNA vaccine, coding for lumazine synthase and an Omp31 insert, provided superior protection against B. ovis and equivalent protection against B. melitensis when compared to the widely used Rev 1 attenuated vaccine strain .
An alternative to protein subunit vaccines are the LPS, and more specifically the PS, component. There has been a long rich history of investigations dealing with these. Huddleson and Johnson in 1933  prepared the filtrate reagent Brucellin which they used as a therapeutic for patients to clear their illness. In 1939, Miles and Pirie [157,158] reported that the predominant antigen in these extracts was a formamino dihydroxylsugar. Over several decades, the Brucella cell-wall associated PS has been characterized and as noted before, antibodies against these were protective in the mouse model [159-163]. If PS has the potential for being subunit vaccine candidates, why hasn’t it been used? In part, the reason against its use as vaccines has been experimental evidence. As noted previously, only rough strains (i.e strains lacking cell-associated PS, such as strains RB51 for B. abortus and Rev1 for B. melitensis) were found to be effective vaccines in animals. Killed or live smooth Brucella cells were ineffective. Also, the PS was a very poor antigen that did not induce a significant titre of antibody against Brucella , and this cellular component, when tested in the mouse model challenged intranasally with B. melitensis, was found not to be protective .
Appearances can be deceiving. Live rough Brucella strains used as attenuated vaccines have been found to produce PS, but some, such as B. melitensis strain B115, were defective for linking this to the bacterial surface . Brucella abortus RB51 produced very low, but present, amounts of PS . Possibly even these rough strains vaccinated animals with PS. Smooth killed cells did have PS, but these also had Lipid A, as part of the LPS [168,169], and lipoproteins , both which interfere with host immunity. PS may be a poor inducer of antibody, but this group of antigens can act as an immune modulator of cell-mediated responses [171,172] that are more relevant for guarding against Brucella as an intracellular parasites. Brucella melitensis was particularly difficult to protect against, especially when given as an intra-nasal challenge, but curiously, LPS containing PS provided protection for mice when given by a different route .
Studies have found that PS was indeed protective when given as a vaccine against brucellosis in 3 animal models. Mice given a single low dose of B. abortus PS (1 μg in sterile saline), without adjuvant, had 10,000-fold less B. abortus in their spleens than unvaccinated control mice . In a study in Colombia, three of four pregnant guinea pigs given 10 or 100 μg of polysaccharide had no sign of the bacterium in their blood or spleens . For a large swine trial done in Venezuela, B. abortus and B. suis PS, given either by intra-muscular injection or orally, gave sows very high levels of protection against a field strain of B. suis transmitted sexually by infected boars . In this latter study, the PS vaccine had been stored lyophilized and kept on the shelf at room temperature for a decade before use on farms in remote locations. The field trials showed that cold chain shipment was unnecessary for this thermostable vaccine. More recently we have found that PS and exopolysaccharide extracted from B. suis 145, which expresses both the B. abortus A-antigen and B. melitensis M-antigen, protected mice from all 3 Brucella species, those most pathogenic for humans. A single dose of 1 μg vaccine, in sterile saline and without adjuvant, protected mice for 15 months from B. suis 145 infection.
Treatments after infection
Antibiotics: There have been several publications on the sensitivity and Minimum Inhibitory Concentration (MIC) of Brucella species to different antibiotics in vitro [176-179]. However, as noted in the review by Young , the usefulness of these may differ in vivo. Influencing factors may be the extent of intracellular penetration, the blood-brain barrier in neurobrucellosis, the tissues invaded such as the heart or bone marrow, the age and health of the patient, and their refusal to comply if they experienced adverse side-effects [22,51]. It has also been found that some antibiotics act synergistically, being more effective at lower concentrations for shorter times when used together than each individually . Taking all of this together, studies involving large numbers of patients have found doxycycline with rifampin and streptomycin to be the most effective for clearance of infection [51,181-183]. It should be noted that the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) and the Centers for Disease Control and Prevention (CDC) recommend that the treatment of brucellosis patients should be a combination of antibiotics in high amounts (doxycycline, 100-200 mg, oral; rifampin, 600-900 mg, oral; for acute complicated cases add 1 gram streptomycin by intramuscular injection), daily for several weeks to several months [41,50].
As well as the side-effects of patients taking some antibiotics, such as hearing loss from aminoglycoside use  and photoallergy from those taking quinolones , there are other complications. If the patient has a large load of Brucella in their tissues and the therapy is too effective, the sudden death of bacteria and the release of toxic compounds may kill . However, this rarely occurs because the bacterium has evolved not to compromise its host, its sLPS being 10,000-fold less toxic than that of other bacteria such as E. coli . With regards to clearance, after an aggressive antibiotic schedule, the blood cultures and bone marrow sampling will likely be negative for the bacterium, the patient will feel fine, and after antibiotic use has stopped they will continue to appear healthy. This may be a false sense of security. The bacterium is likely persistent at very low numbers within cells, controlled by a vigilant immunity. From investigations using sensitive PCR methods, it appears that patients that have recovered from brucellosis will unknowingly have the infection for the rest of their lives . Perhaps a key question is not how the pathogen continues to exist within the host for so long, but how it is that the host’s immune system manages to suppress its growth over several decades.
Anti-Brucella antibodies: In theory, once an infectious agent or toxin has entered the mammalian cell, antibodies which are outside in the serum will not be able to play any role on threat agents inside. If this was always the case, it would not explain how anti-botulinum antiserum therapy can have a positive effect several days after a patient has been poisoned . Some antibodies can enter the mammalian cell and bind to antigens is evident in auto-immune diseases such lupus erythritosis/ nephritis, migraines and diabetes . For brucellosis, human trials in the 1930s showed that giving antiserum from recovered patients could in turn alleviate the symptoms of those with acute infections . For water buffalo, resistance to B. abortus has been correlated to antibody titres and enhanced control of intracellular replication of the bacterium . The action of antibodies on pathogens within the mammalian cell has only been sparsely reported, but the current findings suggest the potential for exciting novel applications [191-193].
Vaccines: Vaccines are viewed as preventative measures to be given before infection, not as treatments after infection. Even with this dogma, concepts are beginning to change. Vaccination with melanomaspecific antigens enhanced survival of cancer patients  and it is now recommended that those infected with Bacillus anthracis receive both aggressive antibiotic therapy and protective antigen vaccination . The immune responses may be different for these two examples, the first dealing with immune modulation and an activation of cytokines, the latter an active immunization to deal with spores that germinate after antibiotic therapy has been discontinued. With regards to brucellosis, in the 1930s it was found that Brucellin, filter-sterilized culture filtrates of B. abortus or B. melitensis, reduced the severity and length of illness for patients . Perhaps a subcellular vaccine can be developed that can be given after infection to facilitate clearance of the bacterium from the patient.
Future directions for research and development of medical countermeasures against brucellosis
Subunit vaccines: There is no need to inoculate people with live attenuated strains if the “magic bullet”, a subunit component as vaccine, can be identified. A description has been given that DNA encoding specific outer membrane proteins of Brucella are more effective, and cross-protective to more than one species of Brucella, than Omps by themselves . Also, a very low amount of single-dose of PS without adjuvant can give long-term cross-protective immunity against Brucella spp. in animal models [164,174,175]. In the swine model, oral vaccination was as effective as intra-muscular injections and the PS thermostable vaccine did not require cold chain shipment .
With regards to new subunit vaccine candidates, it was found that when either the supernatant or the cells were treated with hot (70°C) phenol-water, both PS and an equivalent amount of glycosylated proteins (about two-thirds carbohydrate, one-third protein) were extracted. The latter fraction was found just as effective as PS for protecting mice [Cherwonogrodzky, unreported results]. Perhaps these glycosylated proteins are the best of both candidates, combining protective proteins and protective PS of Brucella. Instead of synthetically conjugating the two to improve their effectiveness , perhaps all that is needed is to use that already made naturally. On the topic of glycosylated proteins, it used to be dogma that prokaryotes did not produce these. It is now known that bacterial flagellin, pilin and enzymes can be glycosylated [196-198]. Glycosylated proteins of Brucella should be investigated as novel vaccines. As with other bacteria, such as Burkholderia mallei , Brucella is non-motile but does express flagellar proteins shown to induce protection from B. abortus infection in the mouse model . Flagellin, LPS, and PS bind to toll-like receptors that play a role in immunity against pathogenic bacteria [201-203].
Immunomodulators: Until recently, immunomodulators were viewed as either suppressants of inflammation (e.g. corticosteroids) or crude particulate material that would irritate the body to respond to a foreign object. In our laboratory we have found that Brucella PS, either that of unusual composition such as the 4,6-dideoxy-4-formamido- D-mannose composition of the PS, or that of unusual linkage such as the cyclic 1,2-beta-glucan, could double mouse macrophage activity against yeast zymosan. Cyclic 1,2 beta glucan is both a common bacterial PS used for osmotic regulation and a virulence factor for some bacteria such as Brucella [99,204-207], beta-glucans induces innate immunity in part by stimulating cytokines [208,209] which in turn play a role in clearance of this bacterium [169,210]. Where Brucella has commandered the mammalian cell, it may be possible to override the cell’s incapacitation with potent immune stimulating compounds.
Liposome encapsulated antibiotics and vaccines: Once the bacterium has invaded the cell and tissues, it is difficult to clear. To deliver the antibiotic in high concentration directly into the cell, liposome encapsulation has been evaluated. It was found that positively charged pluri-lamellar vesicles were the most effective for delivery of antibiotics into mouse monocytes . The usefulness of liposomes has been extended for enhanced delivery of antigens and DNA vaccines [212-214]. Advances for this cell delivery vehicle continue to develop (see United States Patents and Trademarks office number 6,221,386, Cherwonogrodzky et al. ). As monocytes, macrophages and dendritic cells of the body contain mannose receptors [216,217], a Japanese laboratory has recently improved on liposomal delivery of anti-cancer drugs into macrophages by coating liposomes with a synthetic oligomannose that bound to these receptors .
Antibody therapy: There have been different descriptions and categories of anti-Brucella antibodies. One antibody group reported was Type 1 in that it bound to the length of the PS and was produced in high titres in infected animals. The other group was Type 2 which bound to the tip of the PS and was produced in vaccinated animals [44,219,220]. No studies have been done to determine if the tip region was the free end of the PS or that carrying the remnant of the core region, reported necessary for vaccine efficacy , after release by hydrolysis. It is unclear whether agglutinating/non-protective and nonagglutinating at neutral pH/protective antibodies are Type 1 and Type 2 antibodies respectively [44,222,223]. The latter may have protective or therapeutic value as medical counter measures. In providing a therapeutic, two locations of the infectious agent have to be considered. The first is to destroy the bacterium outside the cell, either before it enters or after it is released from infected cells. Curiously, less is more in that low levels of antibody, not high amounts, allow complement killing of Brucella in the blood . The second is to enhance clearing once the bacterium gets inside the cell. It was discussed previously that in some instances antibodies may act inside the cell. Possible mechanisms may be antibody targeting the pathogen to lysosomes within the cell  or interacting with the cytosolic IgG receptor, TRIM-21, which targets the pathogen to a proteasome for its degradation .
Serum Components Other Than Antibodies: When one thinks of an immune response, one is likely to think of the production of antibodies and the induction of complement lysis against the threat agent. However, the body’s defences are far more diverse and robust than this single mechanism. Although Brucella appear to have evolved a resistance to serum cationic peptides called defensins , with its polysaccharide coating composed of mannose derivatives, the bacterium has been found to be sensitive to the mannose binding lectin in the blood which also activates complement lysis . On a similar theme, although the mechanism has been resolved with a fungal model, when the macrophage has been exposed to mannose polymers, the receptor dectin-1 can induce the macrophage mannose receptor to be shed, bind to the pathogen and enhance its destruction . These serum components should be investigated further to determine if these play a role in long term immunity against Brucella (See also www.uspto.gov, https://www.freshpatents.com/-dt20090702ptan20090166200.php).
Cross-reactions cross-protection: The observation that exposure to one agent can protect someone against a different one is nothing new. In 1796 Jenner reported that milkmaids with blisters from cowpox were protected from smallpox . In a similar manner, we have found that vaccination with B. suis 145 PS protected mice from B. suis, B. melitensis and B. abortus [manuscript submitted, see also USPTO patent number 6,582,699]. During the course of testing this vaccine candidate in mice, we also noticed that a few of the unvaccinated control mice acted as vaccinates, having 1000-fold less bacteria in their spleens than their littermates after B. suis challenge [manuscript submitted]. There is a long list of microbes that are glycosylated with sugars similar to that of Brucella, some deadly, some only discomforting [214,231-249]. It was likely that the unvaccinated but protected mice had been inadvertently exposed to the latter. Regardless, if surrogate markers of protection from brucellosis could be determined, it would be very useful to identify and call upon first responders, military personnel, researchers or veterinarians who are already protected naturally from Brucella or other biothreat sand are better able to deal with an incident. The other benefit to understanding immunity against brucellosis and the surrogate markers of protection is in the development of novel medical countermeasures against other biological threats. Although it is unlikely that a vaccine against one bacterium will completely protect against another, we have found that the Brucella PS partially protected mice from cross-reactive Francisella tularensis .
The author gratefully acknowledges the Defence Research and Development Canada for their continued support to his studies on countermeasures against biothreat agents, and especially the support of their Vaccine Development Initiative. Much of the insights and concepts presented in this review were a result, over the years, of his collaborations with colleagues at DRDC Suffield, discussions with members of the Brucellosis International Research Conference and the United Nations University Brucellosis Research Network.
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