Возможность применения патогенных микроорганизмов, токсинов как биологических агентов

• Бора Дж.
• Хазра Р.
• Малик Сумира
• Лата С.
• Банерджи С.
• Пал С.
• Дешвал Р.К.
• Мондал С.
• Талукдар Н.
• Рустаги С.
• Рамнивас C.

Резюме

Достижения в области биотехнологии и генной инженерии за последнее столетие увеличили риски биотерроризма и биологической войны, особенно в отношении использования микробов в качестве биологического оружия. Поэтому необходимо оценить и лучше понять возможность использования таких агентов. Микробы, такие как бактерии, вирусы, грибы, а также растительные и животные яды могут быть использованы в качестве биологического оружия. Биологическое оружие особенно опасно из-за своей невидимой природы и способности оказывать замедленное воздействие. Это делает его значительной угрозой для человечества, поскольку такое воздействие может проявляться во многих поколениях. Широко доступные биологические средства легко применить в качестве биологического оружия, которое даже в небольших количествах способно оказать значительное поражающее действие. Биологические атаки могут приводить к значительному количеству заболеваний и смертей, порождая массовую панику и общественные беспорядки. Биотерроризм имеет сходство с биологической войной, но имеются также и заметные различия, которые требуют уникальных решений. В обзоре рассмотрена роль биологического оружия как возможность совершения актов биотерроризма и развертывания биологической войны.

Ключевые слова: биотерроризм; биологическая война; биологическое оружие; токсины; микроорганизмы

Introduction

Occurrences of contagious diseases present a recurring menace to worldwide well-being. The likelihood of the utilization of biological weapons against humanity is no longer unimaginable. The deliberate modification and dissemination of pathogens constitute a specific category of artificially induced disease outbreaks, with the intention of causing communal disturbance. While nuclear and chemical weapons are also considered weapons of mass devastation, biological weapons evoke the greatest fear. However, our level of preparedness to handle such a scenario is the lowest. The use of biological agents or toxic substances as a means to harm enemy forces has been employed since ancient times. Frequently, in times of conflict, diseases have resulted in a greater number of fatalities than the collective employment of all military forces, despite the fact they have not been deliberately utilized as weapons. The aftermath of the release of an aerosol cloud containing predominantly pathogenic biological agents is distinct from other emergency situations such as natural disasters, fires, or explosions. The term "mass devastation" is not entirely accurate when referring to biological munitions, as they lack the capability to demolish infrastructure, buildings, or equipment. Their excessive ability to disseminate information makes their control significantly difficult, resulting in dread and panic among innocent individuals. In addition to their role in state-sponsored biological warfare, they could also be employed by outlaws or terrorist organizations. Biological agents are used in combat, terrorism, or criminal acts.

From an international viewpoint, efforts are made to control, detect early, and organize preventive activities regarding these agents. Given the resilience of genetically modified agents against different treatments, we are not only confronted with natural illnesses but also harbor concerns about the dangers of biological warfare or bioterrorism. Gene manipulation leads to the development of new harmful traits, resulting in organisms with modified properties that can be used as bioweapons in future generations. Biological weapons are used in several ways to gain a defensive edge against the enemy, either through the use of threats or actual deployment. These agents can be either lethal or non-fatal and can be directed towards a person, a collection of humans, or even a whole population. The clinical signs, such as the characteristics and intensity of poisoning, are influenced by the specific biological agent used, the amount administered, the method of entry, individual differences, and environmental conditions. Given that the Biological Weapons Convention considers the use of toxins produced by some live organisms, there is a significant overlap between biological warfare and bioterrorism. Biowarfare or military action is more susceptible than biological terror or civilian strike since it impacts individuals of different ages and unique health conditions. The progression of time is anticipated to bring about significant transformations in society and lifestyle through breakthroughs in biology or biotechnology. Nevertheless, we must not disregard the concept of “black biology” in biotechnology, which involves the development and application of biological agents. The frequent modifications in the objectives of biotechnology’s progress often pose challenges in distinguishing reality from falsehood [1, 2].

Background

The advancements in biochemistry and biotechnology over the past century have greatly facilitated the production and advancement of bioweapons. The widespread accessibility of biological agents, their ease of manufacturing, and sophistication have not only contributed to the rising proliferation of biological arms but also heightened the aspiration among poor countries to possess them. Evidence of a biological warfare programme may be traced back to the 19th century, when the employment of biological weapons in conflict was first observed. During World War I, there were reports of German attempts to inoculate cattle and horses with microbes such as Bacillus anthracis and Pseudomonas pseudomallei. Furthermore, Germany also engaged in the dissemination of the plague in St. Petersburg, Russia, and cholera in Italy. Nevertheless, Germany refuted these charges by citing their bombing of British positions as evidence [3]. Furthermore, Hitler issued directives to ban the advancement of bioweapons. Belgium, France, Great Britain, Canada, Poland, Italy, and Japan, among other countries, were signatories to the Geneva Protocol of 1925. Shortly after its ratification, these countries actively engaged in the development of biological and chemical weapons.

Multiple nations launched a bio warfare research programme during World War II [4]. Amidst the war, there were many accusations and counter-accusations surrounding this event. Additionally, the Japanese military conducted experiments on prisoners in the Unit 731 camps, where they used infected rats to develop plague as a bioweapon in laboratories. In 1949, The Soviet Army tribunal in Khabarovsk tried 12 Japanese inmates for the production and use of bioweapons. In 1942, the Military Research Service implemented a repugnant biological warfare programme in the United States. Experienced military commanders of middle age discovered that individuals afflicted with contagious diseases could potentially be utilised as weapons. The Hittite literature from 1500-1200 BCE documents the deliberate deployment of bioweapons, namely infecting individuals with tularaemia and sending them to enemy territories, which led to the outbreak of an epidemic. During the 16^th century AD, biological weapons were extensively used in various regions of Africa, Scythia, and Rome. These weapons included poisoned arrows, swords, and dust that were distributed across warfronts. Consequently, this resulted in the infection of victims with tetanus. Britain weaponized plague, tularaemia, horse encephalomyelitis, and vaccine viruses in the 1950s. However, this programme was terminated in 1956. In addition to this, the American Warfare Laboratories also weaponized anthrax, Q fever, and other diseases. The 14th century witnessed a widespread and devastating pandemic known as the Black Death, which affected Europe, North Africa, and the Near East. This outbreak of plague is considered one of the most disastrous public health incidents in recorded history [5]. The French Indian War (1754-1767) saw the intentional deployment of smallpox as a potent bioweapon to reduce the indigenous Indian population that was opposed to the British. This led to an outbreak of pox among the Indian tribes residing in the Ohio River Valley. Table 1 presents a comprehensive overview of significant past endeavours to employ illnesses or agents that cause illness in biological attacks. This highlights the challenges associated with differentiating deliberate biological warfare from suspected acts of bioterrorism, a problem that persists to this day.

Assessing the bioweapons threat

Biological weapons encompass microorganisms such as bacteria, viruses, fungi, or other poisons that are deliberately created and deployed with the aim of inducing illness and mortality in people, pets, or plants. In order to be chosen for weaponization, an agent must possess specific properties that can effectively overcome the technical limitations that would normally render the weapon delivering the agent unappealing to users, regardless of its high pathogenicity or toxicity. Fig. 1 illustrates the primary potential biological weapons. A bioweapon must meet certain requirements: it must be mass-produced, have a rapid effect, be resistant to environmental conditions, and have a curable infection or an available vaccination to protect soldiers. As a result, only a small fraction of naturally occurring diseases is appropriate for military applications [6]. Fig. 2 depicts the key distinctive characteristics that biological agents used as armaments must possess.

A medically catastrophic event requires at least two components: one or more pathogens (such as bacteria, viruses, or even toxins) with a means of spreading them. In addition to their great transmission capacity and lethality, potential biological agents are also invisible and extremely difficult to detect in the near term, making prompt diagnosis impossible until the number of infections has increased. With the exception of poisons and bacterial spores, most biological weapons possess a unique characteristic that sets them apart from other non-conventional weapons like chemical and radioactive weapons. Table 2 provides a concise overview of the possibility for biopathogens to be weaponized. Biological agents have the ability to reproduce inside their host organism and then spread to other hosts, causing unforeseen impacts on the population, including the number of casualties and the geographical extent of the spread.

The ability to reproduce within a host is the primary property of biological agents, which grants them their inherent potential. The disease is caused by the complex interaction among the agent, the person being infected (including their immune-mediated, nutritional, and physical condition), and the environment (such as cleanliness, temperature, water quality, and population density). The intricate interplay of factors is seen in the consequences of employing biological agents for the purpose of inducing illness.

Bioterrorism as a potential global warning

Bioterrorism refers to the intentional release or danger of the release of biological agents, such as viruses, bacteria, fungi, or their toxins, with the intention of inflicting illness or fatalities among people or food crops and livestock, in order to instil fear among civilians. Any pathogenic microorganism has the potential to cause bioterrorist strikes. In order for microorganisms to be considered successful as bioterrorist agents, they must be capable of consistently causing death or sickness even at low doses. The agent must possess a high level of infectivity and exhibit a short and likely incubation period. The desired population should possess minimal or non-existent immunity against the pathogen. Biological agents used in operations and their spread should possess the ability to be economically mass produced, stored, and possess all other necessary properties for weaponization. The target population should not be immediately discernible from the native population, and no prophylactic should be accessible to them. In the context of bioterrorism, victims are infected surreptitiously, without their knowledge or awareness, in contrast to other forms of terrorist assaults. Consequently, over time, individuals develop symptoms that are ultimately lethal. Assessing the danger of bioterrorism is challenging since it carries significant repercussions but occurs infrequently. The application of traditional assessment methodologies becomes intricate due to the existence of a sophisticated adversary who can adjust to the implementation of effective countermeasures.

The creation of a highly effective bioweapon is a complex and daunting challenge, contributing to the difficulties of carrying out a bioterrorist strike on a human population [7]. Several weaponized anti-personnel agents, such as anthrax, are inefficiently transmitted among humans. Therefore, in order to inflict significant harm to a wide number of people, a substantial amount must be distributed simultaneously. Several analysts have asserted that terrorist operations against crops or livestock are unlikely to instil terror. However, they are equally worrisome due to their potential for easier execution and significant economic consequences [8]. Efficient biological warfare weapons, such as anti-crop agents, must possess characteristics that allow for easy cultivation, convenient storage, simple dissemination, and a high level of virulence against the intended population. Incorporating pathogens such as FMD, African Swine Fever, Soybean Rust, Philippine Downy Mildew of Maize, Potato Wart, and Citrus Greening could result in significant consequences. The ease with which numerous agricultural infections can be introduced increases the likelihood of terrorists spreading pathogens across various places, thus triggering simultaneous outbreaks. This could potentially trigger the immune system’s ability to respond, leading to an uncontrolled spread of the disease. The primary distinction between a bioterrorist strike and spontaneous disease transmission lies in this aspect. While small outbreaks might cause significant economic repercussions, their psychological impact may not be as substantial as that of an individual dying from anthrax or smallpox. Brown and Slenning asserted that the introduction of diseased animals through smuggling poses a significant risk to the spread of anti-animal diseases. This method of assault does not require the use of aerial spraying to spread the infection. Rather, the pathogen is deliberately introduced through a planned biological warfare operation or a form of bioterrorism.

Bioterrorism encompasses three scenarios: the hoax, the large-scale attack, and the minor or covert strike. The hoax is the most frequent situation in which a person is informed about being exposed to a certain virus. Subsequently, they initiate communication with emergency services by dialling 911 and establish contact with the specialised unit responsible for determining the necessary precautions to ensure safety. Furthermore, the perpetrator is subjected to legal prosecution. The extensive assault entails the deployment of a bio-toxin, leading to a significant number of individuals being affected. Subsequently, the health staff members are subjected to the assault while carrying out the process of diagnosis. Local laboratories have a significant impact in both managing patients and identifying the agent. Ultimately, in the event of a highly feared clandestine assault, a small number of individuals who are ill and present themselves at the doctor’s office are instructed to return home and recuperate by resting and consuming water. Alternatively, if their condition worsens, the hospital labs are solely intended for determining the likelihood of being infected by the pathogen. Specimens will then be forwarded to a laboratory that will provide a substantial treatment [9].

Biowarfare as an anticipating danger

The risk of biowarfare persists, along with the apprehension of bioterrorism that has the potential to cause catastrophic harm to humanity. Biowarfare is the intentional utilisation of microbes and poisons, primarily derived from microorganisms, plants, or animals, to induce diseases and fatalities in humans, livestock, and crops. It leads to significant harm to civilians and resulting in substantial economic and societal upheaval [10]. The primary objective of this mission is to specifically focus on the military or army, which consists of a very uniform group of physically fit warriors who are probably already vaccinated. Prior knowledge of the time and location of exposure to biological warfare allows for a strategic reaction that takes into account the specific bioweapon used, its typical method of transmission, and the period of time it takes for symptoms of the disease to appear. The primary goal of biological warfare is to cause significant destruction or minimal disruption to hostile forces [4]. Nation-states employ biowarfare as a means to weaken the ability and willingness of an adversary to retaliate, resulting in the death or impact on significant numbers of enemy military personnel, civilians, agricultural products, and livestock through the deployment of biological weapons. Biological weapons can result in significant loss of life by eradicating an entire population quickly, with few logistical needs. An inherent risk factor associated with biowarfare is the potential for biological weapons to surpass control and have a more detrimental impact on the army than the intended target.

Biological warfare agents can be differentiated from other weapons of immense destruction, such as nuclear and chemical weapons, through several means. While several systems are capable of detecting biological agents, the majority of them experience a time lag between acquiring the agent and accurately identifying it. As a result, both the release of the agent and the subsequent impact of the attack cannot be promptly detected. Individuals may come into contact with an agent at any point following its release, but the infection necessitates a certain amount of time to manifest as a disease, known as the incubation period. Therefore, the key signs of biological warfare may include the occurrence of a disease outbreak followed by the persistence of its effects even after the discharge of the harmful agent or pathogen. If an individual becomes infected with a communicable agent, such as smallpox or Ebola virus, at the location where it is being spread, that individual has the potential to move and spread the agent to others. This could result in secondary infections in distant locations that were not initially exposed to the disease and are unprepared for it.

Routes of delivery and dissemination techniques for biological weapons

Bioagents are categorised into three groups - categories A, B and C - based on their distinctive properties (see Fig. 3). The most effective method of delivering these bioterrorism or biological warfare agents is aerosol systems, which can handle both wet and dry agents. Aerosol technology creates a nearly invisible mist of tiny particles or droplets that can remain airborne for long periods of time. These particles, ranging in size from 0.5 to 10 micrometres, can penetrate deep into the lungs when inhaled, posing a significant respiratory hazard. Although dry agents offer better dispersion and storage advantages, they require more complex manufacturing techniques. For atomisation, spraying devices mounted on mobile vehicles can release agents during operation. When spraying perpendicular to the wind direction, any downwind objects within range are potentially exposed. The effective range depends on several factors, including wind speed and direction, atmospheric stability, agent properties, and the presence of inversion conditions. In addition to aerosol delivery, pathogens can spread by other means. These include zoonotic transmission, where animals carry and transmit diseases to humans, and contamination of water and food sources. With regard to food and water safety, heat effectively eliminates most viruses and toxins. Therefore, raw food or cooked food is more vulnerable to penetrating agents. Standard water purification methods have limitations - chlorination does not cope with spores, and filtration alone cannot completely prevent transmission of spores and cysts, viruses and various bacteria. The effectiveness of biological weapons varies considerably depending on geographic location, delivery system, time of day, weather conditions and terrain. All of these factors must be considered when assessing potential risks and developing countermeasures [11, 12].

Characteristics and transmission routes of infectious agents and toxins

Biological agents refer to a collection of microbes and chemical or biological toxins that can be intentionally employed as weapons in acts of biological warfare. Besides the aforementioned harmful bacteria capable of living and reproducing, bio-agents also encompass chemical poisons and biotoxins. Over 1200 various kinds of bio-agents were identified and investigated for their potential use as weapons. Biological agents have the capacity to have detrimental impacts on human health through a range of mechanisms, including moderate allergic reactions to severe health issues, long-lasting impairments, or even fatality. These microorganisms can be present in soil, water, plants, or animals. Genetic modifications have the potential to greatly enhance their ability to cause harm or render them resistant to conventional therapies and preventive measures. Bacillus anthracis is a type of bacteria that forms spores and is responsible for causing the zoonotic disease known as Anthrax. This highly transmissible and lethal illness has a significant historical connection with humans and has been effectively utilised as a weapon in the past, owing to its inherent characteristics. Vibrio cholerae is a highly prevalent pathogen with significant potential as a bioweapon, making it crucial to be well-prepared for its presence. Out of the several strains exhibited by this bacterium, O1 and O139 are specifically recognised for their ability to trigger outbreaks and epidemics. Yersinia pestis (Y. pestis) is a type of bacteria that is shaped like a coccobacillus and has a negative reaction to the Gram stain. It is responsible for causing the zoonotic disease known as plague. The life cycle of the plague involves a complex interplay between rodents and fleas, occasionally leading to human infection. The plague is regarded as a very significant strategic weapon due to its ability to meet the standards of a highly hazardous future weapon of biological warfare or biowarfare. Furthermore, Brucella is a minute, Gram-negative, aerobic, non-motile, non-spore-forming, encapsulated coccobacillus. Out of the six species with distinct biotypes, four have the ability to cause diseases in humans. These species are Brucella abortus, B. melitensis, B. suis, and B. canis. This zoonotic illness mostly happens throughout the Mediterranean basins, the Arabian Gulf, the Indian subcontinent, even certain regions of Mexico, Central America, and South America. Brucellosis is an age-old illness and continues to be the predominant zoonotic disease worldwide. Brucellosis is well recognised as the most prevalent infection acquired in laboratories across the globe [13]. Viral disorders encompass viral haemorrhagic fever, a severe medical ailment caused by viruses from one of four separate families: Filoviridae, Arenaviridae, Bunyaviridae, and Flaviviridae. Haemorrhagic fever viruses such as Ebola, Marburg, Kyasanur Forest Disease, Rift Valley fever, Lassa fever, New World arenaviruses, yellow fever, and Omsk haemorrhagic fever pose a significant threat as potential biological weapons. Ebola haemorrhagic fever is a contagious illness characterised by a significant fatality rate. While fruit bats serve as the primary reservoir for Ebola, non-human primates can also act as hosts and become infected [14]. Variola major, the causative agent of the smallpox is a sizable virion with a complicated structure. It has a diameter of around 200 nm and is shaped like a brick. This virus is a DNA virus that is classified within the Orthopoxviridae genus [15]. Historical records indicate that smallpox emerged during the Neolithic era and has the potential to impact individuals of all age groups. This is an extremely contagious illness in which individuals become infectious as soon as the first sores emerge in their oral cavity and oesophagus (early rash stage). Nipah virus (henipavirus) is a zoonotic pathogen transmitted by bats, which results in Nipah virus infection. It is a highly lethal paramyxovirus that induces infection in humans as well as animals. The virus has a genome made of single-stranded RNA that is not segmented and has negative polarity. This RNA genome is surrounded by protein. The virus is extremely contagious and can cause severe illnesses that pose a threat to the lives of both animals and humans. Additionally, it has the potential to be utilised as a biological weapon [16]. In addition to bacterial and viral pathogens, fungi such as Coccidioides immitis and Coccidioides posadasii are two particular kinds of Coccidioides that are accountable for the development of Coccidioidomycosis infection. These fungi are dimorphic and are naturally found in soil, existing either as mould or mycelia. Phytophthora infestans represents a pathogenic fungus responsible for causing severe infections in potatoes and tomatoes, commonly referred for as late blight, potato blight. This organism also parasitizes on other species of the Solanaceae family. The fungus forms sporangia and sporangiophores in the potato stems and leaves and is visible on the underside of the foliage. The spores are disseminated through wind, leading to rapid spread to adjacent plants, hence causing significant impact on a large number of vegetation and resulting in crop destruction. Peronosclerospora philippinensis is the pathogen responsible for the fungal infection known as Philippine downy mildew. It results in decreased crop productivity, shrivelled leaf appearance, and impaired reproductive structures. The organism parasitizes maize and sugarcane, leading to a significant reduction in population size. This condition promotes growth in certain regions while inhibiting it in other aspects of development. Furthermore, the pollen possesses a hollow structure and exhibits wrinkles. These pathogens that induce illnesses in plants are highly efficient as biowarfare agents [3].

Clostridium botulinum, a gram-positive anaerobic bacterium, is the main source of botulinum toxin [17]. Botulism is the neurological disorder that occurs as a result of botulinum. Botulinum neurotoxins, generated by species of C. botulinum, are the most potent known toxins to humans. The two most plausible techniques for utilising botulinum toxin to create a bioweapon are purposeful contaminations of food and beverages, or its emission through an aerosol. Ricin is derived from the seeds found in the castor plants (Ricinus communis). The substance exhibits high stability and can be found in various forms such as powder, mist, pellets that dissolve in water, or mild acid. It permanently inhibits the process of protein synthesis. Additionally, it possesses numerous potential applications in the field of medicine. Abrin is derived from the Jequirity bean (Abrus precatorius) and has exceptional stability [18]. Abrin functions by infiltrating the body’s cells and impeding the creation of cellular proteins. The degree of danger of abrin toxicity differs based on the route through which someone is exposed to the chemical (whether it is swallowed, breathed, or injected). It can also be conveyed through three pathways: breathing, ingesting, and absorption. Even in minuscule quantities, this substance is deadly and can induce severe symptoms, making it an intriguing and menacing bioweapon [1]. Table 3 displays the attributes of specific biological warfare agents and biotoxins.

Conclusion and future prospective

Both warfare and terrorism are intentionally orchestrated to inflict detrimental consequences onto society and humanity. Terrorist acts exert a potent psychological impact, characterised by their random nature and driven by a strategic objective that goes beyond the immediate consequences of the act. Terrorism may not always have the objective of causing large casualties, but rather aims to instil fear and worry. War, in contrast, is typically more pervasive as it is conducted by nation-states employing armed forces and weaponry. Both war and terrorism encompass acts of extreme brutality or violence, motivated by political in nature, ideological, or strategic reasons and perpetrated by individuals against others. When it comes to biowarfare and biological warfare, we observe a comparable situation. Both pose a significant threat to national security by facilitating widespread transmission and have the potential to result in a high rate of illness and death, thus having a large impact on public health. While sharing similarities in certain respects, biowarfare and bioterrorism display distinct differences. Bioterrorism, which occurs in civilian settings, involves intentional acts that result in mass casualties. In contrast, biowarfare, which occurs in military contexts, is premeditated and systematic rather than random. Preventive vaccination is less feasible for bioterrorism compared to biowarfare, as bioterrorism leads to a widespread dissemination of harmful agents, unlike biological warfare. These attacks not only result in public agitation, panic, and social disturbance, but also prompt specialised public health preparedness measures such as improved diagnostic capacity and disease surveillance. Bioterrorism generates social paralysis, characterised by mass terror, bewilderment, and community disturbance, in addition to the primary cause of mass casualties. During times of conflict, it is highly probable that these biological agents will be disseminated through aerosol means. Due to their minuscule size (ranging from 0.3 to 5.0 microns in diameter), low weight, and inability to be seen, these particles can be ingested and enter the alveoli inside the lungs. This can be accomplished by the utilisation of aerosol generators strategically positioned in certain areas or affixed to various vehicles such as trucks, cars, boats, and even ballistic missiles and planes fitted with canisters and spray nozzles. Nevertheless, this approach is influenced by various environmental variables such as wind speed, humidity, extent of cloud cover shielding from direct sunshine, and precipitation. Aerosols are commonly distributed in bioterrorist scenarios, although the pathways are frequently indirect. In this scenario, the aerosols could be introduced into ventilaton or air-conditioning systems. Alternative pathways may encompass correspondence or packages, while food and whater may also function as potential conduits for the local transmission of diseases. Biological agents serve as weapons in acts of terrorism and conflict. This review has examined the close relationship between biological warfare and bioterrorism, which are connected by the use of bioweapons as a means of attack. In addition, further research is needed into the genetic modifications of this potential biological weapon.

Acknowledgement. The authors express their gratitude to the Amity Institute of Biotechnology, Amity University Kolkata, and Jharkhand for their unwavering support in the composition of this review study.

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