The pathogenesis of Bacillus anthracis

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Overview

By [Tony Amolo]

Figure1. Vegetative form of Bacillus Anthracis with stain. http://www.sciencedirect.com/science/article/pii/S0378113509003769].

Anthrax is an infectious disease caused by the bacteria Bacillus anthracis. Bacillus anthracis is a microorganism from the family Bacillaceae. Figure 1 shows its vegetative form. Unlike other bacillus microorganisms which are harmless saprophytes, Bacillus anthracis is an obligate bacillus pathogen that infects many vertebrates. Based on its physical characteristics, Bacillus anthracis can be categorized with other microorganisms such as Bacillus cereus, Bacillus thuringiensis and Bacillus mycoides. This categorization exists because it is difficult to characterize these organisms based on their 16s rRNA sequences [10]. Organisms from the bacillus genus are mostly extremophiles. They have the ability to grow in severe conditions which other microorganisms cannot withstand [4].

Anthrax is as old as man, it was given its name by a Greek physician named Hippocrates because of the black sore it causes on the skin of human and animals(1). It generally affects warm blooded animals including humans. Aloys Pollender, a German physician who was acknowledged for identifying the disease described Bacillus anthracis as “chyllus corpuscles” after analyzing the abdomen of infected cows that had died of anthrax [2]. Anthrax was broadly studied in the 1870s by Robert Koch and Louis Pasteur. Koch applied the suspended drop culture method to understand the life cycle of the bacteria and found that the spores formed could survive for long period in harsh environment [3].Koch’s studies on Bacillus anthracis helped him come up with the germ theory of disease.

Cell Structure and Metabolism

Figure 2. The spore form of Bacillus Anthracis with Shoeffer Fulton Stain . http://www.sciencedirect.com/science/article/pii/S0378113509003769.


Bacillus anthracis is a gram positive, endospore forming bacteria. Figure 2 shows Bacillus anthracis in its spore form. It is capsulated, immobile and rod shaped. Bacillus anthracis has the ability to make ATP in the presence or absence of oxygen and cannot be seen unless with a microscope. It is 5-6 micrometer long, 1-1.5micrometer wide and looks like bamboo canes in tissue [13]. Despite its small size, the diverse abilities of many species of its genus allows them to survive in different environments [4]. They have the ability to form chains, colonies and biofilms.

Habitat and Ecology


Bacillus anthracis is a soil borne bacteria. It lives best in black steppe soils with lots of calcium and at pH levels between (7-9). Endemic anthrax areas have been associated with warmer temperatures, higher soil moisture content and topography [15].

Spore Formation, Anatomy and Germination

Figure 3. Transmission Electron Micrograph of Bacillus Anthracis endospore . http://www.ncbi.nlm.nih.gov/pmc/articles/PMC303457/.

Bacillus anthracis forms one endospore per cell. Its spores form when its non reproductive cells are deficient of certain nutrients . The spores are oval in shape and sporulation occurs within 48 hours. Bacillus anthracis requires oxygen to sporulate. Spores can tolerate heat, cold, dehydration, radiation and even antibacterials [8]. The formation of spore commences when cells septate asymmetrically to create a forespore and a mother cell. After septation, the mother cell swallows the forespore and covers it with different layers. The spore is made up of several layers. These layers are the coat, the exosporium and the cortex. Figure 3 reveals these layers through a transmission electron micrograph. The innermost layer is the core. It contains proteins which holds the chromosome. Half of the spore is composed of the spore coat. The flexibility of the spore coat enables the spore to hold the core especially during germination. It protects the spore from harmful chemicals and aids germination. The cortex containing peptidoglycan protects the spore from radiation, heat and makes the core dry. The exosporium is the outermost layer of the spore. It is a protein rich, balloon-like, loose fitting structure covering a spore [8]. The exosporium has been studied to understand the use of anthrax as a weapon because of its quality and unique structure. The disintegration of the mother cell to produce the spore indicates the completion of spore formation. The mature spores have a structured arrangement that enables them withstand and endure physical damage and severe environmental conditions. Outside a host, the mature spores of Bacillus anthracis are inactive. Upon entry into a host, they have the ability to germinate and become non reproductive cells that can easily replicate all around the host's internal organs and cause damage.The availability of host’s environment with sufficient nutrients causes germination to occur[17]. Non reproductive cells transform back to spores whenever the host dies. Germination and growth of spores in the host cells are essential for the release of its virulence factors.

Pathogenesis and Virulence factors

Figure 4. Mechanism of action of the Anthrax Toxin. http://jama.jamanetwork.com/article.aspx?articleid=194886


Bacillus anthracis contains two toxic plasmids: the pX01, which produces the edema factor, the protective antigen and the lethal factor, and the pX02, which encodes the production of the capsule. Bacillus anthracis carries out its pathogenic process by using its capsule and producing toxics consisting of three proteins(EF, LF and PA)[13]. The combination of lethal toxin, which constitutes the protective antigen and the lethal factor and edema toxin which constitutes the protective antigen and the edema factor can induce severe cases of the disease [7]. Out the three factors, the protective antigen plays a crucial role in the toxic action of Bacillus anthracis. Figure 4 shows the three different ways humans and animals can be exposed to anthrax. It reveals how the toxins of Bacillus anthracis enters the cell. It also indicates other pathogenic mechanisms of the bacteria. Protective antigen is important in anthrax poisoning because it allows the connection and entry of the lethal factor and Edema factor into the cytosol. It also helps bind the cell receptor, the lethal factor and the edema factor to the host cell. Protective antigen is a primary antigen that exists in anthrax vaccines [11]. The edema factor is a cyclase that causes an imbalance of water homeostasis. The edema toxin may increase host susceptibility to infection by disrupting the cytokine response of monocytes and by suppressing neutrophil functions [11]. The lethal factor is a metalloprotease that cleaves major pathways to surface receptors for the transcription of certain genes within the nucleus [12] while the capsule enhances the virulence by inhibiting the phagocytosis of Bacillus anthracis.

Transmission and Prevention

Figure 5. A goat infected by anthrax disease being disposed by burning in Indonesia. http://go.galegroup.com/ps/i.do?id=GALE%7CCX3045200023&v=2.1&u=kenyon&it=r&p=GVRL&sw=w&asid=8b34ef35c63fa98997477f3845a915f4

The common ways of transmission of the anthrax disease are through wounds, the pharynx, gastrointestinal tract, the digestive system after ingesting spore contaminated food or water, skin lesions or abrasions caused by biting flies and the breathing in of air containing anthrax spores. After transmission through one of these route, the spores travel to the lymph nodes where they begin to multiply rapidly and the produce spores which germinate to produce the virulence factors [13]. The disease can infect humans in 3 different ways namely the cutaneous anthrax, the pulmonary or inhalation anthrax and the gastrointestinal anthrax. Each type of anthrax disease is unique in its method of infection and symptoms. The lethal dose of inhalation anthrax in humans is approximately 8,000 to 10,000 spores, however, scientists have revealed that little dosage inhaled did not cause or show symptoms of the disease [23]. Transmission of anthrax between animals occurs when infected animals are placed in the same environment as healthy animals. Proper prevention measures in mostly agricultural settings include proper disposal of infected animals, polluted equipment and vaccination. Figure 5 shows how the animal husbandry department of Indonesia tries to prevent the escalation of the disease by burning an infected goat in a pit in October 2004 [23].

Vaccines and Treatment


Anthrax was the first bacterial disease for which effective preventive treatment (prophylaxis) was developed [11]. Prophylaxis played a major role in controlling anthrax in animals and protection to individuals from infection. Several vaccines has been produced for the anthrax disease. Louis Pasteur is known as the first microbiologist to produce the first anthrax vaccine in 1881 [2]. The vaccines were made of spores from weakened genetic variant of Bacillus anthracis. Vaccines produced to combat the disease include non-living vaccines, In vitro protective antigen, Boor and Tresselt vaccine, production in non-proteinaceous media, UK vaccine, American vaccines(Aerobic antigen and Anaerobic antigen) and Russian antigen [6]. Special therapy can also be provided to treat anthrax if it is applied immediately to the infected animal or human. Aside from vaccines, antitoxin and antibiotics have been used to treat the disease. Penicillin, ciprofloxacin and doxycycline have been used to treat the susceptible genetic variants of anthrax [14]. Different methods have been adopted to create an enhanced vaccine for humans. The objective is to develop a vaccine that is non reactogenic and involves little administration to perform efficiently [11]. However, the difficult aspect of checking the potency of anthrax vaccine is making an assessment in humans. Tests using this pathogenic bacteria is not safe for humans and animals and requires special precautions.

Application to Bioterrorism


Out of many pathogenic bacteria, Bacillus anthracis is one that can be used for bioterrorism. Of its three types (cutaneous, inhalation and gastrointestinal), inhalation anthrax has been related to bioterrorism because of its mode of transmission. Bacillus anthracis makes a good model weapon for bioterrorism because its spores can be produced in the laboratory,it survives longer in the environment and can be found easily. Also, because of its small size, it can be placed in food and letters like in 2001 when powdered anthrax spores were mailed to the U.S postal office. Twenty-two cases of anthrax infections were confirmed. Half of these cases involved cutaneous anthrax and no death resulted. The remaining eleven were identified as inhalational anthrax and produced five deaths. Several countries like the past Soviet Union and Iraq have been known to produce Bacillus anthracis as a bioweapon [22]. Aside from inflicting this pathogenic bacteria through letters, aerosol delivery can also be implemented. It entails aiding the bacteria to travel a longer distance while keeping it odorless and unseen before release by the use of technology [22]. A global awareness should be created to reject the development of anthrax as weapons and provide a better means to fight this deadly disease. Health Agencies and organizations should emulate the work of agencies such as the Centers for Disease Control and Prevention (CDC), the Federal Bereau of Investigation (FBI) and the World Health Organization (WHO) to find a better understanding of this deadly disease and ensure the safety of human and animal lives, and property.

References

1] Annabel Guicharda, Victor Nizetb, c, Ethan Biera "New insights into the biological effects of anthrax toxins: linking cellular to organismal responses." 2012.

2] Joseph A Witkowski,Lawrence Charles Parish "The story of anthrax from antiquity to the present: a biological weapon of nature and humans."2002.

3] George Sternbach "The history of anthrax."2003.

4] Peter C. B. Turnbull "Bacillus."1996.

5] Maxime Schwartz "Dr. Jekyll and Mr. Hyde: A short history of anthrax."2009.

6] Peter Hambleton, J.Anthony Carman, Jack Melling "Anthrax: the disease in relation to vaccines."1984.

7] Mahtab Moayeri, Stephen H Leppla "The roles of anthrax toxin in pathogenesis."2004.

8] Jeremy A. Boydston, Ling Yue, John F. Kearney, and Charles L. Turnbough, Jr. "The ExsY Protein Is Required for Complete Formation of the Exosporium of Bacillus anthracis."2006.

9] W. Beyer, P.C.B. Turnbull. "Anthrax in animals."2009.

10] Les Bailliea, , Timothy D Read. "Bacillus anthracis, a bug with attitude!."2001.

11] Stephen F Little, Bruce E Ivins. "Molecular pathogenesis of Bacillus anthracis infection."1999.

12] Laurence Abrami, Nuria Reig, F. Gisou van der Goot. "Anthrax toxin: the long and winding road that leads to the kill."2005.

13] Antonio Fasanellaa, Domenico Galantea, Giuliano Garofoloa, Martin Hugh Jones. "Anthrax undervalued zoonosis."2010.

14] Martin Hugh-Jonesa, Jason Blackburn. "The ecology of Bacillus anthracis."2009.

15] Jocelyn C. Mullins, Giuliano Garofolo, Matthew Van Ert, Antonio Fasanella, Larisa Lukhnova, Martin E. Hugh-Jones, Jason K. Blackburn. "Ecological Niche Modeling of Bacillus anthracis on Three Continents: Evidence for Genetic-Ecological Divergence?."2013.

16] [1]

17] Adam Driks. "The Bacillus anthracis spore."2009.

18] [2]

19] Theresa M. Koehler. "Bacillus anthracis physiology and genetics."2009.

20] Nicholson WL. "Roles of Bacillus endospores in the environment."2002.

21] [20] Hongbin Liu1, Nicholas H. Bergman, Brendan Thomason, Shamira Shallom, Alyson Hazen, Joseph Crossno, David A. Rasko, Jacques Ravel, Timothy D. Read, Scott N. Peterson, John Yates, and Philip C. Hanna. "Formation and Composition of the Bacillus anthracis Endospore."2003.

22] Thomas V. Inglesby, Tara O'Toole, Donald A. Henderson, John G. Bartlett, Michael S. Ascher,Edward Eitzen,MPH; Arthur M. Friedlander, Julie Gerberding, Jerome Hauer,James Hughes, Joseph McDade, Michael T. Osterholm, Gerald Parker,Trish M. Perl, Philip K. Russell,Kevin Tonat, DrPH. "Anthrax as a Biological Weapon, 2002 Updated Recommendations for Management"2002.

23] Ed. Brenda Wilmoth Lerner and K. Lee Lerner. "Anthrax."2008.

Edited by student of Joan Slonczewski for BIOL 238 Microbiology, 2009, Kenyon College.