Ames strain

The Ames strain is one of 89 known strains of the anthrax bacterium (Bacillus anthracis). It was isolated from a diseased 14-month-old Beefmaster heifer that died in Sarita, Texas in 1981. The strain was isolated at the Texas Veterinary Medical Diagnostic Laboratory and a sample was sent to the United States Army Medical Research Institute of Infectious Diseases (USAMRIID).[1] Researchers at USAMRIID mistakenly believed the strain came from Ames, Iowa because the return address on the package was the USDA's National Veterinary Services Laboratories in Ames and mislabeled the specimen.[2]

The Ames strain came to wide public attention during the 2001 anthrax attacks when seven letters containing it were mailed to media outlets and US Senators on September 18, 2001, and October 9, 2001.

Because of its virulence, the Ames strain is used by the United States for developing vaccines and testing their effectiveness. Use of the Ames strain started in the 1980s, after work on weaponizing the Vollum 1B strain ended and all weaponized stocks were destroyed after the end of the U.S. biological warfare program in 1969.[3]

Virulence

Virulence plasmids

Researchers have identified two specific virulence plasmids in B. anthracis, with the Ames strain expressing greater virulence compared to other strains. The virulence of B. anthracis results from two plasmids, pXO1 and pXO2. Plasmid pXO2 encodes an antiphagocytic poly-D-glutamic acid capsule, which allows B. anthracis to evade the host immune system. Plasmid pXO1 encodes three toxin proteins: edema factor (EF), lethal factor (LF) and protective antigen (PA). Variation in virulence can be explained by the presence or absence of plasmids; for example, isolates missing either pXO1 or pXO2 are considered attenuated, meaning they will not cause significant infection. One possible mechanism that may be responsible for the regulation of virulence is the copy number of plasmids per cell. The number of plasmids among isolates varies, with as many as 243 copies of pXO1 and 32 copies of pXO2 per cell. Studies have shown that pXO2 contributes significantly to the observed variation in virulence, as mutants producing greater amounts of the capsule show a higher level of virulence.[4] Virulent strains that were cured of the pXO1 plasmid, but had the Ames pXO2 plasmid were still fully virulent for mice; thus, the Ames pXO2 plasmid specifically appears to give a higher level of virulence, as strains that are missing one of the plasmids are usually attenuated. Additionally, isolates that carried the Ames pXO2 were found to be more virulent than those with the Vollum 1B strain pXO2, also a virulent strain.[5] Another well-known strain of anthrax, the Sterne strain, is avirulent, meaning it does not cause significant illness in animals or humans.

Antibiotic resistance

The Ames strain is resistant to antibiotics, while other strains do not show the same level of resistance. The Ames strain is difficult to treat because it contains both an inducible 𝛃-lactamase and a cephalosporinase; thus, treatment with penicillin or amoxicillin alone is no longer recommended.[6] Ciprofloxacin is the recommended treatment for respiratory anthrax, but studies have shown that a newer fluoroquinolone, gatifloxacin, can increase the survival of mice susceptible to the Ames strain.[7]

The Sterne strain has two functional 𝛃-lactamases, but gene expression is usually not sufficient to allow drug resistance. The Sterne strain acts as a good comparison to other anthrax strains, as it is a prototypical and easy to work with strain, with sensitivity to penicillin.[8]

Anthrax vaccines

Vaccine development using attenuated strains

Virulence can usually be reduced by removing the virulence plasmids, and these attenuated strains can be used to make vaccines against B. anthracis. If either the pXO1 or pXO2 plasmid is missing, the strain cannot produce all of the virulence factors, and is considered attenuated. The Sterne strain naturally lacks a pXO2 plasmid; thus, it is attenuated and can be safely used to generate an immune response.[9] To create attenuated strains, the virulence plasmid pXO1 is usually removed, but the Ames strain can still be virulent in mouse models if the pXO1 plasmid is removed, but the pXO2 plasmid remains.

Anthrax vaccines are used for both livestock and human immunization. One of the most used anthrax vaccines today is based on the Sterne strain, in the form of a live-spore vaccine for animals. A vaccine with live spores is dangerous for humans, so vaccines based on the secreted toxin protein, protective antigen (PA), have been explored. However, PA vaccines are less protective than live-spore vaccines, and a PA-based vaccine against the Ames strain for humans has not been developed.[10]

Existing anthrax vaccines

The only licensed human anthrax vaccine in America, Anthrax vaccine adsorbed (AVA), is based on protective antigen, and has varying success against Ames depending on the animal model. This inconsistency suggests that multiple model organisms must be studied when testing vaccines for human use.[11] Currently, researchers are investigating a way to inactivate anthrax spores, such as with formaldehyde; this would provide an alternative to the live spore and PA vaccines.[10]

Strain tracking

The identification of strain-specific single-nucleotide polymorphisms (SNPs) in the Ames strain allows for the development of diagnostic tests that can help track outbreaks. SNPs can define specific genetic groups, and are therefore important for detecting and subtyping bacterial pathogens. Six SNPs are identified as highly specific and are seen only in the Ames strain; there are four on the chromosome, one on the pXO1 plasmid and one on the pXO2 plasmid. Any of the six SNPs can differentiate the Ames strain from the other 88 B. anthracis strains. However, one of the SNPs has less discriminatory power against strains that are closely related to Ames.

Using Ames strain-specific SNPs and real-time PCR, investigators can either confirm or disconfirm thousands of samples as the Ames strain. The stability of these SNPs as diagnostic markers results from the low mutation rates in the DNA of B. anthracis. The lack of these mutational events limits the likelihood of observing a false positive in these assays, as the strain is unlikely to mutate to a novel or ancestral state.[12] Additionally, anthrax has this reduced genetic variability because its spores can remain dormant for an extended period of time, and should not accumulate genetic mutations as they remain inactive.[13] Thus, the stable nature of the Ames strain allows researchers to look for small genetic variations and connect them to a source sample. The approach of using strain-specific SNPs allows for highly specific strain identification that can be widely applied to other bioterror agents.

References
  1. Rasko DA, Worsham PL, Abshire TG, Stanley ST, Bannan JD, Wilson MR, et al. (March 2011). "Bacillus anthracis comparative genome analysis in support of the Amerithrax investigation". Proceedings of the National Academy of Sciences of the United States of America. 108 (12): 5027–32. Bibcode:2011PNAS..108.5027R. doi:10.1073/pnas.1016657108. PMC 3064363. PMID 21383169.
  2. Warrick J (2002-01-29). "One Anthrax Answer: Ames Strain Not From Iowa". The Washington Post.
  3. Fainaru S, Warrick J (2001-11-25). "Deadly Anthrax Strain Leaves a Muddy Trail". Washington Post.
  4. Coker PR, Smith KL, Fellows PF, Rybachuck G, Kousoulas KG, Hugh-Jones ME (March 2003). "Bacillus anthracis virulence in Guinea pigs vaccinated with anthrax vaccine adsorbed is linked to plasmid quantities and clonality". Journal of Clinical Microbiology. 41 (3): 1212–8. doi:10.1128/JCM.41.3.1212-1218.2003. PMC 150325. PMID 12624053.
  5. Welkos SL, Vietri NJ, Gibbs PH (May 1993). "Non-toxigenic derivatives of the Ames strain of Bacillus anthracis are fully virulent for mice: role of plasmid pX02 and chromosome in strain-dependent virulence". Microbial Pathogenesis. 14 (5): 381–8. doi:10.1006/mpat.1993.1037. PMID 8366815.
  6. Bouzianas DG (November 2009). "Medical countermeasures to protect humans from anthrax bioterrorism". Trends in Microbiology. 17 (11): 522–8. doi:10.1016/j.tim.2009.08.006. PMID 19781945.
  7. Steward J, Lever MS, Simpson AJ, Sefton AM, Brooks TJ (July 2004). "Post-exposure prophylaxis of systemic anthrax in mice and treatment with fluoroquinolones". The Journal of Antimicrobial Chemotherapy. 54 (1): 95–9. doi:10.1093/jac/dkh276. PMID 15163650.
  8. Chen Y, Succi J, Tenover FC, Koehler TM (February 2003). "Beta-lactamase genes of the penicillin-susceptible Bacillus anthracis Sterne strain". Journal of Bacteriology. 185 (3): 823–30. doi:10.1128/JB.185.3.823-830.2003. PMC 142833. PMID 12533457.
  9. "CDC - Anthrax Sterne, General Information - NCZVED". www.cdc.gov. Retrieved 2020-11-25.
  10. Brossier F, Levy M, Mock M (February 2002). "Anthrax spores make an essential contribution to vaccine efficacy". Infection and Immunity. 70 (2): 661–4. doi:10.1128/iai.70.2.661-664.2002. PMC 127709. PMID 11796596.
  11. Fellows PF, Linscott MK, Ivins BE, Pitt ML, Rossi CA, Gibbs PH, Friedlander AM (November 2001). "Erratum to "Efficacy of a human anthrax vaccine in guinea pigs, rabbits, and rhesus macaques against challenge by Bacillus anthracis isolates of diverse geographical origin" [Vaccine 19 (2001) 3241–3247". Vaccine. 20 (3–4): 635. doi:10.1016/s0264-410x(01)00411-x.
  12. Van Ert MN, Easterday WR, Simonson TS, U'Ren JM, Pearson T, Kenefic LJ, et al. (January 2007). "Strain-specific single-nucleotide polymorphism assays for the Bacillus anthracis Ames strain". Journal of Clinical Microbiology. 45 (1): 47–53. doi:10.1128/JCM.01233-06. PMC 1828967. PMID 17093023.
  13. Rasko DA, Worsham PL, Abshire TG, Stanley ST, Bannan JD, Wilson MR, et al. (March 2011). "Bacillus anthracis comparative genome analysis in support of the Amerithrax investigation". Proceedings of the National Academy of Sciences of the United States of America. 108 (12): 5027–32. Bibcode:2011PNAS..108.5027R. doi:10.1073/pnas.1016657108. PMC 3064363. PMID 21383169.
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