Fusarium & trichothecene mycotoxins: Implications for use as biological weapons

by JS

The intentional use of infectious agents as weapons of war has been a heinous aspect of humanity’s past, with records dating as far back as 1155 AD (1). Even in the early history of the United States, the British used smallpox-infested blankets as biological weapons against the Native Americans, killing as many a 100,000 (1;2). Despite international treaties made in 1925 and 1972 that banned the use of biological weapons, advances in research and large-scale production of disease-causing agents exhibit daunting weapons for acts of terrorisms or use in warfare (3). One group of these biological warfare (BW) agents, trichothecene mycotoxins, pose a great threat to humans, agricultural crops, and, potentially, water supplies.

            Trichothecene mycotoxins have been found to be produced by five genera of fungi: Alternaria, Aspergillus, Claviceps, Penicillium, and Fusarium (4). Fusarium species have been identified to produce more than 40 trichothecene mycotoxins (5). The molecular structure of trichothecenes differ, but the presence of an epoxide group is responsible for their toxicity. Trichothecene toxins kill rapidly dividing cells by inhibiting protein synthesis after penetration of the skin (6). The toxin binds the ribosomal machinery used for translation and disrupts the activity of peptidyl transferase which normally forms bonds between amino acids to create proteins (6).

Although the CDC (8) does not have Fusarium, or the trichothecene mycotoxins they produce, listed as biological threats, there is contradicting evidence that the toxins have been used as weapons by the Vietnamese during the Korean War in 1981 (1). Analysis of “yellow rain” samples collected in Laos at this time revealed the presence of four trichothecene mycotoxins: T-2 toxin (T-2), nivalenol (NIV), 4-deoxynivalenol (DON) and diacetoxyscirpenol (DAS) (9). Skeptical scientists suggested that toxins present in the samples were produced by naturally occurring Fusarium, but Rosen and Rosen (9) countered this with the finding of synthetic material, possibly used as an emulsifier for the dispersal of toxins in water. Other reports indicate that trichothecenes have also been used as BW agents in Cambodia, Afghanistan, and Iraq (4).

            As a result of these biological threats, the U.S. Department of Agriculture began research on trichothecene toxins in 1984 (5). These toxins have been found to be the only BW toxin with cutaneous activity and manifestations, allowing for easier contraction of ailment and disease (10). Topical exposure of trichothecene mycotoxins causes blistering and death of skin (4). Studies of dermal exposure to trichothecenes often use solvents to enhance absorption (11), as was found in yellow rain samples from Laos (9). As far back as the 1800s, outbreaks of a human disease associated with consumption of Fusarium graminearum-contaminated grains occurred in Japan, China, Korea, and Russia (5). Ingestion of grains contaminated with F. sporotrichioides caused thousands of deaths in Russia during World War II (5). Ingestion causes alimentary toxic aleukia with symptoms including vomiting, diarrhea, inflammation, and hemorrhage (4;5;10). Creasia and colleagues (12) showed that inhalation is a more potent route of infection compared to ingestion. Inhalation of these toxins can cause death in humans within hours (10).

            Yet another difficult aspect of trichothecenes is their stability in water. In Cleveland, Ohio, fatal pulmonary hemorrhage in infants was thought to have been caused by trichothecene poisoning (10). The toxin was proposed to have come from sources growing in damp walls of insufficiently maintained homes. Trichothecenes have been shown to have stability in water at room temperature, specifically the T-2 toxin (4). Breakdown of the toxin does not occur rapidly enough to relieve health concerns over a seven day period. Although research has shown that cleanup is efficient, as removal from water using reverse osmosis is 99.9% efficient (4), the stability of trichothecene toxins still impose threats to persons and plants in exposed environments for an extended period of time.

Along with clinical symptoms in humans and animals and contamination of water, Fusarium species also have pathology in plants. Trichothecene-producing Fusarium can infect maize, wheat, rye, barley, and rice (13). However, the production of trichothecene toxins are not the sole cause of disease in plants. Fusarium oxysporum, for example, is found in soil throughout the world and pathogenic strains causes root rot in numerous plants, including agriculturally important crops (14). In 1973, the bioweapons program of the former Soviet Union was reportedly weaponizing Fusarium species to be used as anticrop agents (15). Through horizontal gene transfer, genetic information is exchanged between individual organisms allowing non-pathogenic Fusarium to become infectious (14). The easy transfer of pathogenicity poses a large issue for both intentionally released and naturally occurring Fusarium in our agricultural crops.

The threats to water, food, animal and human health make Fusarium and trichothecene mycotoxins potentially devastating weapons for use in warfare or terroristic crimes. Trichothecene mycotoxins have been shown to be deliverable as dusts, droplets, aerosols, or smoke (6), which greatly increases threats to to humans as topical exposure causes severe skin ailments and inhalation causes death. While warfare and acts of terrorism have become ongoing and often occurrences in our present world, the ability to protect ourselves, our food sources, and our water sources from BW attacks seems necessary.

References

1.     Frischknecht F. 2003. The history of biological warfare. Human experimentation, modern nightmares and lone madmen in the twentieth century. EMBO Rep 4 Spec No:S47–52.

2.     Brown T. 2006. Did the U.S. Army Distribute Smallpox Blankets to Indians? Fabrication and Falsification in Ward Churchill’s Genocide Rhetoric. Plagiary Cross-Disciplinary Stud Plagiarism, Fabr Falsif.

3.     Christopher GW, Cieslak TJ, Pavlin JA, Eitzen EM. 1997. Biological warfare. A historical perspective. JAMA 278:412–7.burrow

4.     Burrows WD, Renner SE. 1999. Biological warfare agents as threats to potable water. Environ Health Perspect 107:975–84.

5.     Desjardins AE. 2009. From yellow rain to green wheat: 25 years of trichothecene biosynthesis research. J Agric Food Chem 57:4478–84.

6.     Wannemacher RW Jr, Wiener SL 1997. Trichothecene mycotoxins. In: Medical Aspects of Chemical and Biological. Washington, DC:TMM Publications. 655-676.

7.     Cundliffe E, Davies JE. 1977. Inhibition of Initiation, Elongation, and Termination of Eukaryotic Protein Synthesis by Trichothecene Fungal Toxins. Antimicrob Agents Chemother 11:491–499.

8.     CDC. 2015. Bioterrorism Agents/Diseases: Emergency Preparedness & Response. Retrieved November 13, 2015, from http://emergency.cdc.gov/agent/agentlist.asp

9.     Rosen RT, Rosen JD. 1982. Presence of four Fusarium mycotoxins and synthetic material in “yellow rain”. Evidence for the use of chemical weapons in Laos. Biomed Mass Spectrom 9:443–50.

10.  McGovern TW, Christopher GW, Eitzen EM. 1999. Cutaneous Manifestations of Biological Warfare and Related Threat Agents. Arch Dermatol 135:311–322.

11.  Pang V. 1987. The toxicity of T-2 toxin in swine following topical application *1I. Clinical signs, pathology, and residue concentrations. Fundam Appl Toxicol 9:41–49.

12.  Creasia DA, Thurman JD, Jones LJ, Nealley ML, York CG, Wannemacher RW, Bunner DL. 1987. Acute Inhalation Toxicity of T-2 Mycotoxin in Mice. Toxicol Sci 8:230–235.

13.  Desjardins AE, Hohn TM, McCormick SP. 1993. Trichothecene biosynthesis in Fusarium species: chemistry, genetics, and significance. Microbiol Mol Biol Rev 57:595–604.

14.  van der Does HC, Lievens B, Claes L, Houterman PM, Cornelissen BJC, Rep M. 2008. The presence of a virulence locus discriminates Fusarium oxysporum isolates causing tomato wilt from other isolates. Environ Microbiol 10:1475–85.

15.  Wilson TM, Logan-Henfrey L, Weller R, and Kellman B. 2000. Agroterrorism, biological crimes, and Biological Warfare Targeting Animal Agriculture. In: Emerging diseases of animals. Washington, DC: ASM Press. 23-57.