Wednesday, January 13, 2016

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.

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This blog represents the work of students from one of the few courses devoted to Eukaryotic Microbiology as a whole. This is a new experiment for this course that we hope will be a successful fusion of student learning and science communication. Enjoy, but play nice, comments are welcome but mean-spirited comments will be deleted.