快猫短视频

IN THE early 1970s, a mysterious epidemic hit several hospitals in
California. Infections鈥攎ost of them blood-borne or respiratory鈥攚ere
sweeping through the wards, but doctors and public health officials couldn鈥檛 put
their finger on the source. In desperation, they enlisted the help of a team of
infectious disease specialists at the University of California, Berkeley. After
a careful search, the microbial detectives reached a startling conclusion. The
epidemic was caused by a plant disease鈥攁 bacterium called Pseudomonas
aeruginosa that infected both the flowers brought in to cheer up sick
patients and the salads and vegetables on their plates. Amazingly, the same
bacterium that attacked the plants was also causing illness in people.

For the next two decades, scientists regarded this as no more than a curious
one-off. But in the past few years, the parallels uncovered between plant and
animal disease have spread far beyond Pseudomonas. The pathogens that
cause sickness in these two disparate kingdoms of life are turning out to use
much the same molecular machinery鈥攁nd their hosts use remarkably similar
countermeasures. Because of these striking similarities, researchers are now
looking to our green cousins to learn more about diseases that afflict people.
Using knowledge and techniques developed in plants, they are beginning to search
for previously unsuspected disease-resistance genes lurking in the genomes of
mammals. And others are importing weapons from the plants鈥� disease-fighting
arsenal to see if they might someday work in people.

Such cross-fertilisation would have been regarded as heresy only five years
ago, when there seemed to be an unbridgeable gulf between the worlds of plant
and animal microbiology. Plant researchers focused on agricultural applications
such as finding disease-resistance genes, studying them and breeding them
into crops, while medical researchers addressed the cell biology of disease. But
suddenly, the medical people have gained a new-found respect for the secrets
their plant colleagues can reveal about animal diseases.

In particular, plant biologists have long understood the struggle between
pathogen and host as a gene-on-gene duel. Many bacteria target their hosts via
virulence factors encoded by Avr genes (short for 鈥渁virulence鈥�,
ironically, because they were discovered in strains rendered ineffective by
mutation). Plants parry this attack by evolving resistance factors produced by
R genes, then pathogens respond with new genes, and so on. Over the
years, plant pathologists have identified many of the genes involved by
bombarding virulent microbes with X-rays or chemicals that mutate their DNA at
random. The resulting mutants are then let loose on healthy hosts. Those
microbes that can鈥檛 infect plants, or do so only weakly, have probably picked up
mutations in genes that encode crucial virulence factors.

Animal researchers hadn鈥檛 approached disease pathogens that way until the
plant-animal similarities began coming to light. 鈥淚t taught the animal people
that they might be missing the tip of the iceberg by only focusing on normal
infection. Disease resistance is really an abnormal infection,鈥� says Jeff Dangl,
a plant geneticist at the University of North Carolina at Chapel Hill. By
studying such failed infections, medical researchers might find virulence genes
that disease-causing bacteria use to attack humans, and develop antibiotic drugs
to blunt the attack.

But spotting the genes responsible for virulence and resistance in animals is
a daunting task. It would take at least 30 000 mutants to systematically comb
the entire genome of P. aeruginosa for all possible virulence factors
made by the bug, estimates Lory Rahme, a plant pathologist turned molecular
microbiologist at Harvard Medical School in Boston. Test each mutant on 10 host
animals鈥攖o make sure the result is statistically significant鈥攁nd you
are faced with a screening nightmare if the hosts are, say, mice. But even that
is not enough. You鈥檒l want to go still further and systematically test the
mutated pathogens in several strains of mutated hosts. 鈥淚n animals, it would
simply be impossible,鈥� Rahme concludes.

But maybe there鈥檚 an easier way. In 1992, Rahme, who was searching for a
postdoctoral project, turned to Milt Schroth, a plant pathologist at the
University of California at Berkeley. 鈥淲hy not start in plants and move to
animals?鈥� she proposed. Schroth, a member of the team that first collared
Pseudomonas in the hospital infections 20 years earlier, gave her the 80 or
so Pseudomonas isolates he had saved from that investigation.

Rahme took those to Boston, where she teamed up with microbiologist Frederick
Ausubel at Harvard and Ronald Tompkins, chief of staff at Shriners Burns
Hospital. Together, they set up a massive screening system that begins in
mustard plants, moves through flies and nematode worms, and ends up in mice.

The researchers start by randomly mutating lots of P. aeruginosa and
then squirting the altered bacteria onto the leaves of mustard plants. Any bugs
harbouring mutations in crucial virulence factors will be unable to grow or
reproduce as effectively as the normal microbes, which infect the plants with
ease. The team then picks out these Pseudomonas duds and injects them
into fruit flies鈥攚hich normal Pseudomonas can also
attack鈥攖o see if they are impotent in this host, too. The least infective
bacterial mutants also pass through Ausubel鈥檚 lab, where investigators test
their virulence in worms and, across the street, to Tompkins鈥檚 lab, where the
mutant Pseudomonas strains are screened in mice that are especially
susceptible to infections.

Attack genes

So far, the researchers have divided the mutants into eight classes according
to which combination of hosts the putative virulence factors target. For
example, one class carries mutations in genes that, if normal, would help to
infect mustard plants and fruit flies and nothing else. Another class carries
mutations in genes that work in plants, worms and mice, but not flies. Right
now, Rahme and her colleagues are concentrating on a group of 24 promising
virulence gene candidates that control the severity and persistence of infection
in at least three of the four groups. In fact, half of those 24 genes work in
all four hosts, Rahme reported in December at a colloquium on plant-animal
disease similarities in Irvine, California, hosted by the National Academy of
Sciences. The researchers have located the genes where these 24 mutations reside
and are now trying to figure out what the genes actually do. 鈥淲e are getting out
information on what mechanisms of infection may be universal and what may be
host-specific,鈥� says Rahme.

At least some of the genes produce something called the Type III secretion
system鈥攅ssentially a molecular syringe made up of 30 or so proteins that
some bacteria use to inject toxins or other molecules into host cells. Some of
the syringe pieces鈥攖he ones responsible for pumping the toxins or
molecules out of the bacterial cell鈥攁re so universal that last year,
geneticists found they could mix and match genes from plant and animal pathogens
without affecting the working of the syringe (Proceedings of the National
Academy of Sciences, vol 96, p 12 839).

Sure enough, back in 1995 Rahme鈥檚 team had reported that a syringe protein
produced by one of a class of genes known as hrp genes is necessary to
make Pseudomonas virulent in both plants and mice (Science,
vol 268, p 1899). Since then, the researchers have found several more
hrp genes among their 24 most widely active virulence genes. Within two
years or so, they hope to begin testing drugs to block these virulence
factors鈥攑erhaps using plants, rather than mice, for the initial screening
process.

What about the other side of the coin鈥攖he hosts鈥� defences? Mammals,
like plants, seem to have genes affecting their susceptibility to certain
pathogens. For example, a mutation in a certain strain of mice prevented them
from being killed by a mutant strain of Bordetella bronchiseptica,
which usually causes respiratory tract infections in many mammals, Jeff Miller
of the University of California at Los Angeles told researchers at last
December鈥檚 colloquium. The interaction looks remarkably like the gene-for-gene
thrust and parry familiar to plant disease specialists.

But plants and people share an even deeper similarity in their response to
invading germs鈥攁n ancient immune system handed down from our common
ancestor hundreds of millions of years ago. Here鈥檚 how it works in plants: a
pathogen attacks a plant tissue and unwittingly emits a signal that is picked up
by a protein encoded by a resistance gene. Most R-genes encode
receptors, and many of these closely resemble a receptor first discovered in
fruit flies called Toll, which also orchestrates the immune response in
insects.

Once triggered, the R-gene response branches into two pathways
(see Diagram).
At the site of infection, an enzyme called MAP kinase kicks off
a cell-suicide program called the hypersensitivity response, which involves
the release of nitric oxide, a gaseous signal molecule. In the second pathway,
the gas works in concert with salicylic acid to circulate throughout the plant
and eventually unleash an army of antimicrobial molecules well beyond the
infection site, says Daniel Klessig of Rutgers University in Piscataway, New
Jersey.

The whole process is almost identical to the inflammatory response of
mammals. When a pathogen attacks or a tissue is injured, mammalian cells release
tumour necrosis factor, a signal that binds to a Toll-like receptor called the
interleukin-1 receptor. This receptor triggers a MAP kinase that initiates a
cell-suicide program called apoptosis. And this is mediated by鈥攜ou鈥檝e
guessed it鈥攏itric oxide. The carnage that results is familiar as the pus
that fills an inflamed wound. The kinase also flicks on cell signalling
molecules that enter the circulation and trigger the release of potent
inflammatory, clotting and antimicrobial agents.

鈥淭o me, the hypersensitivity response is an abscess in plants,鈥� says Carl
Nathan, an immunologist at Cornell University鈥檚 Weill Medical College in Ithaca,
New York. Until last December, Nathan admits, he hadn鈥檛 paid any attention to
the plant phenomenon. 鈥淚 had read about it but never seen it. When I did, I was
blown away by the similarity.鈥�

Tuberculosis clue

Indeed, Nathan and others now think mammals might carry specific resistance
genes that鈥攍ike the R genes of plants鈥攔ecognise classes of
germs and spur a generalised inflammatory response to deal with the invaders
before the more specialised immune system鈥攂ased on antibodies and
T-cells鈥攃an kick in. Nathan had already learned that mutations in a gene
for an enzyme called nitric oxide synthase-II (or drugs that block the enzyme)
render mice susceptible to some pathogens, such as the tuberculosis bacterium,
that they would normally resist.

Something similar may occur in people. Nathan estimates that 90 per cent of
people infected with TB never show signs of the disease unless they become
malnourished or immunosuppressed. 鈥淲hat is it about the unlucky 10 per cent that
renders them susceptible?鈥� he asks. The answer could be variations in specific
genes. Already, Nathan has found a number of candidate genes and is mutating
them in mice to see what their contribution to the disease might be.

So if plants have cell death and signalling pathways similar to those in
animals, might the two respond to the same drugs? The answer is an emphatic yes.
In people, aspirin (acetylsalicylic acid) has long been known to relieve
inflammation by blocking prostaglandin production. Its parent, salicylic acid,
was first isolated from the bark of willow trees, where it enhances defence by
aiding the signalling role of nitric oxide.

Those seem like opposite effects, but plant researcher Bud Ryan at Washington
State University in Pullman has an explanation. Plants crank up salicylic acid
production when attacked by microbes. Salicylic acid then shuts down the plant鈥檚
production of jasmonic acid, which would otherwise signal the production of
protease inhibitors and cross-linking agents that prevent insects from digesting
its tissues (left branch in Diagram),
in favour of the hypersensitivity response
(right branch in Diagram).
In other words, when faced with both threats, the
plant focuses all its energies on dealing with the microbe. In people, aspirin
blocks the same pathway of inflammation, probably targeting at least two enzymes
similar to those that it blocks in the plant pathway.FIG-mg22264101.JPG

Rethinking aspirin

But plant researchers know that salicylic acid plays many other roles in
plants. Klessig speculates that aspirin may likewise act through a variety of
similar mechanisms in people. If so, plants may shed new light on one of
medicine鈥檚 star performers.

The close parallel between plant and animal defence systems may yield other
useful drugs. Intriguingly, in 1996, Ryan鈥檚 group found that ultraviolet light
activates the defensive response in plants just as it does in humans. So perhaps
compounds such as flavonoids鈥攚hich protect the plant against ultraviolet
light鈥攎ight also serve as anti-inflammatory drugs for people. Likewise,
Klessig and other researchers are studying a class of broad-spectrum plant
antibiotics called phytoalexins that they hope may also work in animals.
Conversely, the synthetic anti-tumour drug suramin鈥攚hich can prevent UV
light from causing inflammation in humans鈥攁lso blocks the wounding
response of tomato plants, Ryan鈥檚 group has found, in research to be published
this spring in the Proceedings of the National Academy of Sciences.
Suramin is extremely toxic to patients in its present form, but if
pharmacologists can find ways to mitigate its side effects, they may be able to
find other uses for the drug.

With so many similarities emerging between diseases of plants and
people鈥� interchangeable molecular syringe parts, related receptors and
signals, and pathogens that can infect species in both kingdoms鈥�
researchers say there must have been an ancient, common ancestor that passed
down the crucial pieces of a basic immune response. 鈥淭he cogs are the same, but
how they are connected up is different in different species,鈥� says plant
pathologist Jonathan Jones at the John Innes Centre in Norwich, who studies
Toll-like receptors.

So it鈥檚 no surprise that pathogens have similar parts鈥攔elics of the
diseases that afflicted our common ancestor hundreds of millions of years ago.
This brings a fresh unity of purpose to plant and animal disease experts. 鈥淭he
key is animal people have strengths that we don鈥檛 have, and we have strengths
that they don鈥檛 have,鈥� says Dangl. 鈥淚t鈥檚 always good to look at your problem
from a slightly oblique viewpoint.鈥� Plant and animal pathologists know this only
too well, as they discover that all along, they have been unwittingly reading
from the same page of the Book of Life.