The Sciences; March/April '98: "Blood Feud" - Tick Article

[Rita Stanley]

Thanks, Adrianna, for the scan.

Rita

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BLOOD FEUD

By Cynthia Mills

The Sciences; 1998, March/April; 34-38.

LOOK FOR IT IN THE GRASS, NOT THE BUSHES. Concentrate on the uphill side of
the trail; it stays away from the downhill side as if it were taboo.
Examine each blade of grass for spots—the spot might have legs. Breathe on
it softly and the legs will flare out, reaching for you.
If it latches on, it might take a meal. Or maybe it who leave a visitor
behind: an invisible, twisted germ called a spirochete—the kind that causes
Lyme disease—or some other from its tribe of pathogenic hitchhikers. If
conditions are right, it may inject a neuro toxin that paralyzes you, even
to the point of suffocation.

As parasites go, a tick seems a simple, even stupid thing— less fleet than a
mosquito, less insidious than a roundworm. From birth until death, some
three years later, it leads a life of uncommon sloth: hiding in leaf litter
as a larva and nymph, lumbering up grass blades as an adult, grabbing onto
hosts when the need arises. But it rarely arises. Ticks spend 95 percent of
their time lounging around, bloated and self-satisfied, digesting their last
meal. (Thanks to pleats in their skin, some ticks can swell to contain
nearly IOO times their weight in blood.) Entomologists long suspect-ed that
they entered diapause, a kind of arthropod hiber-nation, between its
feedings. Now it seems that ticks are just lazy—so lazy they suck water from
the air and only bother to breathe four times a day. As one investigator
puts it, "Nothing's on but the pilot light."

And yet ticks make up in stealth and biochemical cun-ning what they lack in
speed and industry. Using their bod-ies as miniature laboratories, they have
evolved chemical compounds that can breach every one of a target animal's
defenses, from coagulation to inflammation. To top it off, ticks have
reinvented their weapons again and again, species by species. Today, they
transmit more disease in the United States than any other insect or
arachnid.

Ticks seem to have staked all their evolutionary resources on spit.
Clustered together like grapes, the salivary glands form the second-biggest
organ in a tick's body, after its gut. Furthermore, the glands can swell 25
percent larger when their owner attaches to a host. Inside those elastic
walls, a chemical arsenal is made ready and strategically deployed:
anticoagulants and platelet-aggregation inhibitors, prostaglandin and the
latex-like cement that makes ticks so hard to remove. Some of the chemicals
are huge-proteins; some are only fragments; but each represents a
substantial investment in energy, resources and genetic planning.
Biol-ogists discovered long ago that tick spit carries blood thin-ners, but
in the past ten years they have found an array of other molecules as
well—some of them entirely new to science. And each is designed to
outmaneuver a host's defenses in a different way.

Happily, there is a reassuring side to this creepy tale. By identifying the
chemicals that ticks secrete, a few investigators are learning how to
bolster the body's defenses against them. Better yet, the same chemicals can
be put to other uses. Blood-sucking arthropods, biochemists are finding,
have great ideas. In the course of hundreds of millions of generations,
ticks have tested, mod-ified and perfected potent compounds, applying the
process of natural selection to zero in on the ones that work. As it
happens, compounds that do what tick compounds do—anticoagulants, for
instance—are worth billions of dollars to the pharmaceutical industry.
Inside every tick, it seems, there lurks a minia-ture Eli Lilly.

BIOLOGISTS FIRST BEGAN to appreciate blood-suckers by smashing them. If a
bug was flattened after it had eaten, investigators found, the blood in its
gut would remain liquid. Somehow, these creatures-
could keep blood from clotting. In 1914 two British Army officers in
India, J.W. Cornwallis and W.S. Patton, began to suspect that the bugs
inhibited coagulation with their saliva, thereby keeping their small
suctioning mouth parts from getting gummed up. To test their hypothesis-,
the investigators mixed blood with crushed salivary glands from
bloodsuckers; as they expected, the blood failed to clot.

At the time, that finding seemed an intriguing but useless fact. It was
decades before anyone looked further, or bothered to extract the responsible
agents. More than half a century later, however, a related fact caught the
attention of Jose M.C. Rebio, a medical entomolo
gist now at the Laboratory of Parasitic Diseases, part of the National
Institute of Allergy and Infectious Diseases in Beheads, Maryland. In 1977
Rebio had just finished his master's thesis on an enzyme called ATPase,
which breaks down the molecule ATP. (ATP is a kind of molecular battery,
storing energy in all cells.) He was looking for a new project when a
friend, an insect physiologist, told him about a similar enzyme found iri
the- saliva of blood-sucking parasites known as kissing bugs.

It seemed an odd place for such an enzyme. ATP was known to be useful only
inside the cell. Why would an organism make the enzyme, only to spit it out?
When Rebio gathered his own samples and tested them, he found that the
kiss-ing-bug enzyme was not as simple as reported: whereas ATPase broke off
one phos-phate group from the ATP molecule, the kissing-bug enzyme broke off
two.. That put it into a controversial class of enzymes called apyrases.

Now THINGS WERE GETTING INTERESTING. MANY BIOCHEMISTS had argued that true
apyrases did not even exist. When a test substance detached two phosphate
groups, they maintained, it must contain two enzymes, not one, each of which
took off only one phos-phate group. Yet here, in a bloodsucker, Rebio had
found a real apyrase, being secreted where it had no known purpose. Although
Rebio had never intended to study bugs, he couldn't resist. He went back to
the library and pulled every abstract he could track down on the putative
apyrase. He read the argument that an apyrase could not be one enzyme. He
learned that the level of apyrase activity was higher in potatoes than in
any other source, and chat Sigma Chemical Com-pany in St. Louis, Missouri,
purified, packaged and sold potato apyrase to hematologists, who used it to
study platelets.

Platelets, Rebio knew, had come into the scientific limelight in recent
decades. Although they had long been known to be minute components of blood,
smaller even than red blood cells, they had been dismissed as cellular
debris until the Second World War. A lot of people bled during that war, and
physicians noted that peo-ple with fewer platelets than usual bled more.
Their blood thick-ened and clotted normally, but they bled anyway.

When the physicians took a closer look with a microscope, they saw why.
Whenever a blood vessel tore, platelets collected around the tear, stuck
together and plugged it up. one substance that could keep the platelets from
collecting was the potato apyrase—hence its value to hematologists. "When I
found that out I almost threw the papers on the ceiling," Rebio remembers.
"I realized why the bug has it." Kissing bugs had found another way to keep
blood flowing, not only through their own mouth parts, but from the host as
well.
Rebio went on co expand his study, finding apyrase in the saliva of
mosquitoes and fleas. But it was wilth ticks that he hit the jackpot.

If any bugs should know how to keep a host bleeding, Rebio rea-soned, ticks
should. They have not survived some 3OO million years simply by sticking
their mouth parts into a host and hoping to hit an artery. Rather, they must
slash through the skin. tear open a blood vessel—any vessel—and inject
whatever is necessary to keep the food coming indefinitely. Then they can
suck and drool, drool and suck at their leisure.

In fact, Rebio found, tick spit contains an apyrase as well as the
anticoagulants others had found in it. But what else might it have? A host's
body has three ways to stop hemorrhage: it can form a blood clot, it can
plug a hole with platelets and it can constrict a blood vessel to pinch off
the flow. If ticks already knew how to inhibit clots and platelets, had they
found a way to prevent vessels from constricting as well? Rebio and others
began to study how tick saliva affects the bands of muscle within blood
vessel walls. Sure enough, tick spit carried enough vasodilators to make
even the aorta relax.

Soon investigators were examining compounds taken from the saliva of
ticks, mosquitoes, sand flies, kissing bugs, bat bugs, bedbugs, lice, fleas
and more. Although there was overlap, they found that many of the species
had invented and used their own vasodilators, their own anticoagulants,
their own platelet inhibitors. In 1995, when Rebio surveyed the scientific
literature, he found that six bug genera made anti-clotting agents, twelve
made vasodilators and twenty-vie made platelet inhibitors—and those were
only the ones mentioned in the journals.
At the same time, investigators were finding a host of new compounds. There
were molecules that blocked the pain of a bite; others that blocked
chemicals chat cause inflammation, such as histamine and thromboxane; and
the ticks' own versions of prostaglandin, which do everything from relaxing
blood vessels to suppressing immune response. In fact, if you took the time
to look for a molecule, it seemed that some bug probably carried it.

These were compounds that pharmacologists dearly wanted to learn to make, or
make better. Anti-clotting agents had fumed open-heart surgery into a
reality and made survival after a heart attack possible. The only drug that
can reliably inhibit platelets is aspirin, and it has its drawbacks. As soon
as the bug molecules were found, isolated and purified, therefore,
pharmacologists took them apart. often the new compounds proved too large to
be useful in and of themselves. But now that pharmacologists knew which
salivary molecules did the work, they could design new compounds that had
the same effect, and that the human body could tolerate. A peptide in tick
spit was recently tested by investigators at Merck & Company as an
anticoagulant, though it proved too powerful to be useful. A sand fly
compound, the most potent vasodilator known, appears to help hair grow, and
a vasodilator in black flies may help heal wounds. And there are plenty of
other compounds left to pick apart.

For a tick, Ribeiro insists, synthesizing new compounds is not such a hug
revolutionary task. The salivary glands and the nervous system are, in a
sense, cellular cousins. Both arise from the outer, or ectodermal, layer of
the embryo, long before organs have differentiated into anything
recognizable. It comes as no surprise, therefore, that some of the molecules
in drool are modified neurotransmitters (molecules that convey messages
between cells). If they benefit a tick in some way, the molecules continue
to be secreted and are gradually improved through natural selection. As
Rebio puts it, "The salivary gland is a place where you can shuffle the
whole genome and see what comes out."

Luckily, the body has a formidable line of defense: the immune system.
Immunologists and physicians long doubt-ed that the body could fight off
ticks. Antibodies and killer T cells might be a match for bacteria and
viruses, but how would they fare against creatures billions of times their
own size? And yet the immune system often does force ticks to drop off too
early, before they can molt or lay eggs. on occasion, it can even kill a
tick as it takes a meal.

When a tick punctures the skin, it breaks cells apart, tearing the membrane
that binds them. If the immune system senses the damage, immune cells in the
skin go to work, along with a series of activating proteins called the
com-plement system. Those are only first-line defenders: al-though they may
be able to harm a tick by themselves, they are mainly present to alert and
recruit the rest of the immune system. If all go" well, white blood cells
known as Iymphocytes will soon be churning out antibodies for the chemicals
in tick spit. Granulocytic white blood cells, mean-while, will collect at
the bite site, releasing his-tamine, peroxides and other molecules that
cause inflammation. (A good dose of histamine can kill a tick outright.) Any
white blood cells chat get sucked in by the tick will explode like suicide
bombers in its gut.

If a host has been invented before, things could go even worse for a tick.
There may already be antibodies circulating through the host's blood. Those
antibodies will help recruit white blood cells and may damage or clog a
tick's mouth -parts if it swallows them.

AN AROUSED IMMUNIUNE SYSTEM IS NO pushover, clearly, but it does nod off
from time to time. Even hosts unaccustomed to ticks will tolerate a few here
and there; only a full-scale infestation or two will trigger an immune
response. And hosts accustomed to ticks—white-footed mice for example—may
never become immune to them. over the course of millennia, ticks seem to
have reamed to hide from the mice as well as from their immune systems.
Hiding is what ticks do best. After all a host's best defense is simply
to -scratch or pluck the raider o£ Yet ticks can creep around on a host's
skin or spend days feeding on its blood with-out ever being noticed—or at
least not until it is nearly too late. In 1996 in Spokane, Washington, a
woman spent nine days in the hospital growing steadily weaker and more
paralyzed. She could hardly breathe, and physicians were about to put her on
a respirator when a careful resident made a critical discovery: a female
tick was embedded in the woman's scalp. When the tick was pulled out, the
woman improved within hours. In a sense, the discovery came as no surprise:
that particular hospital has as many as six cases of tick paralysis a year
(the neurotoxin that causes the paralysis has never been identified), and
physicians had already searched the woman for ticks. Yet the tick almost got
away.

If you have ever failed to feel an injection, you can imagine how easy it is
to miss the bite of an arthropod. A tick's mouth parts, after all, are quite
a bit smaller than a hypo-dermic needle. Now think of a splinter. You may
not notice it immediately, but you do before long, because as a foreign body
it causes inflammation. But a tick knows how to stifle the inflammatory
response before it starts. Among the chemical tricks hidden in its salivary
glands is a molecule that breaks apart bradykinin, the chemical that causes
pain at the bite site.

In fact, ticks can divert all of the immune system's reac-tions for a time.
Tick-injected molecules can prevent the complement system from being
activated and inhibit the natural killer cells. They can reduce
inflammation, immune reactions, even sensation, giving. a tick the time it
needs to feed (an adult tick may hang on for a week or more). -The effects
of those actions can be detected in immune cells that lie as far away as the
spleen.

But what a tick does to the second-line immune response is the most
ingenious. Rather than blocking the white blood cells, it simply misdirects
them, whispering in their ears like a miniature Iago: "Yes, you're in
trouble; now just follow my simple advice." White blood cells known as
macrophages and T Ivmphocvtes are the field marshals of the immune system:
they send out the chemical signals that tell the other white blood cells
what to do. But when a tick latches on, it secretes molecules that
selec-tively dampen those signals. White blood cells still rush to defend
the body, but they largely pass the tick by, leaving it to suck and drool,
drool and suck.

Sneaky as they are, most ticks get only a few drops of blood from people
before they drop offer are discovered. Unfortunately, their subterfuges also
help them spread disease. Stephen K. Wikel, an immunologist at Oklahoma
State University in Stillwa-ter, has spent twenty-four years intimately
detailing how ticks and the pathogenic organisms they carry interact with
hosts. one of the first things Wikel noticed was that it took more disease
organisms to induce disease if you inject-ed them with a needle than if you
let a tick do it for you.

How much; Wikel wondered, do the pathogens depend on the tick? Do they use
the tick as more than just a traveling syringe? To find out, he exposed mice
to uninfected ticks until the mice became immune to them. Then he expose d
immature mice to ticks, carrying Borrelia burgdorferi spirochete – the
spirochete that causes Lyme disease. Whereas all Wikel's control mice became
infected, less than 2O percent of the immune mice did. Immunity to ticks
conferred immunity to Borrelia.

"The vector is the pimp for the pathogen"—that is how the immu-nologist and
veterinarian Nordin S. Zeidner puts it. Zeidner works at the Division of
Vector-Borne Infectious Diseases at the Fort Collins, Colorado, branch of
the Centers for Disease Control and Prevention. He repeated Wikel's, work,
but with a twist. Instead of immunizing the mice, he simply resupplied them
with the signaling compounds that ticks suppress. When Zeidner exposed the
hosts to infected ticks, 95 percent of them remained free of Borrelia.

Because they clear the way for pathogens bio-chemically, as well as giving
them a free ride, ticks are among the most pernicious disease vectors in the
world. Every year they cost the world's cattle industry alone billions of
dollars. East Coast fever, loup-ing ill, heartwater and numerous other
diseases are passed on by ticks, and the same neurotoxin that nearly killed
the Spokane woman can fell entire herds at once. More grue-some still, ticks
sometimes literally bleed cattle to death. Adult females of the species
Hyalomma asiaticum, for instance, can consume two teaspoons of blood apiece,
and no cow's tail can dislodge them.

Aldhough tick-bome diseases rarely kill people, they are still a major
health concern. Rocky Mountain spotted fever and relapsing fever, the first
diseases found to be transmit-ted by ticks, tend to strike in unpredictable
ways. Rocky Mountain spotted fever, for instance, was discovered in
Col-orado early in this century. Then in the late 197Os it sud-denly
appeared in the south and southeast, where it still afflicts about 8OO
people every year. New tick-borne dis-eases, meanwhile, are taking an even
greater toll. In the United States, cases of Lyme disease—first discovered,
along with the tick species that carries it, in the 197Os— have risen from
491 in 1989 to more than 13,OOO in 1994.

Lyme disease is now the most commonly reported vec-tor-borne disease in the
country. It can cause long-term arthritis, heart disease and neurological
conditions similar to multiple sclerosis. There have been outbreaks in
West-ern Europe and Eurasia, and suspected cases have been reported in
Australia and South Africa. Unlike the Ebola virus, ticks do not need jets
to travel between continents; they simply hop on migratory seabirds.

Like Lyme disease, most of the tick-borne diseases, if caught at an early
stage, are easily treated. Not so the virus-es. That makes the report last
summer of a so-called "deer tick virus," carried by ticks collected in
Massachu-setts and Connecticut, particularly alarming. The new disease fits
into a family of tick-borne ~encephalitis viruses, one of which causes
Russian spring-summer encephalitis. That disease kills 4O percent othose who
con-tract it and leaves most survivors with severe nervous system damage for
months or years after infection.
If the tick is the landscape on which the pathogen evolves, as Ribeiro puts
it, then we humans are an evolutionary landscape for the tick. Our skin has
shaped its mouthparts, our blood inspired salivary master-pieces. our
complexity has led it to feats of biochemical genius. To thwart ticks, in
tum, we will need to come up with some inspired inventions of our own.

Wikel, Zeidner and others are now striving to do just that. "The Holy
Grail is a vac-cine, " Zeidner says, which would protect against ticks as
well as all the diseases they carry. Australian investigators have already
designed a vaccine against a specific local tick, Boophilus microplus. But
Wikel and Zeidner have something more ambitious in mind. Wikel hopes to make
a vaccine that blocks ticks as well as other vectors, such as mosquitos.
Zeidner wants to create an entirely new kind of vaccine—one that will beat
the tick at its own game. First he plans to isolate the chemicals that ticks
use to make the macrophages and T lymphocytes ignore them.-Then he wants to
combine those chemicals with others that tell the immune system, even more
firmly, to defend against parasites. The resultant vaccine would teach the
immune system to override the tick's instructions, and to attack it after
all.

The idea has a certain poetic justice: the Iagos of the arthropod world
tricked into telling the truth at last. For now, Zeidner's vaccine exists
only in theory. But if it does materialize, people will have outmaneuvered
their sim-ple, spineless foes—if only for an evolutionary moment.
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DESIRABLE DESTINATIONS FOR THE DISCRIMINATING TICK

Every tick is a cabinet of wonders, replete with, biochemical inventions and
behavioral mysteries that investigators have yet to unlock one of the most
puzzling and potentially important questions is also the simplest: Why do
ticks go where they go?. Entomologists all over the world have dusted ticks
with fluorescent powder, then followed them day after day, month after
month. They now know that ticks move only a few feet in a lifetime, and
that in areas where they infest lizards and mice, ticks prefer the uphill
side of a trail. But why ticks prefer the uphill side and for that matter,
how they know which side they are on—is still anyone's guess. It could be
that lizards and mice are the on a that prefer the uphill side, and that
ticks simply land on that side when they fall off. But that only leaves you
wondering about lizards and mice.

Luckily, just knowing where ticks go is useful enough. If you want to kill
ticks that carry Lyme disease, for instance, you need not spray an entire
forest with pesticide. Instead, you can line the uphill sides offset trails
with a device recently designed by the entomologist Gary Maupin of the
Division of Vector-Bome Infectious Diseases at the Fort Collins, Colorado,
branch of the Centers for Disease Control and Prevention, and tested by the
entomology Robat S. Lane of the University of California at Berkeley. Maupin
and Lane make their tick traps out of PVC pipe. Inside the pipe they lay a
block of paraffin embedded with
grain to attract mice, and on both ends they glue pieces of carpet soaked
with pesticide. When the mice squeeze through the openings, the poison
repels or kills the ticks on their fur.

The bigger the trail, it seems, the less discrirninating the tick. When
Richard L. Stewart Jr. at Ohio State University in Columbus studied ticks in
his area, he found that virtually all the adults headed for the sides: of
roads when searching for a host. Presumably they were drawn by the carbon
dioxide, heat and vibrations that cars generate, much as the ticks' hosts
do. Because ticks are seasonal, Stewart reasons, spraying or mowing two to
three feet along roadsides in June end July should help control their
populations.

Nature also lends a hand in controlling disease-carrying ticks. In the
Bitterroot Valley of Montana, for example, only ticks on the western slope
carry Rickzettsia rickettsii, the organism chat causes Rocky Mountain
spotted fever. Ticks on the eastern slope carry the benign Rickettsia
peacockii. (As usual no one knows exactly why.) In California, meanwhile,
Lane found alas adults of the tick species Ixodes pacificus are less likely
to carry Lyme disease than are the nymphs. (In the northeastern United
States, adult ticks are twice as likely to carry it as nymphs are.)
Californians have lizards to thank for that, Lane found: the California tick
nymphs prefer to feed on the western fence lizard (Sceloporis occidentalis),
and that diet seems to rid them of the Lyme disease spirochete. —C. M.

Cynthia Mills is at doctor of veterinary science and writer living In Salem,
Oregon. She is a frequent contribtlor to" THE SCIENCES".

[MHHirsch]

Thanks Rita and Adrianna for posting this incredible article!
Is "the Sciences" a magazine or a newspaper supplement? Sounds like a great
article to send a response to the publisher - in praise of good writing and
research and pointing out some other facts about Lyme disease! We need to
respond when good articles are published as well as pointing out the errors in
other articles. Do you know how to contact the publication and/or the author?
I know that some people at Ohio State University are analyzing the tick
"spit" to see if the anesthetic characteristic of it can be somehow made
useful.
If Pliny in ancient Rome could know that ticks were "the foulest creatures
that be," we know that ticks have had a long time to become even more foul.
Thanks again Adrianna!
Ann

[Rita Stanley]

MHHirsch wrote in message
<199803260134...@ladder03.news.aol.com>...

> Thanks Rita and Adrianna for posting this incredible article!

> Is "the Sciences" a magazine or a newspaper supplement?

>. Do you know how to contact the publication and/or the author?

Good question! And I don't have the answer. I obtained the article from L
& E Letter - they copy interesting articles and send them out. There was
nothing indicating contact information. Maybe someone else knows about the
publication......
.
> Thanks again Adrianna!
> Ann

Thanks for thanking my daughter, Ann. Makes her smile to know folks "out
there" like her work.

Rita

[Phyllis Mervine]

Thanks, Adrianna and Rita, for that fantastic article. I am glad you
have a scanner - I didn't like the idea of a sweet young thing sitting
for hours to type long articles as I think you did before.

[Rita Stanley]

Phyllis Mervine wrote in message <351C02...@pacific.net>...

>Thanks, Adrianna and Rita, for that fantastic article. I am glad you
>have a scanner - I didn't like the idea of a sweet young thing sitting
>for hours to type long articles as I think you did before.

Oh, my sweet young thing earns money for her labors. I haven't had to
loosen the leg irons but once in the last 6 months, Phyllis. Left her some
room for growth.

Ask her if you think there is a problem here.

Rita

[Jean Hubbard]

Ann, Rita and Adriana,

The Sciences (a slick pop science magazine) is published by the New York
Academy of Sciences. This was in the March/April 1998 issue. At the
bottom of their several page-long letters to the editor section (which
they charmingly call "Peer Review"!!!!), they say:

"The Sciences welcomes correspondence from readers. Please send
electronic mail to scie...@nyas.org and regular mail to 655 Madison
Avenue, 16th Floor, New York, NY 10021-8043. All letters should
include a daytime telephone number and a complete street address, and
all letters are subject to editing."

The reason I know this is because I too was so struck by the article
when I read it in Betty G's H & E Newsletter that I went down to my
local magazine store, which had one copy left. She's a wonderful
writer.

Jean