Parasitic worms "read" the body's immune condition and reproduce accordingly

Tiny parasitic worms that infect 250 million people worldwide and cause the
debilitating disease schistosomiasis can thrive undetected in the blood for
years. New research shows that the worms not only evade immune defenses but
actively use molecules of the immune system to grow and reproduce.

In experiments with mice, University of California, San Francisco scientists
discovered that the worms develop normally into adults as long as they are in
direct contact with a potent class of immune cells in their host’s liver or
with products from these cells. If the worms fail to connect with their
targets, known as CD4+ T lymphocyte cells, their development slows. The worms
will still mature eventually, but will produce far fewer eggs than normal, the
research shows.

Other parasites are known to adapt to host signals but the UCSF research is the
first to identify a specific host cell that a parasite “partners with” and to
suggest the molecules the parasite may recognize as a signal in this remarkably
refined exploitation. Clarifying the molecular mechanisms could aid vaccine
development by identifying ways to block the parasite’s evasion of immune
defenses.

The UCSF scientists suggest that the worms’ dependence on their host’s CD4+
cells evolved as a means for the parasites to gauge their host’s overall
health. When a person is weak or sick and the immune cell count is low, the
parasitic worms automatically switch to the mode that takes less of a toll on
the host, decreasing the chance that the worm’s meal ticket will die. When the
person recovers from malnutrition or whatever infection had dampened the CD4+
count, the worms may sense the increased CD4+ cell levels and switch to their
more rapid development rate and robust egg production.

Discovery of the dual-track reproduction strategy may explain reports by
researchers in Africa that HIV-positive people with schistosomiasis experience
milder infections from the worms than do those who are HIV-negative. According
to the new findings, when the worms encounter fewer CD4+ cells in their
HIV-positive hosts, they cut back on the their normal rate of development and
egg production, thus taking a lower toll on their host.

The new finding not only demonstrates the novel survival strategies adopted by
the worms but suggests for the first time that the liver, and not just the
spleen, is an important source of novel immune cells.

A report on the research discovery appears in the November 9 issue of the
journal Science.

“Schistosomes have already taught us a lot about immunology, but this is an
even more remarkable lesson,” said James McKerrow, MD, PhD, UCSF professor of
pathology and an expert on the tropical parasitic worms. “You would expect the
worms to have a good means of evading the immune system of the host, but here
we find they actually exploit the immune response for their own reproduction.”
McKerrow is senior author of the Science report and also an investigator at the
UCSF-affiliated Veteran Affairs Medical Center in San Francisco.

Lead author is Stephen Davies, BVSc, PhD, a veterinarian serving as a
postdoctoral scientist in McKerrow’s laboratory.

“Schistosomiasis takes quite a toll throughout the tropics,” Davies said. “It’s
rarely fatal, but it is commonly contracted by children and reaches its most
severe stages—with fatigue, some muscle wasting and slow destruction of the
liver—when people are in their teens to early 20’s. It drags down the local
society.”

Understanding what immune molecules promote the worms’ normal development may
help researchers develop selective immunotherapies, the scientists said. Once
the specific immune signals used by the parasite are identified, drugs might be
developed to deprive the worms of those signals in healthy hosts, and thus
trick the parasites into developing more slowly and producing fewer eggs.

The Schistosoma life cycle reads like a classic parasitic tale: Freshwater
becomes contaminated with Schistosoma eggs when infected people urinate or
defecate in the water, McKerrow explained. The eggs hatch in the water, and the
parasites can grow and develop inside certain snails. They leave the snail as
larvae and can penetrate the skin of people wading in the water. Within weeks
they grow inside the blood vessels of the body and produce eggs. Some of the
eggs travel to the bladder or intestines and are passed into the urine or
feces.
In one species of schistosome, pairs of adult worms take up residence in the
blood vessels between the host’s liver and intestine, where a pair can live for
as long as 30 years while evading attack by the immune system, McKerrow said.
Beginning five weeks after the initial infection, the females may release as
many as 300 eggs per day. The new report shows that in the “attenuated” mode,
the worms produce between five and ten times fewer eggs.
The scientists made their discovery by examining worm infections in mice that
lack various immune elements. The disease is known to progress in much the same way in humans and mice. The research gradually zeroed in on CD4+ T lymphocytes as the crucial cells without which normal worm maturation and normal egg production did not take place. CD4+ cells give rise to cytokines that normally act as growth inducers, or growth factors, boosting the development of other cells of the immune system.

After the parasites invade their hosts, they reach the liver in about two
weeks, at which point the worms go through a period of “exponential growth.”
into adults.  This rapid growth, the scientists conclude, requires the presence
of the hosts’ CD4+ cells in the liver. And so an intriguing hypothesis emerges:
The worms have evolved in such close step with their hosts that they are
capable of benefiting from their host’s immune response rather than being
killed by it. They appear to thrive from direct physical contact with host CD4+
cells, much as the host’s own immune cells do. Growth factors secreted by the
CD4+ cells normally induce growth of other immune cells, but these secretions
appear also to induce rapid growth in the parasites.

The scientists now want to clarify what CD4+ lymphocyte products the worms are
exploiting, and what might be done to disrupt this interaction to treat or even
prevent infections by the tropical parasites.

Co-authors on the research with McKerrow and Davies are Richard Locksley, MD,
Howard Hughes Medical Institute Investigator at UCSF and professor of medicine;
Jane Grogan PhD, a postdoctoral researcher in Locksley’s laboratory; Rebecca
Blank, BS, a graduate student in the McKerrow lab; and KC Lim, BS, a research
associate with McKerrow’s Tropical Disease Research Unit, UCSF Department of
Pathology.

The research was supported by the National Institutes of Health and the Sandler
Family Foundation.

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