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.