Tiny parasitic roundworms called filarial nematodes are responsible for many diseases in developing countries, including river blindness, loa loa infection, and elephantiasis, a severe swelling of limbs that affects millions of people each year.
The worms are transmitted by mosquitos or mites, which deposit the larvae when biting the skin. The worms then get into the lymphatic system, but it is unknown exactly how they get there.
Using advanced imaging techniques, researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago have discovered just how these worms migrate: by burrowing through the skin until they reach a lymphatic vessel, then mechanically digging a hole in the vessel wall with their head, like a hoe. Once inside the lymphatic vessel, they then follow the direction of fluid flow toward the lymph nodes.
More surprisingly, the researchers found that this movement extended to other non-related roundworms, showing that any nematode (whether it is parasitic or not) can find its way into other areas of the body.
The results, published recently in the journal Nature Communications, could have implications for understanding diseases caused by filarial nematodes, or even in treating other diseases.
“Knowing that potentially all nematodes migrate this way, we can better understand both how diseases are spread, and how we could potentially use this knowledge to our advantage to deliver drugs and vaccines within the body,” said Witold Kilarski, a senior scientist who led the research in the lab of Melody Swartz, William B. Ogden Professor.
The secret behind parasitic nematode navigation
Because these organisms have minimal sensing abilities, researchers did not know how they escape the skin and migrate through the body. The quickest way would be through blood vessels, though these vessels are difficult to penetrate.
To understand migration patterns, Swartz, Kilarski and their collaborators used fluorescent labeling to mark the larvae of one kind of nematode, Litomosoides sigmodontis, and injected it into mouse skin, mimicking how they are introduced by mites and mosquitos. Using confocal microscopy, near-infrared microscopy, and custom intravital immunofluorescence imaging, they were able to watch as the worms made their way from the skin into the lymphatic vessels.
To prove that nematodes were guided by fluid flow, the researchers designed a microfluidic maze that mimicked the lymphatic system. When there was no flow, the nematodes moved randomly. When a simulated lymphatic flow was introduced, they followed it.
The researchers then proposed that the roundworms sensed fluid flow, allowing them to follow lymphatic vessels to the lymph nodes and eventually the blood circulation.
Movement extends to all nematodes
The team also decided to test whether non-parasitic nematodes were able to migrate through the skin and enter the lymphatic system. To do that, they needed to collect nematodes, such as free-living bacterivores that live in an entirely different environment—for example, in the soil.
To do that, Kilarski isolated nematode worms from a soil sample collected on the University of Chicago’s campus.
Interestingly, he found that some of these bacteria-eating nematodes, which are close relatives to a harmless laboratory nematode Caenorhabditis elegans, were able to move within the skin of a mouse model at speeds comparable to the Litomosoides sigmodontis filaria. That means this migration ability likely evolved many millions of years ago and is inherent to all nematodes.
“This shows that all nematodes have the capability to become parasites and spread throughout the body,” Kilarski said. “Knowing this, perhaps we can look to see if some diseases that result from repeated injuries to the lymphatic system are caused by nematodes that become harmful only when presented with an opportunity to migrate into the body, like bruised skin or a hair follicle.”
Understanding what determines paths of nematode parasites in our bodies allows Swartz and Kilarski to identify safe namatodes to introduce drugs or vaccines into the human lymphatic system.
“Using nematodes as carriers would allow us to deliver vaccines directly to the core of the immune system, which could provide a more natural way of immunization,” Swartz said. Research in this area is ongoing.
Other authors on the paper include Coralie Martin and Odile Bain of the Museum national d'Histoire naturelle; Marco Pisano of the École Polytechnique Fédérale de Lausanne; and Simon Babayan of the University of Glasgow.
Citation: “Inherent biomechanical traits enable infective filariae to disseminate through collecting lymphatic vessels.” Kilarski et al. Nature Communications, doi: 10.1038/s41467-019-10675-2
Funding: European Research Commission