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An ancient pathway that reveals a fascinating link between immunity and tick development

Lyme disease is a tick-borne infection caused by the bacteria Borrelia burgdorferi, which can cause neurological damage, arthritis, and heart disease if left untreated. By researching the infection process, a team from the University of Maryland discovered that an ancient signaling system serves an unanticipated function in connecting immunity to tick development in a recent paper published in Science. This study also suggests an entirely new target for the treatment of Lyme disease.

To investigate how ticks' immune systems detect Borrelia burgdorferi, the researchers supplied blood to two sets of ticks infected with Burkholderia spirochetes and blood from uninfected mice, respectively. When the two tick groups were compared, it was discovered that the JAK/STAT signaling pathway was active in the former.

In the vast history of biological evolution, the JAK/STAT pathway has a distinctive role. This conserved signaling pathway is found in all multicellular animals and serves as a primary signaling mechanism for a number of cytokines and growth hormones involved in cell proliferation, differentiation, cell migration, and death.

The JAK/STAT pathway has recently been linked to bacterial infection processes. Borrelia burgdorferi in infected blood, the scientists hypothesized, triggered the tick's JAK/STAT pathway. To put this theory to the test, the researchers extracted germs from blood and injected them directly into ticks. Surprisingly, the JAK/STAT pathway was not activated by these Burkholderia spirochetes.

To find out why, scientists gave the ticks clean blood extracted from Borrelia burgdorferi. As a consequence, even though the pathogen was no longer present in the infected blood, the tick's JAK/STAT pathway was engaged, suggesting that some imprints in the blood left by Spirochaete burgdorferi was the true source of the JAK/STAT activation.

The imprints are the cytokine interferon γ (IFN-γ). Further studies revealed that Dome1 proteins in the tick digestive system act as receptors for JAK/STAT and that these proteins are able to bind to IFN-γ produced by the mammalian immune system, thus initiating the JAK/STAT pathway.

The study also found that JAK/STAT receptors and pathways are critical for normal tick development. The team knocked down the gene needed to synthesize the Dome1 protein, at which point the tick developed abnormally, growing deformed legs, mouthparts, and a digestive system that prevented it from feeding and completing its normal developmental cycle.

These findings convey a wise evolutionary tale. The JAK/STAT signaling cascade and receptors have developed in ticks to integrate the two critical processes of immunity and development. Bacteria compete with ticks for resources in the blood of infected hosts, so ticks access these nutrients by boosting their growth and development when they get signals that their blood is infected. Simultaneously, this mechanism enables the tick to generate an immune response long before the bacteria begin to infect.

"The adaptability of the conserved cell signaling pathway is surprising," said the study's lead author, Professor Utpal Pal, "and it is impressive that this signaling pathway, which exists in all multicellular organisms from sponges to humans, is so flexible that it can accept ligands from evolutionarily distantly related species."

This study identifies prospective targets for the development of anti-tick vaccines and drugs to prevent Lyme disease transmission, as well as fresh insights on the evolution of biomolecular interdependence among species.