Science's first cross-species signaling pathway mystery

Borrelia burgdorferi is a bacterium that causes Lyme disease
.
Research led by a team from the University of Maryland has identified the first interspecific signaling pathway between arthropod parasites and hosts, molecules in the host animal's blood that trigger the parasite's immunity and development
.
Studies have shown that when ticks feed on the blood of mice infected with bacteria, a protein in the mouse's immune system binds to receptors on the surface of tick cells and signals organs to develop rapidly, creating an immune response
before the bacteria themselves begin to infect the ticks.

The study, published January 13, 2023 in Science, identifies potential targets for anti-tick vaccines or treatments to prevent the spread
of infectious diseases such as Lyme disease.
The findings also provide important new insights into the interdependent evolution of biomolecules between species and highlight for the first time the integration of immunity and animal development, as well as the adaptations
of ancient cell signaling systems or pathways that all plant and animal cells use to sense and respond to the environment.

"The adaptive flexibility of this conserved cell signaling pathway is surprising," said
Utpal Pal, senior author of the study and a professor at the Virginia-Maryland College of Veterinary Medicine.
"Remarkably, this pathway that exists in everything from sponges to humans is so flexible that it can adapt to accept ligands (binding molecules)
from another distant species.
" This tool that everyone has is being used
in a way that we did not imagine.
”

This finding suggests that other cell signaling pathways may have adapted to new uses in other organisms and points to a new area in immunology and molecular biology that is ripe
for future exploration.

Pal and his colleagues made the discovery while investigating tick immunity, a little-known area
in tick biology.
In their initial study, trying to understand how the tick immune system recognizes Borrelia, the researchers fed the ticks blood from Borrelia-infected mice or uninfected mice
.
Comparing the two groups, they found that the infected blood activated a protein in the tick's body that normally produces energy
within the cell.
The protein is involved in a simple signaling pathway called JAK/STAT, which is found in
all multicellular organisms.

In all cell signaling pathways, a particular molecule senses something in the environment and then binds to receptors
outside the cell wall.
This triggers a cascade of reactions within the cell, turning specific genes on or off and responding
to perceived external stimuli.

Assuming JAK/STAT was triggered by Borrelia, the researchers isolated the bacteria and injected them directly into ticks to see which molecules bound
to the JAK/STAT receptor.
Surprisingly, the bacteria did not activate JAK/STAT.

To find out why, the researchers removed Borrelia bacteria from the blood of infected mice and fed "clean" blood to ticks
.
The JAK/STAT pathway comes into play
.

The researchers found that one protein in the tick's digestive system is the JAK/STAT receptor, which has evolved to bind to the cytokine protein interferon, which is produced by the immune system of mammals infected with similar bacteria.

The researchers also found that the JAK/STAT receptor and pathway are important for the proper development of ticks, even if the pathway is not activated
by infected blood.
When Pal and his colleagues knocked out the gene that produced the JAK/STAT receptor, the tick grew malformed legs, mouthparts, and digestive system, unable to eat and complete a developmental cycle
of further growth.

These results suggest that in ticks, the JAK/STAT signaling pathway and protein receptor have evolved to combine
immunity with development.
Bacteria compete with ticks for nutrients in the blood of an infected host, so when ticks get signals that blood is infected, rapid growth is a way
for bacteria to consume those nutrients before they get them.
Laboratory experiments confirmed that ticks developed faster in the blood of mice infected with Borrelia than those that fed on the blood of uninfected mice
.

"Understanding this pathway, which integrates immunity and development, has important implications for potential strategies to prevent the spread of tick-borne diseases
," Pal said.
Because if you remove this route, ticks with malformed mouthparts cannot eat or spread disease
.
But what really excites me is that we see this early warning system, where the tick's immune system accelerates its own development
by detecting the pathogen indirectly through the host's immune response rather than the pathogen itself.
”

Dome1–JAK–STAT signaling between parasite and host integrates vector immunity and development