Thursday, October 12, 2017 by Janine Acero
The immune system is a network of cells that detect foreign organisms in the body and defend it against harmful attacks. But pathogens, for their part, have evolved strategies to evade this detection, in an attempt to subvert the immune system. They do this by secreting proteins in host cells which hinder the host’s immune response and allowing infection to take effect.
In a new study, a team of researchers led by Igor E. Brodsky of the University of Pennsylvania identified a “back-up alarm” system in host cells that responds to the pathogen’s attempt to avoid detection.
“In the context of an infection, the cells that are dying are talking to the other cells that aren’t infected,” said Brodsky, an assistant professor in the Department of Pathobiology in Penn’s School of Veterinary Medicine. “I don’t think of it as altruistic, exactly, but it’s a way for the cells that can’t respond any longer to still alert their neighbors that a pathogen is present.”
The findings address the long-standing question of how a host can produce an immune response to something that shuts off that very response. This new understanding may enable the cell-death pathway triggered by bacteria to be harnessed and potentially target tumor cells.
A certain species of bacteria called Yersinia, which cause gastrointestinal disease, is one such pathogen. These bacteria inject a protein called YopJ into immune cells that interferes with pathways, which then block the production of cytokines, cell signaling molecules that aid cell to cell communication in immune responses. This induces apoptosis, a form of cell death commonly occurring in multi-cellular organisms.
In this study, Brodsky’s team discovered that humans and mice can survive Yersinia infections because of their similar immune systems.
To understand how host cells overcome this pathogen, Brodsky’s team focused on the activity of an enzyme called RIPK1. RIPK1 was known to play a key role in signaling cell death in response to tissue damage and pathogen recognition.
“RIPK1 sits at a key decision point for the cell,” Brodsky said. “Depending on the stimuli the cells see, this protein can transduce a signal to activate gene expression, programmed cell death, or apoptosis, or it can activate another form of cell death called programmed necrosis.”
The researchers also relied on a strain of mouse that possesses a specific mutation in RIPK1 that renders the enzyme unable to trigger the apoptosis pathway upon encountering the Yersinia bacteria and found out that when these mice were infected with Yersinia, their cells did not undergo apoptosis. Instead, these animals succumbed to infection that normal mice almost always survive.
Apoptosis is normally considered non-inflammatory, but the study showed that RIPK1-induced apoptosis promotes cytokine production which triggers an inflammatory response and plays a role in the host’s survival. (Related: A War is against Your Immune System, Part I.)
Although the research is still in its early stages, one potential implication of the work could serve as a way to trigger death in cancer cells, which typically grow and thrive without detection from the immune system.
“We could imagine that modifying bacteria that trigger these pathways, or delivering this bacterial protein to tumor cells, could be potentially useful as an anti-cancer therapeutic,” Brodsky said.
Through this study, Brodsky and his team of researchers will further investigate the intricacies of cellular activity — the signals that infected cells release and the most important molecular pathways in the process.
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