Bacterial pathogens are tricky little blighters, incredibly adept at infecting human cells and propagating disease. Certain tools in their arsenal are used to interface with host cell signaling pathways, allowing the invading microbes to fool and evade the immune response. Scientists are hard at work finding ways to deactivate these virulent abilities, but what if instead of disarming those tools, we could harness them? That's exactly what researchers at the University of California, San Francisco attempted to do in a study just published July 22nd in Nature.
The researchers sought to exploit two bacterial effector proteins -- OspF and YopH -- both of which are utilized by virulent bacteria to effectively re-wire cellular pathways, suppressing the immune response. OspF was taken from the bacterium Shigella flexneri, a common cause of diarrhea. YopH was harvested from Yersinia pestis, a pernicious facultative anaerobe (which means it can live in the presence or absence of oxygen) responsible for the plague and the infamous Black Death.
First, researchers introduced OspF into yeast in an attempt to reprogram cellular signaling. According to Dr. Wendell Lim, one of the study's authors, the research team focused on yeast because it is a very simple model organism and it is an important workhorse organism for biotechnological endeavors such as bio-fuel production.
Within yeast cells, the team's specific targets were the mitogen-activated protein kinases (MAPKs), which form a pathway that directs cellular responses to varying stimuli such as heat shock and osmotic stress, as well as regulating mitosis and gene expression. Using OspF, the researchers were successful in their attempts to alter the pathway, inducing various cellular changes effectively on demand.
The next phase of the study presented a more ambitious challenge, with fascinating ramifications. Given the already known ability of OspF and YopH to modify cell responses, the researchers sought to use them to build cellular circuits that could control human T cells, which are key actors in the immune response. At first glance, injecting human T cells with pathogen proteins seems counterproductive. It almost sounds like aiding the enemy. But the researchers had a very specific and beneficial focus in mind.
Engineered T cells are currently used in immunotherapy -- treating a disease by enhancing or suppressing an immune response -- to fight infections and even cancer. But the procedure is risky. The T cells can inadvertently attack and wreak havoc on healthy tissue. They can also spread uncontrollably, leading to a potentially fatal reaction called cytokine storm, in which too many immune cells are activated in one single location, interrupting other biological processes. By controlling T cells with bacterial effector proteins, these side effects could be prevented.
Using the bacterial effector proteins, the researchers started off by successfully engineering human T cells whose response amplitude could be systematically controlled by varying expression of OspF and YopH. They then used the effectors in conjunction with a promoter to create T cells that could effectively be paused (cell division halted) and restarted (cell division re-initiated). In other words, they made an "on-off" safety switch for T cells.
Finally, the researchers tested their pause switch in a T cell type commonly used in immunotherapy, finding that their switch could halt cell proliferation quickly, and then cause it to recover within 6 to 18 hours.
As humans, we often regard virulent pathogens as subversive enemies that must be eradicated at all costs. But as the researchers in this study demonstrate, bacteria may also offer unique, valuable tools with which to improve our health.
"The vast array of bacterial pathogen effector proteins, beyond those studied here, holds promise as a rich and important source of parts for the cellular engineering toolkit," the researchers conclude.
The researchers sought to exploit two bacterial effector proteins -- OspF and YopH -- both of which are utilized by virulent bacteria to effectively re-wire cellular pathways, suppressing the immune response. OspF was taken from the bacterium Shigella flexneri, a common cause of diarrhea. YopH was harvested from Yersinia pestis, a pernicious facultative anaerobe (which means it can live in the presence or absence of oxygen) responsible for the plague and the infamous Black Death.
First, researchers introduced OspF into yeast in an attempt to reprogram cellular signaling. According to Dr. Wendell Lim, one of the study's authors, the research team focused on yeast because it is a very simple model organism and it is an important workhorse organism for biotechnological endeavors such as bio-fuel production.
Within yeast cells, the team's specific targets were the mitogen-activated protein kinases (MAPKs), which form a pathway that directs cellular responses to varying stimuli such as heat shock and osmotic stress, as well as regulating mitosis and gene expression. Using OspF, the researchers were successful in their attempts to alter the pathway, inducing various cellular changes effectively on demand.
The next phase of the study presented a more ambitious challenge, with fascinating ramifications. Given the already known ability of OspF and YopH to modify cell responses, the researchers sought to use them to build cellular circuits that could control human T cells, which are key actors in the immune response. At first glance, injecting human T cells with pathogen proteins seems counterproductive. It almost sounds like aiding the enemy. But the researchers had a very specific and beneficial focus in mind.Engineered T cells are currently used in immunotherapy -- treating a disease by enhancing or suppressing an immune response -- to fight infections and even cancer. But the procedure is risky. The T cells can inadvertently attack and wreak havoc on healthy tissue. They can also spread uncontrollably, leading to a potentially fatal reaction called cytokine storm, in which too many immune cells are activated in one single location, interrupting other biological processes. By controlling T cells with bacterial effector proteins, these side effects could be prevented.
Using the bacterial effector proteins, the researchers started off by successfully engineering human T cells whose response amplitude could be systematically controlled by varying expression of OspF and YopH. They then used the effectors in conjunction with a promoter to create T cells that could effectively be paused (cell division halted) and restarted (cell division re-initiated). In other words, they made an "on-off" safety switch for T cells.
Finally, the researchers tested their pause switch in a T cell type commonly used in immunotherapy, finding that their switch could halt cell proliferation quickly, and then cause it to recover within 6 to 18 hours.
As humans, we often regard virulent pathogens as subversive enemies that must be eradicated at all costs. But as the researchers in this study demonstrate, bacteria may also offer unique, valuable tools with which to improve our health.
"The vast array of bacterial pathogen effector proteins, beyond those studied here, holds promise as a rich and important source of parts for the cellular engineering toolkit," the researchers conclude.
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