Shigella prevents infected cells from sacrificing themselves for the greater good

August 18, 2020

Tokyo, Japan - Enteric pathogens, such as the bacterium Shigella, can cause severe intestinal disease with bloody diarrhea. In a new study, researchers from Tokyo Medical and Dental University (TMDU) discovered a novel molecular survival strategy by which Shigella is able to cause damage to the intestines despite two elaborate protective mechanisms used by host cells.

When bacteria infect the intestines, one of the host's responses is to have its own cells undergo cell death to prevent the pathogen from propagating This sacrifice of infected cells to ensure the overall safety of the host can happen through several mechanisms, two of the most important being apoptosis and necroptosis. While apoptosis results in a non-inflammatory form of programmed cell death through the activation of caspase proteins, necroptosis leads to inflammatory cell death as a form of ultima ratio in a caspase-independent manner. In contrast, during infection with Shigella, cell death is not observed and the resultant survival of the bacteria ensures their proliferation to cause severe inflammatory colitis.

"We know that Shigella are capable of injecting so-called effector proteins to disarm individual protective cell death pathways during the early stage of infection," says the corresponding author of the study Dr. Hiroshi Ashida. "At a later stage of infection, host cells employ a crosstalk between various forms of cell death to ensure that if one failed the other will take over. The goal of our study was to understand the mechanism of the molecular crosstalk between apoptosis and necroptosis, and how Shigella manages to evade both forms of cell death during the late stage of infection."

To achieve their goal, the researchers infected human colon cells with normal Shigella and mutant Shigella lacking various effectors, and found that when OspD3 effector was missing, the colon cells underwent cell death at a higher rate, suggesting that OspD3 is capable of preventing cell death. To understand which form of cell death OspD3 blocks, the researchers investigated the effect of OspD3 on cell death in the presence of RIPK inhibitor, which was able to block the actions of OspD3, suggesting that it blocks necroptosis. To corroborate this finding, the researchers dissected the molecular components of necroptosis and found that OspD3 blocks necroptosis by degrading the proteins RIPK1 and RIPK3.

Having established that Shigella prevents necroptosis through OspD3, the researchers asked what triggers necroptosis during Shigella infection in the first place. Because apoptosis is the first line protection of colon cells during infection, the researchers hypothesized that inhibition of apoptosis triggers necroptosis and thus that both forms of cell death are linked. To test this, they first focused on the protein caspase-8, which activates apoptosis and conversely, activated necroptosis when blocked. The researchers screened a number of Shigella effector proteins and found that OspC1 effector can block caspase-8 and thus apoptosis during Shigella infection. Intriguingly, this concurrently activated the process of necroptosis, demonstrating a molecular crosstalk between apoptosis and necroptosis to ensure cell death and prevent further bacterial multiplication.

"These are striking results that show how colon cells can recognize the blockade of apoptosis and trigger necroptosis as a backup plan for cell death. Our findings provide new insight into the molecular mechanisms by which bacteria disarm the host's protective measures," says Dr. Ashida.
The article, "A unique bacterial tactic to circumvent the cell-death crosstalk induced by blockade of caspase-8," was published in EMBO Journal at DOI: 10.15252/embj.2020104469

Tokyo Medical and Dental University

Related Cell Death Articles from Brightsurf:

Cell death in porpoises caused by environmental pollutants
Environmental pollutants threaten the health of marine mammals. This study established a novel cell-based assay using the fibroblasts of a finless porpoise stranded along the coast of the Seto Inland Sea, Japan, to better understand the cytotoxicity and the impacts of environmental pollutants on the porpoise population.

Gold nanoparticles to save neurons from cell death
An international research team coordinated by Istituto Italiano di Tecnologia in Lecce (Italy) has developed gold nanoparticles able to reduce the cell death of neurons exposed to overexcitement.

New light shone on inflammatory cell death regulator
Australian researchers have made significant advances in understanding the inflammatory cell death regulatory protein MLKL and its role in disease.

Silicones may lead to cell death
Silicone molecules from breast implants can initiate processes in human cells that lead to cell death.

New players in the programmed cell death mechanism
Skoltech researchers have identified a set of proteins that are important in the process of apoptosis, or programmed cell death.

Tumors hijack the cell death pathway to live
Cancer cells avoid an immune system attack after radiation by commandeering a cell signaling pathway that helps dying cells avoid triggering an immune response, a new study led by UTSW scientists suggests.

How trans fats assist cell death
Tohoku University researchers in Japan have uncovered a molecular link between some trans fats and a variety of disorders, including cardiovascular and neurodegenerative diseases.

Bacteria can 'outsmart' programmed cell death
To be able to multiply, bacteria that cause diarrhoea block mediators of programmed cell death, a new study in 'Nature Microbiology' shows.

Cell death or cancer growth: A question of cohesion
Activation of CD95, a receptor found on all cancer cells, triggers programmed cell death -- or does the opposite, namely stimulates cancer cell growth.

Cell death blocker prevents healthy cells from dying
Researchers have discovered a proof-of-concept drug that can prevent healthy cells from dying in the laboratory.

Read More: Cell Death News and Cell Death Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to