Bateria Disables Host Defense Proteins
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Bacteria disarm host-defense proteinSummaryThe article introduces Shigella flexneri, and investigated how did S. flexneri managed to degrade GBP through IpaH9.8, and how this discovery can help develop the use of pathogen biology in the future.Investigation Process（a）What is Shigella flexneri and why should we investigate it?Shigella flexneri is a type of bacteria that causes sicknesses in infants through ingestion of contaminated food and water, resulting in inflammation and leading to eventual death. Guanylate-binding proteins, also known as GBPs, promotes antimicrobial activity against pathogens. Since GBPs interact with auto-phagic proteins that might target bacteria for destruction, GBP may also targets S. flexneri. This leads to a question that whether S. flexneri have a way of countering GBP.[pic 1]Fig.1 This picture showed that when S. flexneri enters a host cell it is initially trapped inside a membrane bound compartment called a vacuole, which it disrupts to escape into the cytoplasm. The bacterium then encounters defense responses that can destroy or disable it, for example through an intracellular degradation pathway called autophagy. However, invading bacteria can transfer proteins directly into their host’s cytoplasm through a needle-like structure called the type III secretion system, helping it to combat the immune response and promote bacterial replication and spread. Shigella flexneri transfers more than a dozen such bacterial proteins and evade destruction through doing this.(b)The investigation processThrough monitoring fluores cent tags and tracking galactin-3 proteins, they found that the cells infected with S. flexneri is void of GBP while galactin-3 is still present. This was unique of S. flexneri because other types of bacteria did not degrade GBP and instead were quickly surrounded by hGBP1, killing the bacteria.So why did the GBP disappear in the first experiment? Next, they investigated this through targeting intracellular destruction with ubiquitin protein tags. When they treated the cells with a proteasemal inhibitor, it prevented hGBP1 loss.
Finally, they determined how this bacteria was able to achieve proteasomal-mediated GBP destruction through testing about 13,000 strains of S. flexneri that had mutant versions of different genes. One strain that was unable to destroy hGBP1 had a disrupted version of the ipaH9.8 gene. Since this gene encodes an enzyme known as an E3 ubiquitin ligase (IpaH9.8), and Shigella flexneri contains a small family of IpaH E3 ubiquitin ligases, the scientists tried to other IpaH family members, but they did not degrade hGBP1. Notably, in vitro tests, scientists found that IpaH9.8 enabled the ubiquitination of more than half of all the GBP family members found in humans and mice (which have 7 and 11, respectively). Hence, IpaH9.8 could enable S. flexneri to degrade many GBPs that often act in concert to restrict bacterial growth. This proved that IpaH9.8 is a unique case.In the final test, they found that in test subjects (mice) expressing IpaH9.8, the animal succumbed whereas ones that lacked IpaH9.8 died. Through experiments, they found out that pathogens such as Shigella flexneri were able to infect by disabling GBPs, and IpaH9.8 is needed for bacteria to specifically evade a GBP-mediated immune response. This discovery further explains the interactions of host defense proteins and the bacterial proteins.