Host–pathogen interactions: how do pathogens escape the process of autophagy?

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A recent study published in PLOS Pathogens has provided new insights into how pathogens are able to escape destruction by the immune system during an infection.  These new insights offer an improved understanding of host–pathogen interactions, and how these could potentially be manipulated in the future for therapeutic applications.

In this study, researchers at the University of Cologne (Cologne, Germany) specifically studied the bacterium Salmonella typhimurium to identify the exact mechanisms it utilizes to disrupt pathogen-induced autophagy.

In mild cases, Salmonella infection usually evokes the destruction of the pathogen by autophagy, which typically helps clear the infection without a need for antibiotic treatment. The lead scientist of this study, Nirmal Robinson (University of Cologne), commented on the importance of this process: “You can imagine autophagy as the vacuum cleaner of the cell. It keeps the cell clean by clearing and degrading pathogens or damaged parts of the cell.”

Infection usually leads to a drop in energy levels, which results in the upregulation of two proteins (Sirtuin1 and AMPK). In response to this energy demand, these proteins subsequently induce autophagy, which engulfs the pathogen and helps towards the clearance of infection in the body.

However, in this investigation, findings suggested that S. typhimurium is able to dampen the activity of both Sirtuin1 and AMPK after this drop in energy. By reducing the duration of their activation, the bacterium therefore also reduces the activation of autophagy during an immune response, allowing it to persist.

Further studies identified the exact mechanisms behind this dampening effect; the proteins responsible for the activation of autophagy are targeted for lysosomal degradation after infection. “The pathogen dismantles the machinery by targeting it for degradation and thereby escapes the immune system”, states Robinson.

Researchers hope that the findings may lead to the development of therapeutics that specifically target the mechanisms involved in inducing autophagy, and will therefore allow us to manipulate these mechanisms in a way that will prevent pathogens from escaping destruction by the immune system.

Certain conditions, such as cancer, also rely on autophagy and so understanding the exact mechanisms of this host–pathogen interaction may provide significant insights into how we can target this process to prevent such conditions.

Robinson highlights the significance of these findings by comparing them to a real-life situation: “Pathogens are like burglars. By following a burglar we can also identify where we are weak.”

Source: Ganesan R, Hos NJ, Gutierrez S et al. Salmonella Typhimurium disrupts Sirt1/AMPK checkpoint control of mTOR to impair autophagy. PLoS Pathog. doi: 10.1371/journal.ppat.1006227 (2017) (Epub ahead of print); https://portal.uni-koeln.de/9015.html?&L=1&tx_news_pi1%5Bnews%5D=4477&tx_news_pi1%5Bcontroller%5D=News

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