Clearing infection from the blood: are endothelial cells unequipped for the job?

Recent findings published in PLoS Pathogens suggest that the endothelial cells lining blood vessels are unequipped for eliminating invading foreign material that enters into the blood. Studies demonstrated that this may be due to the reduced recruitment of ubiquitin, which executes the process of xenophagy.

Osaka University (Japan) Professor, Tamotsu Yoshimori, explains the importance of this process: “Xenophagy is a type of autophagy that acts on foreign invasions. Autophagy is a method through which a cell destroys unneeded or defective material.”

In this study, researchers investigated whether the endothelial cells that line blood vessels are as efficient at eliminating Group A Streptococcus (GAS) as the epithelial cells that line the organs in direct contact with the outside environment.

Yoshimori explained the findings of this study: “We found that Group A Streptococcus can survive and multiply in endothelial cells, but epithelial cells remove GAS infection via xenophagy. The reason for the difference is insufficient ubiquitination of the invading GAS.”

Tsuyoshi Kawabata (Osaka University), who also worked on this project, explained these findings further: “If we coated the GAS with ubiquitin before infecting the cell, we found xenophagy worked in endothelial cells comparably to epithelial cells.”

“If ubiquitin could activate xenophagy, then we know that the cell has all the equipment it needs. The challenge is to identify what molecular targets can activate the system. This information could be used for drug discovery.”

Further studies also suggested that this defect in endothelial cells is associated with reduced nitric oxide signaling in the vascular system, which is known to mediate the ubiquitination process.

With this knowledge, researchers then investigated whether there is a specific regulator that could be targeted to promote nitric oxide signalling in endothelial cells.

Researchers demonstrated that when the chemical 8-nitro-cGMP was inhibited, the survival rate of GAS significantly increased in epithelial cells. However, when this same chemical was inhibited in endothelial cells, no effect on the survival rate of GAS was observed.

Despite these promising results, Kawabata expressed reservations against the practicalities of regulating nitric oxide signalling as a means of eliminating pathogens from the blood: “The problem with nitric oxide is that it is a vasodilator. There is an evolutionary reason that the vascular system does not produce too much nitric oxide because it risks severely low blood pressure.”

Further evidence suggested that nitric-oxide independent factors could also be utilized for activating xenophagy through the recruitment of ubiquitin to eliminate GAS.

Kawabata stated: “We believe there is a nitric oxide-independent pathway that regulates ubiquitination. This pathway could make a promising drug target for a novel approach to fighting GAS.”

Sources: Lu SL, Kawabata T, Cheng YL et al. Endothelial cells are intrinsically defective in xenophagy of Streptococcus pyogenes. PLoS Pathog. doi:10.1371/journal.ppat.1006444 (2017) (Epub ahead of print);


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