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Human Genome-Wide RNAi Screen for Host Factors That Facilitate Salmonella Invasion Reveals a Role for Potassium Secretion in Promoting Internalization

View Article: PubMed Central - PubMed

ABSTRACT

Salmonella enterica can actively invade the gastro-intestinal epithelium. This frequently leads to diarrheal disease, and also gives the pathogen access to phagocytes that can serve as vehicles for dissemination into deeper tissue. The ability to invade host cells is also important in maintaining the carrier state. While much is known about the bacterial factors that promote invasion, relatively little is known about the host factors involved. To gain insight into how Salmonella enterica serovar Typhimurium is able to invade normally non-phagocytic cells, we undertook a global RNAi screen with S. Typhimurium-infected human epithelial cells. In all, we identified 633 genes as contributing to bacterial internalization. These genes fall into a diverse group of functional categories revealing that cytoskeletal regulators are not the only factors that modulate invasion. In fact, potassium ion transport was the most enriched molecular function category in our screen, reinforcing a link between potassium and internalization. In addition to providing new insights into the molecular mechanisms underlying the ability of pathogens to invade host cells, all 633 host factors identified are candidates for new anti-microbial targets for treating Salmonella infections, and may be useful in curtailing infections with other pathogens as well.

No MeSH data available.


The overrepresented molecular function categories for the hit list.The–log(p-value) is plotted with 0.05 being the significance threshold.
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pone.0166916.g003: The overrepresented molecular function categories for the hit list.The–log(p-value) is plotted with 0.05 being the significance threshold.

Mentions: In all, 633 genes were identified as facilitating S. Typhimurium entry into MCF-7 cells. These genes are described in S1 Table. Information on all of the genes screened can be found in S2 Table. The two most prominent string-derived subnetworks are displayed in Figs 1 and 2. Both subnetworks are involved in potassium ion transport. The members of these subnetworks are described in S3 and S4 Tables. The molecular function categories of 633 genes, for which there was significant enrichment are show in Fig 3. The most enriched category by far, with a remarkable p-value of 9.86 X 10−11 was potassium transport. Potassium levels, but not potassium transport, have been shown to play a role in Salmonella pathogenesis. The bacterial potassium transporter Trk and external potassium modulate Salmonella type III secretion, invasion of epithelial cells and pathogenesis in mice and chickens[18,19]. In addition to genes involved in potassium transport, the molecular function categories of metal ion binding and transport were also highly enriched with p-values of 7.15 X 10−8 and 6.49 X 10−7 respectively. Iron has been shown to play a role in regulating invasion[20].


Human Genome-Wide RNAi Screen for Host Factors That Facilitate Salmonella Invasion Reveals a Role for Potassium Secretion in Promoting Internalization
The overrepresented molecular function categories for the hit list.The–log(p-value) is plotted with 0.05 being the significance threshold.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120809&req=5

pone.0166916.g003: The overrepresented molecular function categories for the hit list.The–log(p-value) is plotted with 0.05 being the significance threshold.
Mentions: In all, 633 genes were identified as facilitating S. Typhimurium entry into MCF-7 cells. These genes are described in S1 Table. Information on all of the genes screened can be found in S2 Table. The two most prominent string-derived subnetworks are displayed in Figs 1 and 2. Both subnetworks are involved in potassium ion transport. The members of these subnetworks are described in S3 and S4 Tables. The molecular function categories of 633 genes, for which there was significant enrichment are show in Fig 3. The most enriched category by far, with a remarkable p-value of 9.86 X 10−11 was potassium transport. Potassium levels, but not potassium transport, have been shown to play a role in Salmonella pathogenesis. The bacterial potassium transporter Trk and external potassium modulate Salmonella type III secretion, invasion of epithelial cells and pathogenesis in mice and chickens[18,19]. In addition to genes involved in potassium transport, the molecular function categories of metal ion binding and transport were also highly enriched with p-values of 7.15 X 10−8 and 6.49 X 10−7 respectively. Iron has been shown to play a role in regulating invasion[20].

View Article: PubMed Central - PubMed

ABSTRACT

Salmonella enterica can actively invade the gastro-intestinal epithelium. This frequently leads to diarrheal disease, and also gives the pathogen access to phagocytes that can serve as vehicles for dissemination into deeper tissue. The ability to invade host cells is also important in maintaining the carrier state. While much is known about the bacterial factors that promote invasion, relatively little is known about the host factors involved. To gain insight into how Salmonella enterica serovar Typhimurium is able to invade normally non-phagocytic cells, we undertook a global RNAi screen with S. Typhimurium-infected human epithelial cells. In all, we identified 633 genes as contributing to bacterial internalization. These genes fall into a diverse group of functional categories revealing that cytoskeletal regulators are not the only factors that modulate invasion. In fact, potassium ion transport was the most enriched molecular function category in our screen, reinforcing a link between potassium and internalization. In addition to providing new insights into the molecular mechanisms underlying the ability of pathogens to invade host cells, all 633 host factors identified are candidates for new anti-microbial targets for treating Salmonella infections, and may be useful in curtailing infections with other pathogens as well.

No MeSH data available.