Salmonella Typhimurium Type III Secretion Effectors Stimulate Innate Immune Responses in Cultured Epithelial Cells

Bruno, Vincent M.; Hannemann, Sebastian; Lara‐Tejero, María; Flavell, Richard A.; Kleinstein, Steven H.; Galán, Jorge E.

doi:10.1371/journal.ppat.1000538

Cited by 183 publications

(213 citation statements)

References 59 publications

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“…2.27) were found to be up-regulated also in previous studies (e.g. Bruno et al, 2009;Hannemann et al, 2013). Other early induced mRNAs such as IL6…”

Section: Comparison Of Invaded Host Cells and Non-infected Bystanderssupporting

confidence: 73%

“…Therefore, observations that STnc440 affects the level of Salmonella virulence effectors from SPI-1 (Y. Chao, personal communication) and SPI-2 (see above), implied that also the host response to infection could be influenced by the action of this sRNA (Bruno et al, 2009;Hannemann et al, 2013;Nikai, 2005, 2008). (Yoshimura et al, 2007).…”

Section: Jak/stat and Cytokine Signaling Are Stnc440-affected Host Pamentioning

confidence: 97%

“…In turn, microarrays yielded important insights into the global response of potential mammalian hosts upon cytokine (Zhu et al, 1998) or pathogen-associated molecular pattern (PAMP) stimulation (Hedges et al, 2005;Kerns et al, 2009;Tross et al, 2009), as well as towards diverse bacterial (reviewed in Rappuoli, 2000) or viral infections (Der et al, 1998). Recently, two microarray-based studies reported the response of human epithelial cells to S. Typhimurium infection and found that by secreting effector proteins Salmonella induces pervasive transcriptional reprogramming in the host (Bruno et al, 2009;Hannemann et al, 2013). Less frequently, tag-based approaches have been applied to the field of infection biology, e.g.…”

Section: Transcriptomics: Then and Nowmentioning

confidence: 99%

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Dual RNA-seq of pathogen and host

2012

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SummaryThe infection of a eukaryotic host cell by a bacterial pathogen is one of the most intimate examples of cross-kingdom interactions in biology. Infection processes are highly relevant from both a basic research as well as a clinical point of view. Sophisticated mechanisms have evolved in the pathogen to manipulate the host response and vice versa host cells have developed a wide range of anti-microbial defense strategies to combat bacterial invasion and clear infections.However, it is this diversity and complexity that makes infection research so challenging to technically address as common approaches have either been optimized for bacterial or eukaryotic organisms. Instead, methods are required that are able to deal with the often dramatic discrepancy between host and pathogen with respect to various cellular properties and processes. One class of cellular macromolecules that exemplify this host-pathogen heterogeneity is given by their transcriptomes: Bacterial transcripts differ from their eukaryotic counterparts in many aspects that involve both quantitative and qualitative traits. The entity of RNA transcripts present in a cell is of paramount interest as it reflects the cell's physiological state under the given condition. Genome-wide transcriptomic techniques such as RNA-seq have therefore been used for single-organism analyses for several years, but their applicability has been limited for infection studies.The present work describes the establishment of a novel transcriptomic approach for infection biology which we have termed "Dual RNA-seq". Using this technology, it was intended to shed light particularly on the contribution of non-protein-encoding transcripts to virulence, as these classes have mostly evaded previous infection studies due to the lack of suitable methods. The performance of Dual RNA-seq was evaluated in an in vitro infection model based on the important facultative intracellular pathogen Salmonella enterica serovar Typhimurium and different human cell lines. Dual RNA-seq was found to be capable of capturing all major bacterial and human transcript classes and proved reproducible. During the course of these experiments, a previously largely uncharacterized bacterial small non-coding RNA (sRNA), referred to as STnc440, was identified as one of the most strongly induced genes in intracellular Salmonella.Interestingly, while inhibition of STnc440 expression has been previously shown to cause a virulence defect in different animal models of Salmonellosis, the underlying molecular mechanisms have remained obscure. Here, classical genetics, transcriptomics and biochemical assays proposed a complex model of Salmonella gene expression control that is orchestrated by this sRNA. In particular, STnc440 was found to be involved in the regulation of multiple bacterial target mRNAs by direct base pair interaction with consequences for Salmonella virulence and

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“…2.27) were found to be up-regulated also in previous studies (e.g. Bruno et al, 2009;Hannemann et al, 2013). Other early induced mRNAs such as IL6…”

Section: Comparison Of Invaded Host Cells and Non-infected Bystanderssupporting

confidence: 73%

Section: Jak/stat and Cytokine Signaling Are Stnc440-affected Host Pamentioning

confidence: 97%

Section: Transcriptomics: Then and Nowmentioning

confidence: 99%

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Dual RNA-seq of pathogen and host

2012

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“…are enteric pathogens that invade host cells using a type III secretion system that is able to inject effectors in the cytosol of host cells. Earlier work by the group of Jorge Galan showed that Salmonella effectors could activate epithelial cells through a PRR-independent mechanism that was dependent on the GEF activity of certain effectors and involving target GTPases in the host [7]. Similarly, the Shigella effector, GEF-H1 was shown to augment NF-κB-dependent immune responses in a NOD1-dependent manner also after modifying RhoGTPases [8].…”

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confidence: 97%

RhoGTPases — NODes for effector-triggered immunity in animals

Stuart

Boyer

2013

Cell Res

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“…Recent advances in high throughput measurements allow us to characterize host gene expression profiles (13) and host phosphoproteme dynamics (14) dependent on the presence of SPI1 effectors in an unbiased, comprehensive manner. However, although it is clear that SPI2 T3SS is a major virulence factor contributing to systemic infection, our knowledge of its effects on host responses is limited.…”

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confidence: 99%

Global Impact of Salmonella Pathogenicity Island 2-secreted Effectors on the Host Phosphoproteome

Imami

Bhavsar

et al. 2013

Molecular & Cellular Proteomics

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During the late stages of infection, Salmonella secretes numerous effectors through a type III secretion system that is encoded within Salmonella pathogenicity island 2 (SPI2). Despite the importance of SPI2 as a major virulence factor leading to the systemic spread of the bacteria and diseases, a global view of its effects on host responses is still lacking. Here, we measured global impacts of SPI2 effectors on the host phosphorylation and protein expression levels in RAW264.7 and in HeLa cells, as macrophage and nonphagocytic models of infection. We observe that SPI2 effectors differentially modulate the host phosphoproteome and cellular processes (e.g. protein trafficking, cytoskeletal regulation, and immune signaling) in a host cell-dependent manner. Our unbiased approach reveals the involvement of many previously unrecognized proteins, including E3 ligases (HERC4, RanBP2, and RAD18), kinases (CDK, SIK3, and WNK1), and histones (H2B1F, H4, and H15), in late stages of Salmonella infection. Furthermore, from this phosphoproteome analysis and other quantitative screens, we identified HSP27 as a direct in vitro and in vivo molecular target of the only type III secreted kinase, SteC. Using biochemical and cell biological assays, we demonstrate that SteC phosphorylates multiple sites in HSP27 and induces actin rearrangement through this protein. Together, these results provide a broader landscape of host players contributing to specific processes/pathways mediated by SPI2 effectors than was previously appreciated. Molecular &

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Salmonella Typhimurium Type III Secretion Effectors Stimulate Innate Immune Responses in Cultured Epithelial Cells

Cited by 183 publications

References 59 publications

Dual RNA-seq of pathogen and host

Dual RNA-seq of pathogen and host

RhoGTPases — NODes for effector-triggered immunity in animals

Global Impact of Salmonella Pathogenicity Island 2-secreted Effectors on the Host Phosphoproteome

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