Identification of a Novel Salmonella Type III Effector by Quantitative Secretome Profiling

Cheng, Sen; Wang, Lu; Liu, Qian; Qi, Linlu; Yu, Kaiwen; Wang, Zhen; Wu, Mei; Liu, Yanhua; Fu, Jiaqi; Hu, Mo; Li, Min; Zhou, Daoguo; Liu, Xiaoyun

doi:10.1074/mcp.ra117.000230

Cited by 32 publications

(29 citation statements)

References 38 publications

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“…Six mutants were significantly attenuated for spleen colonization. In addition, Cheng et al have recently identified a novel SPI-1 effector, SopF that is required for Salmonella virulence in mice using a similar proteomic approach (48).…”

Section: Discussionmentioning

confidence: 99%

YggG is a Novel SPI-1 Effector Essential for Salmonella Virulence

Bomjan

Chitale

et al. 2018

Preprint

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22Salmonella is a leading cause of food borne illness and poses a major public health 23 problem worldwide. Two type III secretion systems (TTSSs) are responsible for the 24 delivery of a series of bacterial effectors into the infected cells to reprogram host cell 25 functions to promote bacterial invasion and intracellular survival/replication. Nearly half 26of Salmonella genes encode proteins that are annotated as "hypothetical". We 27 hypothesize that some of these hypothetical proteins might be TTSS effectors and 28 participate in Salmonella virulence. In this study, we employed an in silico screen to 29 identify putative TTSS effector proteins and performed a large scale screening of 30Salmonella effectors using a β-lactamase protein translocation reporter assay. We 31 identified 22 novel effectors that have not been previously reported. One of the effector 32 -YggG, is found to be cytotoxic to mammalian cells when overexpressed suggesting 33 interference with mammalian cell functions and survival. Importantly, Salmonella strains 34 lacking YggG has reduced virulence in the mouse infection model. Our study 35 demonstrated that YggG and its protease activity are required for Salmonella virulence 36in the mouse infection model. Surprisingly, no detectable roles in invasion into epithelial 37 cells and no effect on the survival and replication inside cultured macrophages. We 38 speculate that YggG may be involved in altering some aspects of the host immune 39 system to promote infection. Our finding significantly expands the number of known 40Salmonella effectors, and laid a solid foundation in further understanding Salmonella 41 pathogenesis. 42 43 3 Abstract Importance 44Salmonellosis continues to be public health concern in the USA and the world. 45Salmonella delivers a set of bacterial proteins (effectors) into the host cells to invade 46 non-phagocytic cells and to replicate inside the infected cells. Identification and 47 characterization of these effectors are pivotal to the understanding of how Salmonella 48 causes diseases. In addition, Nearly half of Salmonella genes encode proteins that are 49 annotated as "hypothetical". We have identified 22 novel effectors that have not been 50 previously reported. Our finding significantly expands the number of known Salmonella 51 effectors, and laid a solid foundation in further understanding Salmonella pathogenesis. 52 53

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Section: Discussionmentioning

confidence: 99%

YggG is a Novel SPI-1 Effector Essential for Salmonella Virulence

Bomjan

Chitale

et al. 2018

Preprint

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“…In 2017, our group undertook quantitative secretome profiling to catalogue Salmonella effectors delivered by SPI-1 T3SS [ 40 ]. By using a SPI-1-deficient mutant (∆ invA ) as a control, we identified STM1239 (which we renamed SopF) as a novel substrate of T3SS.…”

Section: Proteomic Tools Assist In the Study Of Bacterial Virulencmentioning

confidence: 99%

Contributions of Mass Spectrometry-Based Proteomics to Understanding Salmonella-Host Interactions

et al. 2020

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As a model pathogen, Salmonella invades both phagocytic and non-phagocytic host cells and adopts an intracellular lifestyle in a membrane-bound compartment during infection. Therefore, a systemic overview of Salmonella adaptations to distinct host cells together with host remodeling will assist us in charting the landscape of host-pathogen interactions. Central to the Salmonella-host interplay are bacterial virulence factors (effectors) that are injected into host cells by type III secretion systems (T3SSs). Despite great progress, functional studies of bacterial effectors have experienced daunting challenges as well. In the last decade, mass spectrometry-based proteomics has evolved into a powerful technological platform that can quantitatively measure thousands of proteins in terms of their expression as well as post-translational modifications. Here, we will review the applications of high-throughput proteomic technologies in understanding the dynamic reprogramming of both Salmonella and host proteomes during the course of infection. Furthermore, we will summarize the progress in utilizing affinity purification-mass spectrometry to screen for host substrates of Salmonella T3SS effectors. Finally, we will critically discuss some limitations/challenges with current proteomic platforms in the context of host-pathogen interactions and highlight some emerging technologies that may offer the promise of tackling these problems.

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“…The use of genome mining in this context will only be useful if information (e.g., homology regions, structural information) about effectors are available. The use of techniques such as proteomics along with bioinformatic mining/analysis has been suggested as more useful tools in combination to identify effectors (Na et al, 2015; Cheng et al, 2017). For example, in recent studies, proteomics have been used to identify novel effectors in Salmonella .…”

Section: The Impossible Made Possible?mentioning

confidence: 99%

Harnessing Macrophages for Controlled-Release Drug Delivery: Lessons From Microbes

2019

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With the effectiveness of therapeutic agents ever decreasing and the increased incidence of multi-drug resistant pathogens, there is a clear need for administration of more potent, potentially more toxic, drugs. Alternatively, biopharmaceuticals may hold potential but require specialized protection from premature in vivo degradation. Thus, a paralleled need for specialized drug delivery systems has arisen. Although cell-mediated drug delivery is not a completely novel concept, the few applications described to date are not yet ready for in vivo application, for various reasons such as drug-induced carrier cell death, limited control over the site and timing of drug release and/or drug degradation by the host immune system. Here, we present our hypothesis for a new drug delivery system, which aims to negate these limitations. We propose transport of nanoparticle-encapsulated drugs inside autologous macrophages polarized to M1 phenotype for high mobility and treated to induce transient phagosome maturation arrest. In addition, we propose a significant shift of existing paradigms in the study of host-microbe interactions, in order to study microbial host immune evasion and dissemination patterns for their therapeutic utilization in the context of drug delivery. We describe a system in which microbial strategies may be adopted to facilitate absolute control over drug delivery, and without sacrificing the host carrier cells. We provide a comprehensive summary of the lessons we can learn from microbes in the context of drug delivery and discuss their feasibility for in vivo therapeutic application. We then describe our proposed “synthetic microbe drug delivery system” in detail. In our opinion, this multidisciplinary approach may hold the solution to effective, controlled drug delivery.

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Identification of a Novel Salmonella Type III Effector by Quantitative Secretome Profiling

Cited by 32 publications

References 38 publications

YggG is a Novel SPI-1 Effector Essential for Salmonella Virulence

YggG is a Novel SPI-1 Effector Essential for Salmonella Virulence

Contributions of Mass Spectrometry-Based Proteomics to Understanding Salmonella-Host Interactions

Harnessing Macrophages for Controlled-Release Drug Delivery: Lessons From Microbes

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