scholarly journals Chemical Inhibitors of the Type Three Secretion System: Disarming Bacterial Pathogens

2012 ◽  
Vol 56 (11) ◽  
pp. 5433-5441 ◽  
Author(s):  
Miles C. Duncan ◽  
Roger G. Linington ◽  
Victoria Auerbuch
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Bacterial Pathogens ◽  
Secretion System ◽  
Effector Proteins ◽  
Host Cells ◽  
Magic Bullet ◽  
Antimicrobial Drugs ◽  
Type Three Secretion System ◽  
Type Three Secretion

ABSTRACTThe recent and dramatic rise of antibiotic resistance among bacterial pathogens underlies the fear that standard treatments for infectious disease will soon be largely ineffective. Resistance has evolved against nearly every clinically used antibiotic, and in the near future, we may be hard-pressed to treat bacterial infections previously conquered by “magic bullet” drugs. While traditional antibiotics kill or slow bacterial growth, an important emerging strategy to combat pathogens seeks to block the ability of bacteria to harm the host by inhibiting bacterial virulence factors. One such virulence factor, the type three secretion system (T3SS), is found in over two dozen Gram-negative pathogens and functions by injecting effector proteins directly into the cytosol of host cells. Without T3SSs, many pathogenic bacteria are unable to cause disease, making the T3SS an attractive target for novel antimicrobial drugs. Interdisciplinary efforts between chemists and microbiologists have yielded several T3SS inhibitors, including the relatively well-studied salicylidene acylhydrazides. This review highlights the discovery and characterization of T3SS inhibitors in the primary literature over the past 10 years and discusses the future of these drugs as both research tools and a new class of therapeutic agents.

scholarly journals Regulation of the Locus of Enterocyte Effacement in Attaching and Effacing Pathogens

2017 ◽  
Vol 200 (2) ◽  
Author(s):  
R. Christopher D. Furniss ◽  
Abigail Clements
Keyword(s):  
Secretion System ◽  
Effector Proteins ◽  
The Core ◽  
Genetic Feature ◽  
Gut Epithelium ◽  
Type Three Secretion System ◽  
Gut Mucosa ◽  
Enterocyte Effacement ◽  
Type Three Secretion ◽  
Complex Regulatory Network

ABSTRACTAttaching and effacing (AE) pathogens colonize the gut mucosa using a type three secretion system (T3SS) and a suite of effector proteins. The locus of enterocyte effacement (LEE) is the defining genetic feature of the AE pathogens, encoding the T3SS and the core effector proteins necessary for pathogenesis. Extensive research has revealed a complex regulatory network that senses and responds to a myriad of host- and microbiota-derived signals in the infected gut to control transcription of the LEE. These signals include microbiota-liberated sugars and metabolites in the gut lumen, molecular oxygen at the gut epithelium, and host hormones. Recent research has revealed that AE pathogens also recognize physical signals, such as attachment to the epithelium, and that the act of effector translocation remodels gene expression in infecting bacteria. In this review, we summarize our knowledge to date and present an integrated view of how chemical, geographical, and physical cues regulate the virulence program of AE pathogens during infection.

scholarly journals Extra! Extracellular Effector Delivery into Host Cells via the Type 3 Secretion System

mBio ◽  
2017 ◽  
Vol 8 (3) ◽  
Author(s):  
Melissa M. Kendall
Keyword(s):  
Host Cell ◽  
Secretion System ◽  
Effector Proteins ◽  
Host Cells ◽  
Alternative Mechanism ◽  
Host Cell Membrane ◽  
Type Three Secretion System ◽  
Host Signaling ◽  
Type 3 Secretion System ◽  
Type 3

ABSTRACT The type three secretion system (T3SS) is critical for the virulence of diverse bacterial pathogens. Pathogens use the T3SS to deliver effector proteins into host cells and manipulate host signaling pathways. The prevailing mechanism is that effectors translocate from inside the T3SS directly into the host cell. Recent studies reveal an alternative mechanism of effector translocation, in which an effector protein located outside the bacterial cell relies on the T3SS for delivery into host cells. Tejeda-Dominguez et al. (F. Tejeda-Dominguez, J. Huerta-Cantillo, L. Chavez-Dueñas, and F. Navarro-Garcia, mBio 8:e00184-17, 2017, https://doi.org/10.1128/mBio.00184-17 !) demonstrate that the EspC effector of enteropathogenic Escherichia coli is translocated by binding to the outside of the T3SS and subsequently gains access to the host cell cytoplasm through the T3SS pore embedded within the host cell membrane. This work reveals a novel mechanism of translocation that is likely relevant for a variety of other pathogens that use the T3SS as part of their virulence arsenal.

scholarly journals Undercover Agents of Infection: The Stealth Strategies of T4SS-Equipped Bacterial Pathogens

Toxins ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 713
Author(s):  
Arthur Bienvenu ◽  
Eric Martinez ◽  
Matteo Bonazzi
Keyword(s):  
Host Cell ◽  
Chronic Diseases ◽  
Bacterial Pathogens ◽  
Secretion System ◽  
Effector Proteins ◽  
Innate Immune ◽  
Host Cells ◽  
Immune Sensing ◽  
Bacterial Effectors ◽  
Innate Immune Sensing

Intracellular bacterial pathogens establish their replicative niches within membrane-encompassed compartments, called vacuoles. A subset of these bacteria uses a nanochannel called the type 4 secretion system (T4SS) to inject effector proteins that subvert the host cell machinery and drive the biogenesis of these compartments. These bacteria have also developed sophisticated ways of altering the innate immune sensing and response of their host cells, which allow them to cause long-lasting infections and chronic diseases. This review covers the mechanisms employed by intravacuolar pathogens to escape innate immune sensing and how Type 4-secreted bacterial effectors manipulate host cell mechanisms to allow the persistence of bacteria.

scholarly journals Modulation of host microtubule dynamics by pathogenic bacteria

2012 ◽  
Vol 3 (6) ◽  
pp. 571-580 ◽  
Author(s):  
Girish K. Radhakrishnan ◽  
Gary A. Splitter
Keyword(s):  
Pathogenic Bacteria ◽  
Bacterial Pathogens ◽  
Small Gtpases ◽  
Microtubule Dynamics ◽  
Effector Proteins ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Survival Strategies ◽  
Future Research ◽  
Bacterial Effectors

AbstractThe eukaryotic cytoskeleton is a vulnerable target of many microbial pathogens during the course of infection. Rearrangements of host cytoskeleton benefit microbes in various stages of their infection cycle such as invasion, motility, and persistence. Bacterial pathogens deliver a number of effector proteins into host cells for modulating the dynamics of actin and microtubule cytoskeleton. Alteration of the actin cytoskeleton is generally achieved by bacterial effectors that target the small GTPases of the host. Modulation of microtubule dynamics involves direct interaction of effector proteins with the subunits of microtubules or recruiting cellular proteins that affect microtubule dynamics. This review will discuss effector proteins from animal and human bacterial pathogens that either destabilize or stabilize host microtubules to advance the infectious process. A compilation of these research findings will provide an overview of known and unknown strategies used by various bacterial effectors to modulate the host microtubule dynamics. The present review will undoubtedly help direct future research to determine the mechanisms of action of many bacterial effector proteins and contribute to understanding the survival strategies of diverse adherent and invasive bacterial pathogens.

scholarly journals The Ruler Protein EscP of the Enteropathogenic Escherichia coli Type III Secretion System Is Involved in Calcium Sensing and Secretion Hierarchy Regulation by Interacting with the Gatekeeper Protein SepL

mBio ◽  
2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Lihi Shaulov ◽  
Jenia Gershberg ◽  
Wanyin Deng ◽  
B. Brett Finlay ◽  
Neta Sal-Man
Keyword(s):  
Host Cell ◽  
Type Iii Secretion ◽  
Bacterial Pathogens ◽  
Type Iii Secretion System ◽  
Secretion System ◽  
Bacterial Virulence ◽  
Effector Proteins ◽  
Host Cells ◽  
Gram Negative ◽  
Type Iii

ABSTRACT The type III secretion system (T3SS) is a multiprotein complex that plays a central role in the virulence of many Gram-negative bacterial pathogens. To ensure that effector proteins are efficiently translocated into the host cell, bacteria must be able to sense their contact with the host cell. In this study, we found that EscP, which was previously shown to function as the ruler protein of the enteropathogenic Escherichia coli T3SS, is also involved in the switch from the secretion of translocator proteins to the secretion of effector proteins. In addition, we demonstrated that EscP can interact with the gatekeeper protein SepL and that the EscP-SepL complex dissociates upon a calcium concentration drop. We suggest a model in which bacterial contact with the host cell is accompanied by a drop in the calcium concentration that causes SepL-EscP complex dissociation and triggers the secretion of effector proteins. IMPORTANCE The emergence of multidrug-resistant bacterial strains, especially those of pathogenic bacteria, has serious medical and clinical implications. At the same time, the development and approval of new antibiotics have been limited for years. Recently, antivirulence drugs have received considerable attention as a novel antibiotic strategy that specifically targets bacterial virulence rather than growth, an approach that applies milder evolutionary pressure on the bacteria to develop resistance. A highly attractive target for the development of antivirulence compounds is the type III secretion system, a specialized secretory system possessed by many Gram-negative bacterial pathogens for injecting virulence factors (effectors) into host cells. In this study, we shed light on the molecular mechanism that allows bacteria to sense their contact with the host cell and to respond with the timed secretion of effector proteins. Understanding this critical step for bacterial virulence may provide a new therapeutic strategy. IMPORTANCE The emergence of multidrug-resistant bacterial strains, especially those of pathogenic bacteria, has serious medical and clinical implications. At the same time, the development and approval of new antibiotics have been limited for years. Recently, antivirulence drugs have received considerable attention as a novel antibiotic strategy that specifically targets bacterial virulence rather than growth, an approach that applies milder evolutionary pressure on the bacteria to develop resistance. A highly attractive target for the development of antivirulence compounds is the type III secretion system, a specialized secretory system possessed by many Gram-negative bacterial pathogens for injecting virulence factors (effectors) into host cells. In this study, we shed light on the molecular mechanism that allows bacteria to sense their contact with the host cell and to respond with the timed secretion of effector proteins. Understanding this critical step for bacterial virulence may provide a new therapeutic strategy.

scholarly journals Salmonella Pathogenicity Island 1 (SPI-1): The Evolution and Stabilization of a Core Genomic Type Three Secretion System

2020 ◽  
Vol 8 (4) ◽  
pp. 576
Author(s):  
Nicole A. Lerminiaux ◽  
Keith D. MacKenzie ◽  
Andrew D. S. Cameron
Keyword(s):  
Transcription Factors ◽  
Pathogenicity Island ◽  
Secretion System ◽  
Effector Proteins ◽  
Gene Promoters ◽  
Salmonella Pathogenicity Island ◽  
Evolutionary Origins ◽  
Type Three Secretion System ◽  
History Of ◽  
Type Three Secretion

Salmonella Pathogenicity Island 1 (SPI-1) encodes a type three secretion system (T3SS), effector proteins, and associated transcription factors that together enable invasion of epithelial cells in animal intestines. The horizontal acquisition of SPI-1 by the common ancestor of all Salmonella is considered a prime example of how gene islands potentiate the emergence of new pathogens with expanded niche ranges. However, the evolutionary history of SPI-1 has attracted little attention. Here, we apply phylogenetic comparisons across the family Enterobacteriaceae to examine the history of SPI-1, improving the resolution of its boundaries and unique architecture by identifying its composite gene modules. SPI-1 is located between the core genes fhlA and mutS, a hotspot for the gain and loss of horizontally acquired genes. Despite the plasticity of this locus, SPI-1 demonstrates stable residency of many tens of millions of years in a host genome, unlike short-lived homologous T3SS and effector islands including Escherichia ETT2, Yersinia YSA, Pantoea PSI-2, Sodalis SSR2, and Chromobacterium CPI-1. SPI-1 employs a unique series of regulatory switches, starting with the dedicated transcription factors HilC and HilD, and flowing through the central SPI-1 regulator HilA. HilA is shared with other T3SS, but HilC and HilD may have their evolutionary origins in Salmonella. The hilA, hilC, and hilD gene promoters are the most AT-rich DNA in SPI-1, placing them under tight control by the transcriptional repressor H-NS. In all Salmonella lineages, these three promoters resist amelioration towards the genomic average, ensuring strong repression by H-NS. Hence, early development of a robust and well-integrated regulatory network may explain the evolutionary stability of SPI-1 compared to T3SS gene islands in other species.

scholarly journals Antibodies Inhibiting the Type III Secretion System of Gram-Negative Pathogenic Bacteria

Antibodies ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 35
Author(s):  
Julia A. Hotinger ◽  
Aaron E. May
Keyword(s):  
Type Iii Secretion ◽  
Pathogenic Bacteria ◽  
Type Iii Secretion System ◽  
The United States ◽  
Secretion System ◽  
Effector Proteins ◽  
Host Cells ◽  
Gram Negative ◽  
Type Iii ◽  
Shigella Spp

Pathogenic bacteria are a global health threat, with over 2 million infections caused by Gram-negative bacteria every year in the United States. This problem is exacerbated by the increase in resistance to common antibiotics that are routinely used to treat these infections, creating an urgent need for innovative ways to treat and prevent virulence caused by these pathogens. Many Gram-negative pathogenic bacteria use a type III secretion system (T3SS) to inject toxins and other effector proteins directly into host cells. The T3SS has become a popular anti-virulence target because it is required for pathogenesis and knockouts have attenuated virulence. It is also not required for survival, which should result in less selective pressure for resistance formation against T3SS inhibitors. In this review, we will highlight selected examples of direct antibody immunizations and the use of antibodies in immunotherapy treatments that target the bacterial T3SS. These examples include antibodies targeting the T3SS of Pseudomonas aeruginosa, Yersinia pestis, Escherichia coli, Salmonella enterica, Shigella spp., and Chlamydia trachomatis.

scholarly journals Role for the Burkholderia pseudomallei Type Three Secretion System Cluster 1bpscNGene in Virulence

2011 ◽  
Vol 79 (9) ◽  
pp. 3659-3664 ◽  
Author(s):  
Tanya D'Cruze ◽  
Lan Gong ◽  
Puthayalai Treerat ◽  
Georg Ramm ◽  
John D. Boyce ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Burkholderia Pseudomallei ◽  
Gene Clusters ◽  
Secretion System ◽  
Host Cells ◽  
Infection Model ◽  
Content Type ◽  
Type Three Secretion System ◽  
Type Three Secretion

ABSTRACTBurkholderia pseudomallei, the causal agent of melioidosis, employs a number of virulence factors during its infection of mammalian cells. One such factor is the type three secretion system (TTSS), which is proposed to mediate the transport and secretion of bacterial effector molecules directly into host cells. TheB. pseudomalleigenome contains three TTSS gene clusters (designated TTSS1, TTSS2, and TTSS3). Previous research has indicated that neither TTSS1 nor TTSS2 is involved inB. pseudomalleivirulence in a hamster infection model. We have characterized aB. pseudomalleimutant lacking expression of the predicted TTSS1 ATPase encoded bybpscN. This mutant was significantly attenuated for virulence in a respiratory melioidosis mouse model of infection. In addition, analysesin vitroshowed diminished survival and replication in RAW264.7 cells and an increased level of colocalization with the autophagy marker protein LC3 but an unhindered ability to escape from phagosomes. Taken together, these data provide evidence that the TTSS1bpscNgene product plays an important role in the intracellular survival ofB. pseudomalleiand the pathogenesis of murine infection.

scholarly journals Rhizobia use a pathogenic-like effector to hijack leguminous nodulation signalling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Safirah Tasa Nerves Ratu ◽  
Albin Teulet ◽  
Hiroki Miwa ◽  
Sachiko Masuda ◽  
Hien P. Nguyen ◽  
...  
Keyword(s):  
Type Iii Secretion ◽  
Xanthomonas Campestris ◽  
Pathogenic Bacteria ◽  
Root Nodule ◽  
Secretion System ◽  
Effector Proteins ◽  
Host Cells ◽  
Nod Factors ◽  
Legume Nodulation ◽  
Nodule Symbiosis

AbstractLegume plants form a root-nodule symbiosis with rhizobia. This symbiosis establishment generally relies on rhizobium-produced Nod factors (NFs) and their perception by leguminous receptors (NFRs) that trigger nodulation. However, certain rhizobia hijack leguminous nodulation signalling via their type III secretion system, which functions in pathogenic bacteria to deliver effector proteins into host cells. Here, we report that rhizobia use pathogenic-like effectors to hijack legume nodulation signalling. The rhizobial effector Bel2-5 resembles the XopD effector of the plant pathogen Xanthomonas campestris and could induce nitrogen-fixing nodules on soybean nfr mutant. The soybean root transcriptome revealed that Bel2-5 induces expression of cytokinin-related genes, which are important for nodule organogenesis and represses ethylene- and defense-related genes that are deleterious to nodulation. Remarkably, Bel2-5 introduction into a strain unable to nodulate soybean mutant affected in NF perception conferred nodulation ability. Our findings show that rhizobia employ and have customized pathogenic effectors to promote leguminous nodulation signalling.

Sign in / Sign up

Export Citation Format

Share Document