Always one step ahead: How pathogenic bacteria use the type III secretion system to manipulate the intestinal mucosal immune system

Similar to pathogenic bacteria, rhizobia can inject effector proteins into host cells directly to promote infection via the type III secretion system. Nodulation outer protein P (NopP), a specific type III secretion system effector of rhizobia, plays different roles in the establishment of multiple rhizobia-legume symbiotic systems. Mesorhizobium amorphae CCNWGS0123 (GS0123), which infects Robinia pseudoacacia specifically, secretes several type III secretion system (T3SS) effectors, including NopP. Here, we demonstrate that NopP is secreted through T3SS-Ⅰof GS0123 during the early stages of infection, and its deficiency decreases nodule nitrogenase activity of R. pseudoacacia nodules. A trafficking protein particle complex subunit 13-like protein (TRAPPC13) ishas been identified as a NopP target protein in R. pseudoacacia roots by screening a yeast two-hybrid library. The physical interaction between NopP and TRAPPC13 is verified by bimolecular fluorescence complementation and co-immunoprecipitation assays. In addition, subcellular localization analysis reveals that both NopP and its target, TRAPPC13, are co-localized on the plasma membrane. Compared with GS0123-inoculated R. pseudoacacia roots, some genes associated with cell wall remodeling and plant innate immunity down-regulated in ΔnopP-inoculated roots at 36 hpi. The results suggest that NopP in M. amorphae CCNWGS0123 acts in multiple process in R. pseudoacacia during the early stages of infection, and TRAPPC13 could participate in the process as a NopP target.

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Salmonella enterica Serovar Typhimurium Exploits Toll-Like Receptor Signaling during the Host-Pathogen Interaction

Infection and Immunity ◽

10.1128/iai.00545-09 ◽

2009 ◽

Vol 77 (11) ◽

pp. 4750-4760 ◽

Cited By ~ 14

Author(s):

Christine E. Wong ◽

Subash Sad ◽

Brian K. Coombes

Keyword(s):

Immune System ◽

Type Iii Secretion ◽

Innate Immune System ◽

Salmonella Enterica ◽

Type Iii Secretion System ◽

Secretion System ◽

Innate Immune ◽

Type Iii ◽

Infection Dynamics ◽

Serovar Typhimurium

ABSTRACT Salmonella survives and replicates in host cells by using a type III secretion system to evade host immune defenses. The innate immune system plays an important role as a first line of defense against pathogens and is mediated in part by Toll-like receptors (TLRs); however, the infection dynamics of Salmonella enterica serovar Typhimurium within macrophages stimulated with TLR ligands is poorly understood. We studied the infection dynamics of Salmonella in murine macrophages previously exposed to TLR ligands and report that treatment of macrophages with four different TLR agonists resulted in their increased phagocytic capacity toward Salmonella but not fluorescent microspheres. Further analysis revealed that the intracellular replication of Salmonella was enhanced in TLR-stimulated macrophages in a manner requiring a functional type III secretion system and enhanced transcriptional activity of the sseA virulence gene operon. Studies of mice that normally resolve an acute primary infection with Salmonella revealed that pretreatment of animals with CpG DNA had a detrimental effect on disease outcome. CpG-treated mice infected with Salmonella all succumbed to infection and had higher bacterial loads in the spleen than did control animals. These data suggest that Salmonella can exploit macrophages activated via the innate immune system for increased intracellular survival.

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

Antibodies ◽

10.3390/antib9030035 ◽

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.

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Natural Product Type III Secretion System Inhibitors

Antibiotics ◽

10.3390/antibiotics8040162 ◽

2019 ◽

Vol 8 (4) ◽

pp. 162 ◽

Cited By ~ 7

Author(s):

Heather A. Pendergrass ◽

Aaron E. May

Keyword(s):

Natural Products ◽

Type Iii Secretion ◽

Pathogenic Bacteria ◽

Type Iii Secretion System ◽

Cellular Level ◽

Secretion System ◽

Host Cells ◽

Type Iii ◽

Symbiotic Organisms ◽

Bacterial Type

Many known inhibitors of the bacterial type III secretion system (T3SS), a virulence factor used by pathogenic bacteria to infect host cells, are natural products. These compounds, produced by bacteria, fungi, and plants, may have developed as prophylactic treatments for potential attack by bacterial pathogens or as an attempt by symbiotic organisms to protect their hosts. Regardless, better understanding of the structures and mechanisms of action of these compounds may open opportunities for drug development against diseases caused by pathogens utilizing the T3SS. This review will cover selected known natural products of the T3SS and detail what is known of their origin and mechanism of action. These inhibitors highlight nature’s ability to modulate interactions between organisms at a cellular level.

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Innovation and Application of the Type III Secretion System Inhibitors in Plant Pathogenic Bacteria

Microorganisms ◽

10.3390/microorganisms8121956 ◽

2020 ◽

Vol 8 (12) ◽

pp. 1956

Author(s):

Xiaochen Yuan ◽

Manda Yu ◽

Ching-Hong Yang

Keyword(s):

Type Iii Secretion ◽

Pathogenic Bacteria ◽

Plant Pathogens ◽

Current Knowledge ◽

Type Iii Secretion System ◽

Transcriptional Regulators ◽

Secretion System ◽

Plant Diseases ◽

Host Cells ◽

Type Iii

Many Gram-negative pathogenic bacteria rely on a functional type III secretion system (T3SS), which injects multiple effector proteins into eukaryotic host cells, for their pathogenicity. Genetic studies conducted in different host-microbe pathosystems often revealed a sophisticated regulatory mechanism of their T3SSs, suggesting that the expression of T3SS is tightly controlled and constantly monitored by bacteria in response to the ever-changing host environment. Therefore, it is critical to understand the regulation of T3SS in pathogenic bacteria for successful disease management. This review focuses on a model plant pathogen, Dickeyadadantii, and summarizes the current knowledge of its T3SS regulation. We highlight the roles of several T3SS regulators that were recently discovered, including the transcriptional regulators: FlhDC, RpoS, and SlyA; the post-transcriptional regulators: PNPase, Hfq with its dependent sRNA ArcZ, and the RsmA/B system; and the bacterial second messenger cyclic-di-GMP (c-di-GMP). Homologs of these regulatory components have also been characterized in almost all major bacterial plant pathogens like Erwiniaamylovora, Pseudomonassyringae, Pectobacterium spp., Xanthomonas spp., and Ralstonia spp. The second half of this review shifts focus to an in-depth discussion of the innovation and development of T3SS inhibitors, small molecules that inhibit T3SSs, in the field of plant pathology. This includes T3SS inhibitors that are derived from plant phenolic compounds, plant coumarins, and salicylidene acylhydrazides. We also discuss their modes of action in bacteria and application for controlling plant diseases.

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Mucosal priming of the murine immune system against enterohemorrhagic Escherichia coli O157:H7 using Lactococcus lactis expressing the type III secretion system protein EspB

Veterinary Immunology and Immunopathology ◽

10.1016/j.vetimm.2012.09.019 ◽

2013 ◽

Vol 152 (1-2) ◽

pp. 141-145 ◽

Cited By ~ 10

Author(s):

B. Ahmed ◽

M. Loos ◽

D. Vanrompay ◽

E. Cox

Keyword(s):

Escherichia Coli ◽

Immune System ◽

Lactococcus Lactis ◽

Type Iii Secretion ◽

Type Iii Secretion System ◽

Secretion System ◽

Enterohemorrhagic Escherichia Coli ◽

Escherichia Coli O157 ◽

Type Iii

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Positive Regulation of the Hrp Type III Secretion System in Pseudomonas syringae pv. phaseolicola

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-23-5-0665 ◽

2010 ◽

Vol 23 (5) ◽

pp. 665-681 ◽

Cited By ~ 40

Author(s):

Inmaculada Ortiz-Martín ◽

Richard Thwaites ◽

Alberto P. Macho ◽

John W. Mansfield ◽

Carmen R. Beuzón

Keyword(s):

Gene Expression ◽

Pseudomonas Syringae ◽

Hypersensitive Response ◽

Type Iii Secretion ◽

Pathogenic Bacteria ◽

Type Iii Secretion System ◽

Secretion System ◽

Virulence Determinants ◽

Type Iii

Disease in compatible hosts and induction of the hypersensitive response in resistant plants by most plant-pathogenic bacteria require a functional type III secretion system (T3SS). Expression of T3SS genes responds to host and environmental factors and is induced within the plant. In Pseudomonas syringae, expression of the T3SS requires HrpL, which is transcriptionally upregulated by HrpR and HrpS. In some pathovars, expression of the hrpRS genes is upregulated by the GacA/S two-component system. Additionally, HrpA, the major component of the T3SS pilus, has also been linked to the regulation of the hrpRS gene expression. Previous studies concerning regulation of hypersensitive response and pathogenesis/hypersensitive response conserved (hrp/hrc) gene expression have used mostly in vitro inducing conditions, different pathovars, and methodology. Here, we analyze the roles of HrpL, GacA, and HrpA in the bean pathogen, using single, double, and triple mutants as well as strains ectopically expressing the regulators. We use real-time polymerase chain reaction analysis in vitro and in planta to quantify gene expression and competitive indices and other assays to assess bacterial fitness. Our results indicate that i) HrpL acts as a general virulence regulator that upregulates non-T3SS virulence determinants and downregulates flagellar function; ii) GacA modulates the expression of hrpL, and its contribution to virulence is entirely HrpL dependent; iii) there is a basal HrpL-independent expression of the T3SS genes in rich medium that is important for full activation of the system, maybe by keeping the system primed for rapid activation upon contact with the plant; and iv) HrpA upregulates expression of the T3SS genes and is essential to activate expression of the hrpZ operon upon contact with the plant.

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The Type III Secretion System of Xanthomonas fuscans subsp. fuscans Is Involved in the Phyllosphere Colonization Process and in Transmission to Seeds of Susceptible Beans

Applied and Environmental Microbiology ◽

10.1128/aem.02906-07 ◽

2008 ◽

Vol 74 (9) ◽

pp. 2669-2678 ◽

Cited By ~ 42

Author(s):

A. Darsonval ◽

A. Darrasse ◽

D. Meyer ◽

M. Demarty ◽

K. Durand ◽

...

Keyword(s):

Type Iii Secretion ◽

Xanthomonas Campestris ◽

Pathogenic Bacteria ◽

Type Iii Secretion System ◽

Secretion System ◽

Regulatory Genes ◽

Population Densities ◽

Host Colonization ◽

Plant Pathogenic Bacteria ◽

Type Iii

ABSTRACT Understanding the survival, multiplication, and transmission to seeds of plant pathogenic bacteria is central to study their pathogenesis. We hypothesized that the type III secretion system (T3SS), encoded by hrp genes, could have a role in host colonization by plant pathogenic bacteria. The seed-borne pathogen Xanthomonas fuscans subsp. fuscans causes common bacterial blight of bean (Phaseolus vulgaris). Directed mutagenesis in strain CFBP4834-R of X. fuscans subsp. fuscans and bacterial population density monitoring on bean leaves showed that strains with mutations in the hrp regulatory genes, hrpG and hrpX, were impaired in their phyllospheric growth, as in the null interaction with Escherichia coli C600 and bean. In the compatible interaction, CFBP4834-R reached high phyllospheric population densities and was transmitted to seeds at high frequencies with high densities. Strains with mutations in structural hrp genes maintained the same constant epiphytic population densities (1 × 105 CFU g−1 of fresh weight) as in the incompatible interaction with Xanthomonas campestris pv. campestris ATCC 33913 and the bean. Low frequencies of transmission to seeds and low bacterial concentrations were recorded for CFBP4834-R hrp mutants and for ATCC 33913, whereas E. coli C600 was not transmitted. Moreover, unlike the wild-type strain, strains with mutations in hrp genes were not transmitted to seeds by vascular pathway. Transmission to seeds by floral structures remained possible for both. This study revealed the involvement of the X. fuscans subsp. fuscans T3SS in phyllospheric multiplication and systemic colonization of bean, leading to transmission to seeds. Our findings suggest a major contribution of hrp regulatory genes in host colonization processes.

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Regulation of the Pseudomonas syringae Type III Secretion System by Host Environment Signals

Microorganisms ◽

10.3390/microorganisms9061227 ◽

2021 ◽

Vol 9 (6) ◽

pp. 1227

Author(s):

Megan R. O’Malley ◽

Jeffrey C. Anderson

Keyword(s):

Pseudomonas Syringae ◽

Type Iii Secretion ◽

Regulatory Networks ◽

Pathogenic Bacteria ◽

Critical Role ◽

Type Iii Secretion System ◽

Secretion System ◽

Fine Tuning ◽

Type Iii ◽

Host Signals

Pseudomonas syringae are Gram-negative, plant pathogenic bacteria that use a type III secretion system (T3SS) to disarm host immune responses and promote bacterial growth within plant tissues. Despite the critical role for type III secretion in promoting virulence, T3SS-encoding genes are not constitutively expressed by P. syringae and must instead be induced during infection. While it has been known for many years that culturing P. syringae in synthetic minimal media can induce the T3SS, relatively little is known about host signals that regulate the deployment of the T3SS during infection. The recent identification of specific plant-derived amino acids and organic acids that induce T3SS-inducing genes in P. syringae has provided new insights into host sensing mechanisms. This review summarizes current knowledge of the regulatory machinery governing T3SS deployment in P. syringae, including master regulators HrpRS and HrpL encoded within the T3SS pathogenicity island, and the environmental factors that modulate the abundance and/or activity of these key regulators. We highlight putative receptors and regulatory networks involved in linking the perception of host signals to the regulation of the core HrpRS–HrpL pathway. Positive and negative regulation of T3SS deployment is also discussed within the context of P. syringae infection, where contributions from distinct host signals and regulatory networks likely enable the fine-tuning of T3SS deployment within host tissues. Last, we propose future research directions necessary to construct a comprehensive model that (a) links the perception of host metabolite signals to T3SS deployment and (b) places these host–pathogen signaling events in the overall context of P. syringae infection.

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