Bacterial Type III Secretion System Effector Proteins are Distinct between Plant Symbiotic, Plant Pathogenic and Animal Pathogenic Bacteria

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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Molecular Targets and Strategies for Inhibition of the Bacterial Type III Secretion System (T3SS); Inhibitors Directly Binding to T3SS Components

Biomolecules ◽

10.3390/biom11020316 ◽

2021 ◽

Vol 11 (2) ◽

pp. 316 ◽

Cited By ~ 1

Author(s):

Julia A. Hotinger ◽

Heather A. Pendergrass ◽

Aaron E. May

Keyword(s):

Type Iii Secretion ◽

Pathogenic Bacteria ◽

Type Iii Secretion System ◽

Systemic Infection ◽

Inhibitory Effect ◽

Secretion System ◽

Effector Proteins ◽

Host Cells ◽

Complex Nature ◽

Type Iii

The type III secretion system (T3SS) is a virulence apparatus used by many Gram-negative pathogenic bacteria to cause infections. Pathogens utilizing a T3SS are responsible for millions of infections yearly. Since many T3SS knockout strains are incapable of causing systemic infection, the T3SS has emerged as an attractive anti-virulence target for therapeutic design. The T3SS is a multiprotein molecular syringe that enables pathogens to inject effector proteins into host cells. These effectors modify host cell mechanisms in a variety of ways beneficial to the pathogen. Due to the T3SS’s complex nature, there are numerous ways in which it can be targeted. This review will be focused on the direct targeting of components of the T3SS, including the needle, translocon, basal body, sorting platform, and effector proteins. Inhibitors will be considered a direct inhibitor if they have a binding partner that is a T3SS component, regardless of the inhibitory effect being structural or functional.

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Faculty Opinions recommendation of Structural and functional similarity between the bacterial type III secretion system needle protein PrgI and the eukaryotic apoptosis Bcl-2 proteins.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1487956.969054 ◽

2010 ◽

Author(s):

Thomas Szyperski

Keyword(s):

Type Iii Secretion ◽

Type Iii Secretion System ◽

Secretion System ◽

Functional Similarity ◽

Type Iii ◽

Needle Protein ◽

Bacterial Type

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Evidence for alternative quaternary structure in a bacterial Type III secretion system chaperone

BMC Structural Biology ◽

10.1186/1472-6807-10-21 ◽

2010 ◽

Vol 10 (1) ◽

pp. 21 ◽

Cited By ~ 14

Author(s):

Michael L Barta ◽

Lingling Zhang ◽

Wendy L Picking ◽

Brian V Geisbrecht

Keyword(s):

Type Iii Secretion ◽

Quaternary Structure ◽

Type Iii Secretion System ◽

Secretion System ◽

Type Iii ◽

Bacterial Type

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Pseudomonas syringae Strains Naturally Lacking the Classical P. syringae hrp/hrc Locus Are Common Leaf Colonizers Equipped with an Atypical Type III Secretion System

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-23-2-0198 ◽

2010 ◽

Vol 23 (2) ◽

pp. 198-210 ◽

Cited By ~ 69

Author(s):

Christopher R. Clarke ◽

Rongman Cai ◽

David J. Studholme ◽

David S. Guttman ◽

Boris A. Vinatzer

Keyword(s):

Pseudomonas Syringae ◽

Type Iii Secretion ◽

Plant Cells ◽

Type Iii Secretion System ◽

Ice Nucleation ◽

Secretion System ◽

Effector Proteins ◽

Population Densities ◽

Type Iii ◽

Effector Genes

Pseudomonas syringae is best known as a plant pathogen that causes disease by translocating immune-suppressing effector proteins into plant cells through a type III secretion system (T3SS). However, P. syringae strains belonging to a newly described phylogenetic subgroup (group 2c) are missing the canonical P. syringae hrp/hrc cluster coding for a T3SS, flanking effector loci, and any close orthologue of known P. syringae effectors. Nonetheless, P. syringae group 2c strains are common leaf colonizers and grow on some tested plant species to population densities higher than those obtained by other P. syringae strains on nonhost species. Moreover, group 2c strains have genes necessary for the production of phytotoxins, have an ice nucleation gene, and, most interestingly, contain a novel hrp/hrc cluster, which is only distantly related to the canonical P. syringae hrp/hrc cluster. This hrp/hrc cluster appears to encode a functional T3SS although the genes hrpK and hrpS, present in the classical P. syringae hrp/hrc cluster, are missing. The genome sequence of a representative group 2c strain also revealed distant orthologues of the P. syringae effector genes avrE1 and hopM1 and the P. aeruginosa effector genes exoU and exoY. A putative life cycle for group 2c P. syringae is discussed.

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An elegant nano-injection machinery for sabotaging the host: Role of Type III secretion system in virulence of different human and animal pathogenic bacteria

Physics of Life Reviews ◽

10.1016/j.plrev.2021.05.007 ◽

2021 ◽

Author(s):

Dipasree Hajra ◽

Abhilash Vijay Nair ◽

Dipshikha Chakravortty

Keyword(s):

Type Iii Secretion ◽

Pathogenic Bacteria ◽

Type Iii Secretion System ◽

Secretion System ◽

Type Iii

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Tethered thiazolidinone dimers as inhibitors of the bacterial type III secretion system

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2009.01.047 ◽

2009 ◽

Vol 19 (5) ◽

pp. 1340-1343 ◽

Cited By ~ 30

Author(s):

Toni Kline ◽

Kathleen C. Barry ◽

Stona R. Jackson ◽

Heather B. Felise ◽

Hai V. Nguyen ◽

...

Keyword(s):

Type Iii Secretion ◽

Type Iii Secretion System ◽

Secretion System ◽

Type Iii ◽

Bacterial Type

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Use of the Galleria mellonella Caterpillar as a Model Host To Study the Role of the Type III Secretion System in Pseudomonas aeruginosa Pathogenesis

Infection and Immunity ◽

10.1128/iai.71.5.2404-2413.2003 ◽

2003 ◽

Vol 71 (5) ◽

pp. 2404-2413 ◽

Cited By ~ 166

Author(s):

Sachiko Miyata ◽

Monika Casey ◽

Dara W. Frank ◽

Frederick M. Ausubel ◽

Eliana Drenkard

Keyword(s):

Pseudomonas Aeruginosa ◽

Type Iii Secretion ◽

Galleria Mellonella ◽

Type Iii Secretion System ◽

Secretion System ◽

Effector Proteins ◽

Triple Mutant ◽

Type Iii ◽

Wax Moth

ABSTRACT Nonvertebrate model hosts represent valuable tools for the study of host-pathogen interactions because they facilitate the identification of bacterial virulence factors and allow the discovery of novel components involved in host innate immune responses. In this report, we determined that the greater wax moth caterpillar Galleria mellonella is a convenient nonmammalian model host for study of the role of the type III secretion system (TTSS) in Pseudomonas aeruginosa pathogenesis. Based on the observation that a mutation in the TTSS pscD gene of P. aeruginosa strain PA14 resulted in a highly attenuated virulence phenotype in G. mellonella, we examined the roles of the four known effector proteins of P. aeruginosa (ExoS, ExoT, ExoU, and ExoY) in wax moth killing. We determined that in P. aeruginosa strain PA14, only ExoT and ExoU play a significant role in G. mellonella killing. Strain PA14 lacks the coding sequence for the ExoS effector protein and does not seem to express ExoY. Moreover, using ΔexoU ΔexoY, ΔexoT ΔexoY, and ΔexoT ΔexoU double mutants, we determined that individual translocation of either ExoT or ExoU is sufficient to obtain nearly wild-type levels of G. mellonella killing. On the other hand, data obtained with a ΔexoT ΔexoU ΔexoY triple mutant and a ΔpscD mutant suggested that additional, as-yet-unidentified P. aeruginosa components of type III secretion are involved in virulence in G. mellonella. A high level of correlation between the results obtained in the G. mellonella model and the results of cytopathology assays performed with a mammalian tissue culture system validated the use of G. mellonella for the study of the P. aeruginosa TTSS.

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