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The Burkholderia Type VI Secretion System 5: Composition, Regulation and Role in Virulence.

ABSTRACT: The soil saprophyte and Tier I select agent Burkholderia pseudomallei can cause rapidly fatal infections in humans and animals. The capability of switching to an intracellular life cycle during infection appears to be a decisive trait of B. pseudomallei for causing disease. B. pseudomallei harbors multiple type VI secretion systems (T6SSs) orthologs of which are present in the surrogate organism Burkholderia thailandensis. Upon host cell entry and vacuolar escape into the cytoplasm, B. pseudomallei and B. thailandensis manipulate host cells by utilizing the T6SS-5 (also termed T6SS1) to form multinucleated giant cells for intercellular spread. Disruption of the T6SS-5 in B. thailandensis causes a drastic attenuation of virulence in wildtype but not in mice lacking the central innate immune adapter protein MyD88. This result suggests that the T6SS-5 is deployed by the bacteria to overcome innate immune responses. However, important questions in this field remain unsolved including the mechanism underlying T6SS-5 activity and its physiological role during infection. In this review, we summarize the current knowledge on the components and regulation of the T6SS-5 as well as its role in virulence in mammalian hosts.

SUBMITTER: Lennings J

PROVIDER: S-EPMC6335564 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The Burkholderia Type VI Secretion System 5: Composition, Regulation and Role in Virulence.

Lennings Jan J West T Eoin TE Schwarz Sandra S

Frontiers in microbiology 20190110

The soil saprophyte and Tier I select agent Burkholderia pseudomallei can cause rapidly fatal infections in humans and animals. The capability of switching to an intracellular life cycle during infection appears to be a decisive trait of B. pseudomallei for causing disease. B. pseudomallei harbors multiple type VI secretion systems (T6SSs) orthologs of which are present in the surrogate organism Burkholderia thailandensis. Upon host cell entry and vacuolar escape into ...[more]

PMID: 30687298

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Project description:Bacterial pathogens utilize a myriad of mechanisms to invade mammalian hosts, damage tissue sites, and evade the immune system. One essential strategy of Gram-negative bacteria is the secretion of virulence factors through both inner and outer membranes to reach a potential target. Most secretion systems are harbored in mobile elements including transposons, plasmids, pathogenicity islands, and phages, and Escherichia coli is one of the more versatile bacteria adopting this genetic information by horizontal gene transfer. Additionally, E. coli is a bacterial species with members of the commensal intestinal microbiota and pathogens associated with numerous types of infections such as intestinal, urinary, and systemic in humans and other animals. T6SS cluster plasticity suggests evolutionarily divergent systems were acquired horizontally. T6SS is a secretion nanomachine that is extended through the bacterial double membrane; from this apparatus, substrates are conveyed straight from the cytoplasm of the bacterium into a target cell or to the extracellular space. This nanomachine consists of three main complexes: proteins in the inner membrane that are T4SS component-like, the baseplate complex, and the tail complex, which are formed by components evolutionarily related to contractile bacteriophage tails. Advances in the T6SS understanding include the functional and structural characterization of at least 13 subunits (so-called core components), which are thought to comprise the minimal apparatus. So far, the main role of T6SS is on bacterial competition by using it to kill neighboring non-immune bacteria for which antibacterial proteins are secreted directly into the periplasm of the bacterial target after cell-cell contact. Interestingly, a few T6SSs have been associated directly to pathogenesis, e.g., roles in biofilm formation and macrophage survival. Here, we focus on the advances on T6SS from the perspective of E. coli pathotypes with emphasis in the secretion apparatus architecture, the mechanisms of pathogenicity of effector proteins, and the events of lateral gene transfer that led to its spread.

Project description:BackgroundKlebsiella pneumoniae (KP) is an opportunistic pathogen that mainly causes respiratory and urinary tract infections. The frequent occurrence of simultaneously virulent and multiple drug-resistant isolates led WHO to include this species in the list of top priorities for research and development of therapeutic alternatives. The comprehensive knowledge of the molecular mechanisms underlying KP virulence may lead to the proposal of more efficient and specific drugs. One of its virulence factors is the Type VI Secretion System (T6SS), which contributes to bacterial competition, cell invasion and in vivo colonisation. Despite the few studies showing the involvement of T6SS in KP pathogenesis, little is known concerning the regulation of its expression. The understanding of regulatory mechanisms may give more clues about the function of the system and the possibilities of future interference in this process. This work aimed to standardise the annotation of T6SS genes in KP strains and identify mechanisms of their transcriptional regulation through computational predictions.ResultsWe analyzed the genomes of Kp52.145, HS11286 and NTUH-K2044 strains to perform a broad prediction and re-annotation of T6SS genes through similarity searches, comparative and linear discriminant analysis. 38 genes were found in Kp52.145, while 29 in HS11286 and 30 in NTUH-K2044. Genes coding for iron uptake systems are encoded in adjacencies of T6SS, suggesting that KP T6SS might also play a role in ion import. Some of the T6SS genes are comprised in syntenic regions. 17 sigma 70-dependent promoter regions were identified in Kp52.145, 12 in HS11286 and 12 in NTUH-K2044. Using VirtualFootprint algorithm, binding sites for 13 transcriptional regulators were found in Kp52.145 and 9 in HS11286 and 17 in NTUH-K2044. Six of them are common to the 3 strains: OxyR, H-NS, RcsAB, GcvA, Fis, and OmpR.ConclusionsThe data presented herein are derived from computational analysis. Although future experimental studies are required to confirm those predictions, they suggest that KP T6SS might be regulated in response to environmental signals that are indeed sensed by the bacteria inside the human host: temperature (H-NS), nutrition-limitation (GcvA and Fis), oxidative stress (OxyR) and osmolarity (RscAB and OmpR).

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The Burkholderia Type VI Secretion System 5: Composition, Regulation and Role in Virulence.

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The <i>Burkholderia</i> Type VI Secretion System 5: Composition, Regulation and Role in Virulence.

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