The C‐terminal extension of VgrG4 from Klebsiella pneumoniae remodels host cell microfilaments

Abstract

Klebsiella pneumoniae is an opportunistic pathogen, which concerns public health systems worldwide, as multiple antibiotic-resistant strains are frequent. One of its pathogenicity factors is the Type VI Secretion System (T6SS), a macromolecular complex assembled through the bacterial membranes. T6SS injects effector proteins inside target cells. Such effectors confer competitive advantages or modulate the target cell signaling and metabolism to favor bacterial infection. The VgrG protein is a T6SS core component. It may present a variable C-terminal domain carrying an additional effector function. Kp52.145 genome encodes three VgrG proteins, one of them with a C-terminal extension (VgrG4-CTD). VgrG4-CTD is 138 amino acids long, does not contain domains of known function, but is conserved in some Klebsiella, and non-Klebsiella species. To get insights into its function, recombinant VgrG4-CTD was used in pulldown experiments to capture ligands from macrophages and lung epithelial cells. A total of 254 proteins were identified: most of them are ribosomal proteins.Cytoskeleton-associated and proteins involved in the phagosome maturation pathway were also identified. We further showed that VgrG4-CTD binds actin and induces actin remodeling in macrophages. This study presents novel clues on the role of K. pneumoniae T6SS in pathogenesis.bacterium-host interactions, cytoskeleton, protein-protein interactions, proteomics, T6SS | INTRODUCTIONKlebsiella pneumoniae is a gram-negative encapsulated member of the Enterobacteriaceae family. This species is ubiquitous in nature, and frequently associated with animals and humans. 1 On one hand, there are the classical pathogenic strains mainly affecting immune-compromised or hospitalized individuals, causing infections in the urinary and respiratory tracts, as well as bacteremia. Frequently, those strains are multiple antibiotic-resistant. 2 In another hand, there are hypervirulent strains that may cause acute community-acquired infections.

Role of Klebsiella pneumoniae Type VI secretion system (T6SS) in long-term gastrointestinal colonization

“…Indeed, the effect on other microbiota members (fungi) and host cells 21 remains to be investigated 46 . T6SS eukaryotic-targeting effectors could enhance pathogen virulence by modulating host epithelial cell integrity or protecting themselves from innate immune response 56 . Overcoming colonization resistance by T6SS related to modulation of host response during infection, making T6SS an efficient virulence factor for pathogens 25 .…”

The Biological and Regulatory Role of Type VI Secretion System of Klebsiella pneumoniae

“…In addition, there is a variable C-terminal region in these proteins that often provides an effector function. 34 The spike complex commonly consists of a trimer of VgrG proteins and a spike complex protein (PAAR) containing proline-alanine-alanine-arginine repeats. 27,35,36 The needle structure (Hcp-VgrG-PAAR structure) is identified as the only part of T6SS that advances into the target cells.…”