Specific host genes required for the killing of Klebsiella bacteria by phagocytes

Abstract

SummaryThe amoeba Dictyostelium discoideum shares many traits with mammalian macrophages, in particular the ability to phagocytose and kill bacteria. In response, pathogenic bacteria use conserved mechanisms to fight amoebae and mammalian phagocytes. Here we developed an assay using Dictyostelium to monitor phagocyte-bacteria interactions. Genetic analysis revealed that the virulence of Klebsiella pneumoniae measured by this test is very similar to that observed in a mouse pneumonia model. Using this assay, two new host resistance genes ( PHG1 and KIL1 ) were identified and shown to be involved in intracellular killing of K. pneumoniae by phagocytes. Phg1 is a member of the 9TM family of proteins, and Kil1 is a sulphotransferase. The loss of PHG1 resulted in Dictyostelium susceptibility to a small subset of bacterial species including K. pneumoniae . Remarkably, Drosophila mutants deficient for PHG1 also exhibited a specific susceptibility to K. pneumoniae infections. Systematic analysis of several additional Dictyostelium mutants created a two-dimensional virulence array, where the complex interactions between host and bacteria are visualized.

TM9SF4 is required forDrosophilacellular immunity via cell adhesion and phagocytosis

“…Nonaspanins are divided into two subgroups presenting differential characteristic features in their N-terminal amino acid sequence (Benghezal et al, 2006;Sugasawa et al, 2001). Subgroup I is characterised by a shorter hydrophilic N-terminal sequence and a characteristic motif at position 50 (VGPYxNxQETY) whereas subgroup II contains a longer N-terminal domain (~280 amino acids) and a conserved sequence immediately after the signal peptide (Benghezal et al, 2003).…”

“…A genetic screen identified PHG1A, alteration of which causes a marked decrease in Dictyostelium adhesion to certain substrates and a strong impairment in bacterial phagocytosis and killing (Benghezal et al, 2003;Benghezal et al, 2006;Cornillon et al, 2000). PHG1A encodes a member of the TM9 protein family (also known as nonaspanins or TM9SF) characterised by the presence of nine transmembrane domains, and a high degree of evolutionary conservation (Chluba-de Tapia et al, 1997;Schimmoller et al, 1998).…”

Mathematical modeling of bacterial virulence and host–pathogen interactions in the Dictyostelium/Pseudomonas system

“…Dictyostelium amoebae are soil microorganisms that feed on bacteria and have been utilized to assess the virulence of many different bacterial genera, including Klebsiella (Benghezal et al, 2006), Aeromonas (Froquet et al, 2007) or Pseudomonas (Cosson et al, 2002;Pukatzki et al, 2002). In this model system, pathogenic bacteria defend against predation by Dictyostelium, activating virulence pathways that impede amoeba cells to grow and to form phagocytic plaques.…”

Is Encephalopathy a Mechanism to Renew Sulfate in Autism?

“…The amoeba, Dictyostellum discoldeum, is an effective model of mammalian neutrophils, given its ability to kill and metabolize bacteria as a source of fuel [59]. Experiments with a genetically engineered mutant defective in the protein kil1, which is nearly homologous to a human sulfotransferase, have shown that kil1 is required for efficient killing of Klebsiella pneumoniae.…”