Convergent evolution of innate immune-modulating effectors in invasive fungal pathogens.

Invasive fungal infections pose a major threat to human health. Bacterial and protozoan pathogens secrete protein effectors that overcome innate immune barriers to promote microbial colonization, yet few such molecules have been identified in human fungal pathogens. Recent studies have begun to reveal these long-sought effectors and have illuminated how they subvert key cellular pathways, including apoptosis, myeloid cell polarization, Toll-like receptor signaling, and phagosome action. Thus, despite lacking the specialized secretion systems of bacteria and parasites, it is increasingly clear that fungi independently evolved effectors targeting pathways often subverted by other classes of pathogens. These findings demonstrate the remarkable power of convergent evolution to enable diverse microbes to infect humans while also setting the stage for detailed dissection of fungal disease mechanisms.

Cholesterol glucosylation by Helicobacter pylori delays internalization and arrests phagosome maturation in macrophages.

BACKGROUND/PURPOSE: Helicobacter pylori colonizes the human stomach and contributes to chronic inflammation of the gastric mucosa. H. pylori persistence occurs because of insufficient eradication by phagocytic cells. A key factor of H. pylori, cholesterol-α-glucosyltransferase encoded by capJ that extracts host cholesterol and converts it to cholesteryl glucosides, is important to evade host immunity. Here, we examined whether phagocytic trafficking in macrophages was perturbed by capJ-carrying H. pylori. METHODS: J774A.1 cells were infected with H. pylori at a multiplicity of infection of 50. Live-cell imaging and confocal microscopic analysis were applied to monitor the phagocytic trafficking events. The viability of H. pylori inside macrophages was determined by using gentamicin colony-forming unit assay. The phagocytic routes were characterized by using trafficking-intervention compounds. RESULTS: Wild type (WT) H. pylori exhibited more delayed entry into macrophages and also arrested phagosome maturation more than did capJ knockout mutant. Pretreatment of genistein and LY294002 prior to H. pylori infection reduced the internalization of WT but not capJ-knockout H. pylori in macrophages. CONCLUSION: Cholesterol glucosylation by H. pylori interferes with phagosome trafficking via a lipid-raft and PI3K-dependent manner, which retards engulfment of bacteria for prolonged intracellular survival of H. pylori.