Francisella tularensis travels a novel, twisted road within macrophages

Abstract

Francisella tularensis is a highly infectious intracellular bacterium that causes fulminating disease and is a potential bioweapon. Although entry of the bacteria into macrophages is mediated by novel asymmetric, spacious pseudopod loops, the nascent phagosome becomes tight fitting within seconds of formation. Biogenesis of the Francisella-containing phagosome (FCP) is arrested for 2-4h at a unique stage within the endosomal-lysosomal degradation pathway, followed by gradual bacterial escape into the cytosol, where the microbe proliferates. By contrast, other intracellular pathogens either proliferate within an idiosyncratic phagosome or escape within minutes into the cytoplasm to avoid degradation. Thus, trafficking of the FCP defies the dogma of classification of intracellular pathogens into vacuolar or cytosolic. The Francisella pathogenicity island and its transcriptional regulator MglA are essential for arresting biogenesis of the FCP. Despite sophisticated microbial strategies to arrest phagosome biogenesis within quiescent macrophages, trafficking of F. tularensis and other intracellular pathogens within interferon-gamma-activated macrophages is similar, in that the bacterial phagosomes fuse to lysosomes. The potential use of F. tularensis as a bioweapon has generated interest in the study of its molecular pathogenesis to identify targets for therapy, vaccination and rapid diagnosis.