Microbiology Select

Pathogens and their hosts have been in an evolutionary arms race for millions of years, and much has been learned about the strategies each has developed to stay on top. This Select focuses on recent papers reporting new insights into the mechanisms used by pathogens to stay in the race, either by hijacking host proteins and cellular pathways or, in one case, by hitching a ride on an insect vector to move from host to host. Legionella pneumophila, the bacterium that causes Legionnaires' pneumonia , is taken up by alveolar macrophages after being inhaled. L. pneumonia bypasses the macrophage's lysosomal network and replicates in an intracel-lular vacuole that recruits vesicles from the host cell's endoplasmic reticulum (ER). Vesicle recruitment depends on the bacterial proteins SidM/DrrA and LidA, which target the host's small GTPase Rab1 to the vacuole. Rab1 is an important regulator of ER to Golgi vesicle transport. Two recent studies (Ingmundson et al., 2007; Machner and Isberg, 2007) now report that the SidM/DrrA exerts a dual function to take control of the host cell's Rab1. First, SidM/DrrA displaces the Rab1 inhibitor GDI (guanine nucleotide dissociation inhibitor) and then acts as a GDP/GTP exchange factor (GEF) for Rab1. SidM/ DrrA therefore encompasses both activities that are required for Rab1 activation. SidM/DrrA also recruits Rab1 to the membrane of the Legionella vacuole. Machner and Isberg provide evidence that the GDI dissociation induced by SidM/DrrA is a prerequisite for LidA to bind to Rab1. They find that LidA is unable to recruit Rab1 to the Legionella vacuole in the absence of SidM/DrrA's GDI displacement activity, implying that the two bacterial proteins act in sequence. Meanwhile, Ingmundson et al. identify another Legionella protein LepB as a downstream effector of Rab1. The authors find that LepB acts as a Rab1 GTPase-activating protein (GAP) and is associated with late Legionella vacuoles, which have recruited ER vesicles. They propose that SidM/DrrA first causes Rab1 activation and recruitment to the pathogen vacuole where Rab1 then mediates fusion of ER vesicles with the vacuole. In late vacuoles, SidM/DrrA disappears from the membrane and LepB could inactivate Rab1 by stimulating its GTPase activity, which coincides with the dissociation of Rab1 from the membrane. The two papers provide evidence that a certain order of events is crucial during early stages of infection with Legionella, suggesting that therapeutic interference with these steps might provide an opportunity to stop this deadly infection …