Okujava, R, Guye, P, Lu, Y, Mistl, C, Polus, F, Vayssier-Taussat, M, Halin, C, Rolink, AG and Dehio, C (2014) A Translocated Effector Required for Bartonella Dissemination from Derma to Blood Safeguards Migratory Host Cells from Damage by Co-translocated Effectors. PLoS Pathogens.

Abstract

Numerous bacterial pathogens secrete multiple effectors to modulate host cellular functions. These effectors may interfere with each other to efficiently control the infection process. Bartonellae are Gram-negative, facultative intracellular bacteria using a VirB type IV secretion system to translocate a cocktail of Bartonella effector proteins (Beps) into host cells. Based on in vitro infection models we demonstrate here that BepE protects infected migratory cells from injurious effects triggered by BepC and is required for in vivo dissemination of bacteria from the dermal site of inoculation to blood. Human endothelial cells (HUVECs) infected with a bepE mutant of B. henselae (Bhe) displayed a cell fragmentation phenotype resulting from Bep-dependent disturbance of rear edge detachment during migration. A bepCE mutant did not show cell fragmentation, indicating that BepC is critical for triggering this deleterious phenotype. Complementation of bepE with BepE<sub>Bhe</sub> or its homologues from other Bartonella species abolished cell fragmentation. This cyto-protective activity is confined to the C-terminal Bartonella intracellular delivery (BID) domain of BepE<sub>Bhe</sub> (BID2.E<sub>Bhe</sub>). Ectopic expression of BID2.E<sub>Bhe</sub> impeded the disruption of actin stress fibers by Rho Inhibitor 1, indicating that BepE restores normal cell migration via the RhoA signaling pathway, a major regulator of rear edge retraction. An intradermal (i.d.) model for B. tribocorum (Btr) infection in the rat reservoir host mimicking the natural route of infection by blood sucking arthropods allowed demonstrating a vital role for BepE in bacterial dissemination from derma to blood. While the Btr mutant bepDE was abacteremic following i.d. inoculation, complementation with BepE<sub>Btr</sub>, BepE<sub>Bhe</sub> or BIDs.E<sub>Bhe</sub> restored bacteremia. Given that we observed a similar protective effect of BepE<sub>Bhe</sub> on infected bone marrow-derived dendritic cells migrating through a monolayer of lymphatic endothelial cells we propose that infected dermal dendritic cells may be involved in disseminating Bartonella towards the blood stream in a BepE-dependent manner. 2014 Okujava et al

Item Type:	Article
Additional Information:	NIBR author: institute: NIBR contributor address: (Okujava, Guye, Lu, Mistl, Polus, Dehio) Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland (Vayssier-Taussat) Unite Sous Contrat Bartonella, Institut national de la recherche agronomique (INRA), Maisons-Alfort, France (Halin) Institute of Pharmaceutical Sciences, ETH, Zurich, Switzerland (Rolink) Department of Biomedicine (DBM), University of Basel, Basel, Switzerland (Guye) Division of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, United States (Polus) Novartis Pharma AG, Novartis Institutes for BioMedical Research, Basel, Switzerland
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/23426