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 ΔbepE mutant of B. henselae (Bhe) displayed a cell fragmentation phenotype resulting from Bep-dependent disturbance of rear edge detachment during migration. A ΔbepCE mutant did not show cell fragmentation, indicating that BepC is critical for triggering this deleterious phenotype. Complementation of ΔbepE with BepEBhe 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 BepEBhe (BID2.EBhe). Ectopic expression of BID2.EBhe 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 ΔbepDE was abacteremic following i.d. inoculation, complementation with BepEBtr, BepEBhe or BIDs.EBhe restored bacteremia. Given that we observed a similar protective effect of BepEBhe 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.
Highlights
Pathogenic bacteria have evolved a multitude of virulence factors in order to manipulate the host to evade immune responses and to reach their replicative niche - a safe compartment to proliferate that is a prerequisite for transmissibility [1]
A striking example is BepE, which is shown here to preserve endothelial cells (ECs) from fragmentation and to inhibit the defects of dendritic cell (DCs) migration caused by BepC and possibly other Bartonella effector proteins (Beps)
BepE is essential for Bartonella dissemination from the dermal site of inoculation to the blood stream where bacteria establish long-lasting intraerythrocytic bacteremia as a hallmark of infection in the mammalian reservoir host
Summary
Pathogenic bacteria have evolved a multitude of virulence factors in order to manipulate the host to evade immune responses and to reach their replicative niche - a safe compartment to proliferate that is a prerequisite for transmissibility [1]. Numerous effector proteins of Salmonella type III secretion systems (T3SS) SPI1 and SPI2 [1] and Shigella T3SS play a critical role in invasion of non-phagocytic intestinal cells, for further dissemination and modulation of the host inflammatory responses [4,5]. In addition to targeting the host cellular components, some bacteria have evolved effectors that regulate an activity of each other at a specific stage of the host invasion; like Legionella Dot/Icm ‘‘metaeffector’’ LubX mediates the degradation of SidH. This interplay may happen in an indirect fashion as for many cases of T4SS/T3SS effectors [6]
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