A Translocated Bacterial Protein Protects Vascular Endothelial Cells from Apoptosis

Abstract

The modulation of host cell apoptosis by bacterial pathogens is of critical importance for the outcome of the infection process. The capacity of Bartonella henselae and B. quintana to cause vascular tumor formation in immunocompromised patients is linked to the inhibition of vascular endothelial cell (EC) apoptosis. Here, we show that translocation of BepA, a type IV secretion (T4S) substrate, is necessary and sufficient to inhibit EC apoptosis. Ectopic expression in ECs allowed mapping of the anti-apoptotic activity of BepA to the Bep intracellular delivery domain, which, as part of the signal for T4S, is conserved in other T4S substrates. The anti-apoptotic activity appeared to be limited to BepA orthologs of B. henselae and B. quintana and correlated with (i) protein localization to the host cell plasma membrane, (ii) elevated levels of intracellular cyclic adenosine monophosphate (cAMP), and (iii) increased expression of cAMP-responsive genes. The pharmacological elevation of cAMP levels protected ECs from apoptosis, indicating that BepA mediates anti-apoptosis by heightening cAMP levels by a plasma membrane–associated mechanism. Finally, we demonstrate that BepA mediates protection of ECs against apoptosis triggered by cytotoxic T lymphocytes, suggesting a physiological context in which the anti-apoptotic activity of BepA contributes to tumor formation in the chronically infected vascular endothelium.

Bacterial Infection of Smad3/Rag2 Double-Null Mice with Transforming Growth Factor-β Dysregulation as a Model for Studying Inflammation-Associated Colon Cancer

“…6 For example, the Gram-negative facultative intracellular pathogen Bartonella is associated with vasoproliferative tumors in humans 55 and utilizes a type IV secretion system to deliver exotoxins that inhibit apoptosis of endothelial cells. 56 Similarly, H. pylori utilizes a type IV secretion system to inject the CagA cytotoxin, which has a number of effects including promotion of cell proliferation and invasion and activation of signaling pathways including NF-B. 25 H. hepaticus has also been found to contain components of a type IV secretion system, 57 suggesting that H. bilis (predominantly used in these studies) may also mediate its effects via a type IV system.…”

Legionella pneumophila inhibits macrophage apoptosis by targeting pro-death members of the Bcl2 protein family

“…Among these, a variety of viruses code for proteins that specifically inhibit host apoptotic pathways to ensure maximal multiplication (1). Similarly, some bacterial pathogens such as Chlamydia trachomatis and Bartonella henselae suppress cell death in infected cells (2,3).…”

Bartonella and Brucella--Weapons and Strategies for Stealth Attack

“…Besides mediating T4SS-dependent translocation into host cells, some BID domains can also directly modulate hostcellular pathways. For instance, the BID domain of BepA promotes apoptosis inhibition and angiogenesis (Schmid et al 2006;Scheidegger et al 2009). The amino-terminal effector domain is best exemplified by the FIC (filamentation induced by cyclic AMP) domain, which is present in some effectors of lineage 3 and most effectors of lineage 4 (Engel et al 2011).…”

“…The VirB T4SS-dependent angiogenesis in B. henselae is the net effect of pro-and antiangiogenic activities of BepA/BepD and BepG, respectively (Scheidegger et al 2009). In a Gasdependent manner, BepA binds adenylyl cyclase, consequently elevating cAMP levels and probably inhibiting NF-kB-dependent caspase activation and DNA fragmentation, two hallmarks of apoptosis (Kirby and Nekorchuk 2002;Schmid et al 2006;. Similar to Bartonella, apoptosis suppression is a characteristic feature of Brucella infection.…”