Coxiella burnetii modulates Beclin 1 and Bcl-2, preventing host cell apoptosis to generate a persistent bacterial infection

Abstract

Coxiella burnetii is the etiological agent of the human disease, Q fever, and is an obligate intracellular bacterium that invades and multiplies in a vacuole with lysosomal characteristics. We have previously shown that Coxiella interacts with the autophagic pathway as a strategy for its survival and replication. In addition, recent studies have shown that Coxiella exerts anti-apoptotic activity to maintain the host cell viability, thus generating a persistent infection. In the present report, we have explored the role of Beclin 1 and Bcl-2 in C. burnetii infection to elucidate how this bacterium modulates autophagy and apoptosis to its own benefit. Beclin 1, a Bcl-2 interacting protein, is required for autophagy. In this study, we show that Beclin 1 is recruited to the Coxiella-membrane vacuole, favoring its development and bacterial replication. In contrast, the anti-apoptotic protein Bcl-2 alters the normal development of the Coxiella-replicative compartment, in spite of also being recruited to the vacuole membrane. Furthermore, both vacuole development and the anti-apoptotic effect of C. burnetii are affected by Beclin 1 depletion and by the expression of a Beclin 1 mutant defective in Bcl-2 binding. Overall, these findings indicate that C. burnetii infection modulates autophagy and apoptotic pathways through Beclin 1/Bcl-2 interplay to establish a successful infection in the host cell.

ATRA-induced upregulation of Beclin 1 prolongs the life span of differentiated acute promyelocytic leukemia cells

“…Beclin 1 mutant with defective Bcl-2 binding, suggesting that the interaction of Beclin 1 and Bcl-2 may modulate apoptosis. 33 These results support the idea, that under some circumstances, the BH3-only domain of Beclin 1 may competitively disrupt the binding of pro-apoptotic proteins (e.g., Bad) to Bcl-2 or Bcl-X L , thus avoiding the induction of apoptosis. Paradoxically, the results of Ciechomska et al showed that the binding of Beclin 1 to Bcl-2 does not modify the Bcl-2-mediated protection against apoptotic stimuli that initiates endoplasmic reticulum or mitochondria death signaling pathways.…”

“…Because Beclin 1 plays a pivotal function in the regulation of cell death processes, 16,[31][32][33] we further investigated whether this protein plays a role in the viability of APL cells differentiated by ATRA. For this study, we downregulated Beclin 1 expression by using a specific siRNA that targets BECN1, and then evaluated autophagy and apoptosis during ATRA treatment of NB4 cells.…”

Coxiella burnetii Phase I and II Variants Replicate with Similar Kinetics in Degradative Phagolysosome-Like Compartments of Human Macrophages

“…Because multiple laboratories have recently employed avirulent NMII to investigate C. burnetii infection of host cells (1,30,38,50,54), it is important to ascertain the degree to which in vitro infection by NMII recapitulates infection by virulent NMI, particularly with respect to PV maturation in human mononuclear phagocytes. To this end, we directly compared the growth kinetics and PV maturation of NMI and NMII in human monocyte-derived macrophages (HMDMs) and phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells, which accurately mimic the properties of human primary macrophages (29).…”

Apoptosis in Normal and Coxiella burnetii–Infected Placentas From Alaskan Northern Fur Seals (Callorhinus ursinus)

“…10 The mechanism for survival includes both altered expression of genes involved in apoptosis as well as increasing and blocking production of anti-and proapoptotic proteins respectively. 7,9,10 Increased apoptosis during disease states has been shown to be detrimental to the fetal viability, 6 but the significance of decreased apoptosis for NFS reproductive health and pup mortality is less clear. While placentas were collected from presumably successful live pup births, 4 nothing is known about the survival of the pup beyond placental detachment.…”