Modulation of the E-cadherin in human cells infected in vitro with Coxiella burnetii.

High concentration of soluble E-cadherin (E-cad) was previously found in sera from Q fever patients. Here, BeWo cells which express a high concentration of E-cad were used as an in vitro model to investigate the expression and function of E-cad in response to infection by Coxiella burnetii, the etiological agent of Q fever. Infection of BeWo cells with C. burnetii leads to a decrease in the number of BeWo cells expressing E-cad at their membrane. A shedding of soluble E-cad was associated with the post-infection decrease of membrane-bound E-cad. The modulation of E-cad expression requires bacterial viability and was not found with heat-inactivated C. burnetii. Moreover, the intracytoplasmic cell concentration of ß-catenin (ß-cat), a ligand of E-cad, was reduced after bacterial infection, suggesting that the bacterium induces modulation of the E-cad/ß-cat signaling pathway and CDH1 and CTNNB1 genes transcription. Finally, several genes operating the canonical Wnt-Frizzled/ß-cat pathway were overexpressed in cells infected with C. burnetii. This was particularly evident with the highly virulent strain of C. burnetii, Guiana. Our data demonstrate that infection of BeWo cells by live C. burnetii modulates the E-cad/ß-cat signaling pathway.

T-Bet Controls Susceptibility of Mice to Coxiella burnetii Infection.

T-bet is a transcription factor known to initiate and coordinate the gene expression program during Th1 differentiation, which is crucial for clearance of intracellular pathogens. Q fever is a worldwide zoonosis caused by Coxiella burnetii. This bacterium is transmitted to humans by aerosol. Indeed, the inhibition of the Coxiella-specific adaptive Th1 immune response leads to persistent infection and organ injury. How deficiency of T-bet affects host infection by C. burnetii has not been investigated. Here, using mice with a deletion of the T-bet gene and an airborne mode of infection to reproduce the natural conditions of C. burnetii infection, we show that infected T-bet-/- mice were more affected than wild-type mice. The lack of T-bet leads to defective bacterial control, intense replication, persistent infection, and organ injury manifesting as an increased number of granulomas. The absence of T-bet was also associated with an impaired immune response. Indeed, the production of the immunomodulatory cytokines interleukin (IL)-6 and IL-10 was increased, whereas the expression of microbicidal genes by splenocytes was impaired. Moreover, the absence of T-bet exhibited impaired production of interferon-γ, the principal cytokine released by Th1 effector cells. Thus, our study highlights the key role of T-bet in the control of C. burnetii infection in mice and leads to a reappraisal of granulomas in the pathogenesis of Q fever disease.

High Concentrations of Serum Soluble E-Cadherin in Patients With Q Fever.

Cadherins switching is a hallmark of neoplasic processes. The E-cadherin (E-cad) subtype is one of the surface molecules regulating cell-to-cell adhesion. After its cleavage by sheddases, a soluble fragment (sE-cad) is released that has been identified as a pro-carcinogenic inflammatory signal in several bacteria-induced cancers. Recently we reported that Q fever, a disease due to Coxiella burnetii infection, can be complicated by occurrence of non-Hodgkin lymphoma (NHL). Therefore, we studied E-cad switching in Q fever. The sE-cad levels were found increased in the sera of acute and persistent Q fever patients, whereas they remained at the baseline in controls groups of healthy donors, people cured of Q fever, patients suffering from unrelated inflammatory diseases, and past Q fever patients who developed NHL. These results indicate that sE-cad can be considered as a new biomarker of C. burnetii infection rather than a marker of NHL-associated to Q fever. We wondered if changes in sE-cad reflected variations in the CDH1 gene transcription. The expression of E-cad mRNA and its intracellular ligand ß-catenin was down-regulated in peripheral blood mononuclear cells (PBMCs) of patients with either acute or persistent forms of Q fever. Indeed, a lower cell-surface expression of E-cad was measured in a minority (<5%) subpopulation of HLADR+/CD16+ monocytes from patients with acute Q fever. However, a very strong increase in E-cad expression was observed on more than 30% of the HLADR+/CD16+ monocytes of persistent Q fever patients, a cell subpopulation known to be a target for C. burnetii in humans. An experimental in vitro infection of healthy donors' PBMCs with C. burnetii, was performed to directly evaluate the link between C. burnetii interaction with PBMCs and their E-cad expression. A significant increase in the percentage of HLADR+/CD16+ monocytes expressing E-cad was measured after PBMCs had been incubated for 8 h with C. burnetii Nine Mile strain. Altogether, these data demonstrate that C. burnetii severely impairs the E-cad expression in circulating cells of Q fever patients.