Abstract
Patients with valvulopathy have the highest risk to develop infective endocarditis (IE), although the relationship between valvulopathy and IE is not clearly understood. Q fever endocarditis, an IE due to Coxiella burnetii, is accompanied by immune impairment. Patients with valvulopathy exhibited increased levels of circulating apoptotic leukocytes, as determined by the measurement of active caspases and nucleosome determination. The binding of apoptotic cells to monocytes and macrophages, the hosts of C. burnetii, may be responsible for the immune impairment observed in Q fever endocarditis. Apoptotic lymphocytes (AL) increased C. burnetii replication in monocytes and monocyte-derived macrophages in a cell-contact dependent manner, as determined by quantitative PCR and immunofluorescence. AL binding induced a M2 program in monocytes and macrophages stimulated with C. burnetii as determined by a cDNA chip containing 440 arrayed sequences and functional tests, but this program was in part different in monocytes and macrophages. While monocytes that had bound AL released high levels of IL-10 and IL-6, low levels of TNF and increased CD14 expression, macrophages that had bound AL released high levels of TGF-β1 and expressed mannose receptor. The neutralization of IL-10 and TGF-β1 prevented the replication of C. burnetii due to the binding of AL, suggesting that they were critically involved in bacterial replication. In contrast, the binding of necrotic cells to monocytes and macrophages led to C. burnetii killing and typical M1 polarization. Finally, interferon-γ corrected the immune deactivation induced by apoptotic cells: it prevented the replication of C. burnetii and re-directed monocytes and macrophages toward a M1 program, which was deleterious for C. burnetii. We suggest that leukocyte apoptosis associated with valvulopathy may be critical for the pathogenesis of Q fever endocarditis by deactivating immune cells and creating a favorable environment for bacterial persistence.
Highlights
Infective endocarditis (IE) has long been recognized as a fatal disease
As the binding of apoptotic cells to monocytes and macrophages is known to inhibit their inflammatory activity, we hypothesized that the high levels of circulating apoptotic leukocytes may be responsible for the immune impairment observed in Q fever endocarditis, an IE due to Coxiella burnetii, a bacterium that survives in monocytes and macrophages
We suggest that leukocyte apoptosis associated with valvulopathy may be critical for the pathogenesis of Q fever endocarditis by deactivating immune cells and creating a favorable environment for pathogen persistence
Summary
Infective endocarditis (IE) has long been recognized as a fatal disease. Despite the availability of antimicrobial agents and cardiac surgery, IE still causes high morbidity and mortality. About 75% of patients with IE have pre-existing cardiac diseases [1], including congenital cardiac malformations, acquired valvular dysfunction and prosthetic cardiac valves [2]. Normal endocardium is resistant to colonization by bacteria [3] unless it exhibits pre-existing lesions. Lesions expose underlying extracellular matrix proteins and enable deposition of fibrin-platelet clots [4], bacterial adhesion [5] and recruitment of monocytes, which produce tissue factor and inflammatory cytokines [6]: this usually leads to the growth of vegetation. Cardiac valve lesions are associated with pathological fluid shear stress [7]. Fluid shear stress modifies the structure and the function of the endothelium [8] and increases apoptosis of neutrophils [9], platelets [10] and monocytes (Mo) [11], suggesting that leukocyte apoptosis may be related to cardiac valvulopathy
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