The Uptake of Apoptotic Cells Drives Coxiella burnetii Replication and Macrophage Polarization: A Model for Q Fever Endocarditis

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. Infective endocarditis (IE) is a problem of public health that still causes high mortality despite antibiotic treatments. Most of the patients who develop an IE have pre-existing cardiac lesions, although the relationship between IE and valvulopathy is not clearly understood. We showed here that patients with valvulopathy exhibited increased levels of circulating apoptotic leukocytes. 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. The binding of apoptotic lymphocytes to monocytes and macrophages increased the replication of C. burnetii by stimulating their anti-inflammatory response. In contrast, the binding of necrotic lymphocytes to monocytes and macrophages induced C. burnetii killing and stimulated an inflammatory response. Interferon-γ, which is associated with the control of C. burnetii infection, prevented the replication of C. burnetii in monocytes and macrophages that have bound apoptotic lymphocytes by stimulating their inflammatory response. In conclusion, 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.