IFN-γ-Mediated Control of Coxiella burnetii Survival in Monocytes: The Role of Cell Apoptosis and TNF

Abstract

The treatment of infectious diseases caused by intracellular bacteria, such as Q fever, may benefit from cytokines acting on macrophages. Monocytic THP-1 cells were infected with Coxiella burnetii, the etiological agent of Q fever, and then treated with IFN-γ. While C. burnetii multiplied in untreated monocytes, IFN-γ reduced bacterial viability after 24 h of treatment and reached maximum inhibition after 96 h. IFN-γ also affected the viability of infected cells. Cell death resulted from apoptosis; occurring 24 h after the addition of IFN-γ, it reached a maximum after 48 h and was followed by necrosis. Reactive oxygen intermediates were not required for C. burnetii killing, since monocytes from patients with chronic granulomatous disease were microbicidal in response to IFN-γ. The role of cytokines was also investigated. IFN-γ elicited a moderate release of IL-1β in infected monocytes. Moreover, the IL-1 receptor antagonist did not affect C. burnetii survival, suggesting that IL-1β was not involved in the bacterial killing induced by IFN-γ. TNF was involved in IFN-γ-induced killing of C. burnetii and cell death. IFN-γ induced mRNA expression and sustained secretion of TNF. Neutralizing Abs to TNF as well as Abs directed against TNF receptors I and II, significantly prevented IFN-γ-dependent killing of C. burnetii and cell death. These results suggest that IFN-γ promotes the killing of C. burnetii in monocytes through an apoptotic mechanism mediated in part by TNF.