Francisella tularensis Live Vaccine Strain Induces Macrophage Alternative Activation as a Survival Mechanism
Year: 2008
Type: article
Abstract: Francisella tularensis (Ft), the causative agent of tularemia, elicits a potent inflammatory response early in infection, yet persists within host macrophages and can be lethal if left unchecked. We report in this study that Ft live vaccine strain (LVS) infection of murine macrophages induced TLR2-dependent expression of alternative activation markers that followed the appearance of classically activated markers. Intraperitoneal infection with Ft LVS also resulted in induction of alternatively activated macrophages (AA-Mphi). Induction of AA-Mphi by treatment of cells with rIL-4 or by infection with Ft LVS promoted replication of intracellular Ftn, in contrast to classically activated (IFN-gamma plus LPS) macrophages that promoted intracellular killing of Ft LVS. Ft LVS failed to induce alternative activation in IL-4Ralpha(-/-) or STAT6(-/-) macrophages and prolonged the classical inflammatory response in these cells, resulting in intracellular killing of Ft. Treatment of macrophages with anti-IL-4 and anti-IL-13 Ab blunted Ft-induced AA-Mphi differentiation and resulted in increased expression of IL-12 p70 and decreased bacterial replication. In vivo, Ft-infected IL-4Ralpha(-/-) mice exhibited increased survival compared with wild-type mice. Thus, redirection of macrophage differentiation by Ft LVS from a classical to an alternative activation state enables the organism to survive at the expense of the host.
Source: The Journal of Immunology
Institution: University of Maryland, Baltimore
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1079889008, G142368768, G2161658832, G2223395877, G255176686, G2776372202, Molecular Mechanisms of IL-4 and IL-13 Signaling, Middle Atlantic Regional Center for Excellence for Biodefense and Emerging Infect, G5769833972, DIFFERENTIATIVE SIGNALS FOR MACROPHAGE ACTIVATION, G6416108813, MOLECULAR MECHANISM OF IL4 SIGNALING
OpenAlex ID: W1560892967