Role of TLR signaling in Francisella tularensis-LPS-induced, antibody-mediated protection against Francisella tularensis challenge

Journal of Leukocyte Biology

Leah E. Cole¹  Kirsty L. Chesko–⁵  Kari Ann Shirey¹  Patricia J. Gearhart³  Stefanie N. Vogel¹  Katharina Richard¹  Rose M. Viscardi– and⁵  Barbara J. Mann⁴  Yang Yang² 

[1] Departments of Microbiology and Immunology and –Pediatrics, University of Maryland, Baltimore, School of Medicine, Baltimore, Maryland, USA;Department of Genetics, School of Medicine, Stanford University, Stanford, California, USA;Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA –Pediatrics, University of Maryland, Baltimore, School of Medicine, Baltimore, Maryland, USA; Departments of Medicine and Microbiology, University of Virginia Health Systems, Charlottesville, Virginia, USA;–Pediatrics, University of Maryland, Baltimore, School of Medicine, Baltimore, Maryland, USA;

关键词: B cells;    bacterial infection;    antibodies;    vaccination;    macrophage activation;    adjuvants;   

DOI  :  10.1189/jlb.0111014

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Immunization with Ft-LPS provokes an antigen-specific, B-1a cell-derived antibody response that protects WT mice against an otherwise lethal challenge with Ft LVS. However, this same regimen offers limited protection to TLR2−/− mice, despite production of WT levels of anti-Ft-LPS antibodies. As Ft-LPS exhibits no TLR2 agonist activity, and macrophage-induced cytokine production in response to Ft LVS is overwhelmingly TLR2-dependent, we hypothesized that treatment of TLR2−/− mice with an alternative, MyD88-dependent TLR agonist would compensate for reduced recognition of Ft LVS in TLR2−/− mice and thereby, restore Ft-LPS-mediated protection. Administration of the nontoxic TLR4 agonist, synthetic Escherichia coli MPL, at the time of Ft-LPS immunization or Ft LVS challenge, fully protected TLR2−/− mice, whereas treatment of WT or TLR2−/− mice with MPL alone conferred partial protection. The TLR5 agonist, flagellin, also synergized with Ft-LPS to protect TLR2−/− mice from lethal Ft LVS challenge. In contrast to Ft LVS, Ft-LPS pretreatment failed to protect mice against i.n. challenge with Ft Schu S4, whereas MPL, administered in the absence or presence of Ft-LPS, conferred significant, albeit partial, protection. MPL treatment of macrophages increased the uptake of Ft LVS and decreased intracellular bacterial survival while shifting the macrophage-differentiation phenotype from “alternatively activated” to “classically activated”. Collectively, our data suggest that optimal, Ft-LPS-mediated protection against Ft LVS infection requires two discrete events, i.e., production of Ft-LPS-specific antibody, as well as TLR-mediated macrophage activation, to fully control Francisella infection.

【 授权许可】

Unknown