TY - JOUR
T1 - Role of TLR signaling in francisella tularensis-LPS-induced, antibody-mediated protection against francisella tularensis challenge
AU - Cole, Leah E.
AU - Mann, Barbara J.
AU - Shirey, Kari Ann
AU - Richard, Katharina
AU - Yang, Yang
AU - Gearhart, Patricia J.
AU - Chesko, Kirsty L.
AU - Viscardi, Rose M.
AU - Vogel, Stefanie N.
PY - 2011/10
Y1 - 2011/10
N2 - 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- LPSspecific antibody, as well as TLR-mediated macrophage activation, to fully control Francisella infection.
AB - 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- LPSspecific antibody, as well as TLR-mediated macrophage activation, to fully control Francisella infection.
KW - Adjuvants
KW - Antibodies
KW - B cells
KW - Bacterial infection
KW - Macrophage activation
KW - Vaccination
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U2 - 10.1189/jlb.0111014
DO - 10.1189/jlb.0111014
M3 - Article
C2 - 21750122
AN - SCOPUS:80053360280
SN - 0741-5400
VL - 90
SP - 787
EP - 797
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 4
ER -