title: Recombinant TLR5 agonist CBLB502 promotes NK cell-mediated anti-CMV immunity in mice.
abstract: Prior work using allogeneic bone marrow transplantation (allo-BMT) models showed that peritransplant administration of flagellin, a toll-like receptor 5 (TLR5) agonist protected murine allo-BMT recipients from CMV infection while limiting graft-vs-host disease (GvHD). However, the mechanism by which flagellin-TLR5 interaction promotes anti-CMV immunity was not defined. Here, we investigated the anti-CMV immunity of NK cells in C57BL/6 (B6) mice treated with a highly purified cGMP grade recombinant flagellin variant CBLB502 (rflagellin) followed by murine CMV (mCMV) infection. A single dose of rflagellin administered to mice between 48 to 72 hours prior to MCMV infection resulted in optimal protection from mCMV lethality. Anti-mCMV immunity in rflagellin-treated mice correlated with a significantly reduced liver viral load and increased numbers of Ly49H+ and Ly49D+ activated cytotoxic NK cells. Additionally, the increased anti-mCMV immunity of NK cells was directly correlated with increased numbers of IFN-γ, granzyme B- and CD107a producing NK cells following mCMV infection. rFlagellin-induced anti-mCMV immunity was TLR5-dependent as rflagellin-treated TLR5 KO mice had ∼10-fold increased liver viral load compared with rflagellin-treated WT B6 mice. However, the increased anti-mCMV immunity of NK cells in rflagellin-treated mice is regulated indirectly as mouse NK cells do not express TLR5. Collectively, these data suggest that rflagellin treatment indirectly leads to activation of NK cells, which may be an important adjunct benefit of administering rflagellin in allo-BMT recipients.
authors.affiliation: Department of Hematology and Medical Oncology, Division of Stem Cell and Bone Marrow Transplantation, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Hossain
authors.affiliation: Department of Hematology and Medical Oncology, Division of Stem Cell and Bone Marrow Transplantation, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Sampath
authors.initials: S
authors.lastname: Ramachandiran
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia, United States of America.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Gewirtz
authors.affiliation: Department of Hematology and Medical Oncology, Division of Stem Cell and Bone Marrow Transplantation, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
mesh_terms: D000818:Animals; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology*; D005408:Flagellin / Q000235:genetics; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology*; D013997:Time Factors; D051198:Toll-Like Receptor 5 / Q000819:agonists*
chemical_list: C528306:CBLB502; D016207:Cytokines; D055650:NK Cell Lectin-Like Receptor Subfamily A; D010455:Peptides; D011994:Recombinant Proteins; D051198:Toll-Like Receptor 5; D005408:Flagellin