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.
Highlights
CMV infection is usually asymptomatic in immune-competent healthy individuals, but may cause severe disease in immunecompromised BMT, HIV-infected AIDS, and elderly patients [1]
To study the mechanism by which flagellin confers protection from murine CMV (mCMV) infection without the immunological complexity created by allo-transplantation, we studied the effects of rflagellin-treatment in non-transplanted WT B6 mice infected with lethal dose of mCMV
Using an established mouse model of mCMV infection, we have explored the mechanism by which rflagellin enhances anti-mCMV immunity of NK cells
Summary
CMV infection is usually asymptomatic in immune-competent healthy individuals, but may cause severe disease in immunecompromised BMT, HIV-infected AIDS, and elderly patients [1]. Tabeta et al showed that innate antimCMV immunity is mostly controlled TLR9- and TLR3dependent signaling during the early phase of infection, and others have shown that flagellin enhances the activation and proliferation of NK cells [6,7]. We have previously shown that prophylactic administration of native flagellin, a TLR5 agonist protein extracted from the flagella of Salmonella typhimurium, protected allo-BMT recipients both from GvHD and lethal CMV infection [8]. Administration of rflagellin reduced radiation-induced toxicity in mice and nonhuman primates [13,14], but the role of flagellin-TLR5 interactions in the anti-MCMV immunity of NK cells has not been described. The present study was undertaken to elucidate the mechanism by which rflagellin-TLR5 regulates NK cells immunity in mice infected with a lethal inoculum of mCMV
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