Abstract
Flagellins evoke strong innate and adaptive immune responses. These proteins may play a key role as radioprotectors, exert antitumoral activity in certain types of tumor and reduce graft-versus-host disease in allogeneic hematopoietic stem cell transplant recipients. Notwithstanding, flagellins are highly immunogenic, and repeated use leads to their neutralization by systemic antibodies. This neutralization is not prevented by using functional deleted flagellins. These observations led us to explore the possibility of preventing initial neutralization by means of another functional flagellin that does not belong to common pathogenic bacteria but that has the capacity to activate TLR5. Here we characterized the functional capacity of the two-phase Marinobacter algicola (MA)-derived flagellins (F and FR) as systemic and mucosal adjuvants and compared their performance with that of Salmonella typhimurium (STF) flagellins (FljB and FliC). We also report for the first time on the in vitro and in vivo capacity of various flagellins to trigger TLR5 activation in the presence of species-specific anti-flagellin antibodies, the cross-neutralization mediated by these antibodies, and the sequential use of these flagellins for TLR5 activation. Our results showed that MA flagellins behave in a similar way to STF ones, inducing pro-inflammatory cytokines (IL8, CCL20, CCL2) and evoking a strong in vivo antibody response against a model epitope. More importantly, MA flagellins were fully functional, in vitro or in vivo, in the presence of a high concentration of neutralizing anti-flagellin STF antibodies, and STF flagellin was not inhibited by neutralizing anti-flagellin MA antibodies. The use of active flagellins from distinct bacteria could be a useful approach to prevent systemic neutralization of this group of adjuvants and to facilitate the rational design of flagellin-based vaccines and/or other therapeutic treatments (against ischemia, acute renal failure, tumors, ionizing radiations and also to improve the outcome of bone marrow transplants).
Highlights
Flagellin proteins are the major structural component of the flagellum, an appendage that confers motility to bacteria [1]
Here we studied the functionality and behavior of the flagellins from Marinobacter algicola (MA), a non-pathogenic bacteria isolated from the marine medium that can be grown in safe conditions
Our results demonstrated that MA flagellins have a similar capacity to Salmonella typhimurium flagellin (STF) ones regarding Toll-like receptor 5 (TLR5) activation, as shown by the induction of similar levels of cytokine expression (IL8, CCL2, CCL20)
Summary
Flagellin proteins are the major structural component of the flagellum, an appendage that confers motility to bacteria [1]. Some flagellins have the capacity to activate the Toll-like receptor 5 (TLR5), which is present at the surface of epithelial, osteoblasts, antigen-presenting cells (APC), and immune cells [2,3,4]. Flagellininduced TLR5 activation leads to signal transduction pathways that involve NF-kb, which trigger the expression of cytokines and co-stimulatory molecules [5,6], increasing both humoral and cell-mediated immune responses [7,8,9,10]. Decreasing ischemia and acute renal failure [14,15].
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