Flagellin is a widespread component found in numerous bacterial species. This protein plays a complex role in the life of bacteria, primarily enabling their movement. Beyond its basic function, flagellin also holds a significant position in the interactions between bacteria and their hosts.
What is Flagellin?
Flagellin is the primary protein subunit that constitutes bacterial flagella, which are long, whip-like appendages extending from the bacterial cell surface. These structures are essential for bacterial motility, allowing them to navigate their environment. Flagellin monomers assemble in a helical pattern to form the hollow cylindrical filament of the flagellum, which can reach lengths of up to 15 micrometers.
The flagellar filament is composed of approximately 30,000 flagellin molecules. Flagellin proteins have a mass of about 40,000 daltons and are highly conserved across different flagellated bacterial species. This conservation is due to the physical constraints imposed by its function in forming the helical structure necessary for movement. The protein is synthesized inside the bacterial cell and then transported through the center of the growing flagellum to its tip, where it polymerizes into the filament.
Flagellin’s Role in Immunity
Flagellin serves as a “Pathogen-Associated Molecular Pattern” (PAMP), a molecular signature that the host immune system recognizes as belonging to pathogens. The immune system detects flagellin primarily through specific receptors, notably Toll-like Receptor 5 (TLR5) and Nod-like Receptors (NLRs). TLR5 is a transmembrane protein expressed on the surface of various immune cells, including epithelial cells, macrophages, and dendritic cells.
When flagellin binds to TLR5, it triggers a signaling pathway, primarily through the adaptor protein MyD88, leading to the activation of immune responses. This activation results in the production of pro-inflammatory cytokines such as IL-6 and TNF-alpha, which are chemical messengers that help coordinate the immune response. Intracellular flagellin can also be recognized by NLRs like NLRC4, which leads to immune activation, including the secretion of IL-1 beta and IL-18. The recognition of flagellin by these receptors is an important part of the innate immune system’s ability to detect and respond to bacterial infections. This dual recognition system, involving both surface and intracellular receptors, makes flagellin a key bacterial signature for immune surveillance.
Emerging Applications of Flagellin
Beyond its natural role in bacterial motility and immune detection, flagellin is being explored for various emerging applications, particularly in medicine. Its strong immune-stimulating properties make it a promising candidate as a vaccine adjuvant. An adjuvant is an ingredient added to a vaccine to enhance the immune response to the vaccine’s antigen, thereby improving its effectiveness. Flagellin’s ability to activate TLR5 and NLRs leads to increased production of cytokines and activation of immune cells, which can boost the body’s protective response against a vaccine’s target.
Flagellin can enhance both humoral immunity, which involves antibody production, and cellular immunity, involving T cells. This property allows for the development of flagellin-antigen fusion proteins, where the vaccine antigen is directly linked to flagellin. Flagellin has been studied as an adjuvant for vaccines against various infectious diseases, including influenza, HIV, and dengue, with some influenza vaccines progressing to clinical trials. Flagellin’s immune-modulating effects are also being investigated for therapeutic uses beyond vaccines, such as in cancer therapy. Introducing flagellin into tumor cells or combining it with tumor antigens has shown potential in enhancing anti-tumor immunity in animal models of various cancers.