|Innate immunity is an essential component of the vertebrate antimicrobial defense system. This protection depends on the integrated activity of highly specialized immune cell-types that are responsible for the recognition and clearance of pathogens. One of these fundamental innate cell responses is called phagocytosis (immune cell eating), which involves dynamic remodeling of the plasma membrane during the capture and ingestion of extracellular material. |
Phagocytosis is an ancient cellular process that was established for simple nutrient acquisition in primitive unicellular organisms, but has since evolved into a complex immune defense response utilized by all multicellular animals. Cells that perform phagocytosis are collectively known as phagocytes and their unique ability to engulf large (>0.5 µm) particulate targets is dependent on the expression of distinct immune receptor-types. The best-characterized phagocytic receptors include the mammalian complement receptors (CR), dectin-1, and members of the Fc receptor (FcR) family. Studies from these model immune proteins have identified phagocytosis as a temporally coordinated process that tightly regulates plasma membrane remodelling events during the capture, ingestion, and eventual destruction of microbes. Each phagocytic receptor-type relays extracellular target binding into dynamic filamentous (F)-actin-mediated remodelling of the plasma membrane through specific intracellular signaling events. Despite the recognized diversity in receptor-mediated phagocytic signaling, phagocytic pathways generally require tyrosine kinase activity, localized phospholipid metabolism, activation of Rho-family small GTPases, and the engagement of various actin nucleation and regulatory factors. Importantly, the molecular components that regulate phagocytosis are also vital for many other biological responses, including: cell adhesion and migration, wound repair, and the clearance of debris from tissues. As a result, phagocytosis is not only an excellent model for studying receptor-mediated signaling events in immunity, but also for investigating fundamental aspects of the regulatory machinery involved in the control of plasma membrane dynamics.
Despite an in-depth understanding of phagocytosis in mammals, very little is currently known in basal vertebrates. Interestingly, there are more than 25,000 known species of teleost fishes that thrive in diverse aquatic ecosystems populated with numerous bacterial, parasitic, and viral pathogens. Fish exhibit robust innate immune mechanisms that deal with this continuous assault, including phagocytosis, but how these responses are specifically regulated in ectothermic vertebrates is largely unknown. Genome sequencing has recently revealed a vast inventory of fish immune genes, including a large number and diversity of immune receptor-types. However, the functional roles played by these teleost receptor proteins remains to be determined. In an effort to understand conserved and divergent aspects of innate immune processes across vertebrates, my research has focused on the characterization of channel catfish (Ictalurus punctatus) leukocyte immune-type receptors (IpLITRs). These efforts have recently uncovered new details regarding teleost immunoregulatory-mediated signaling pathways and their functional capabilities.
My ongoing research program uses IpLITR proteins as an innate receptor model system to study immunregulatory receptor signaling events in vertebrates. Please see Featured Publications and the Stafford LAB page for further details about our research.