Dectin-1 is an innate immune receptor expressed by myeloid phagocytes such as macrophages and dendritic cells that is essential for effective host defense against fungal infections. Dectin-1 recognizes the ?-1,3-glucan polysaccharide that makes up as much as half the dry weight of fungal cell walls, and activation of the receptor triggers phagocytosis, production of microbicidal reactive oxygen species, and production of a host of pro- inflammatory cytokines. Dectin-1 is one of only a few receptors so far shown to be sufficient for triggering phagocytosis, and it has thus become an important model for understanding how such receptors work. This renewal project focuses on further understanding the mechanisms of Dectin-1 signaling. We have previously shown that upon binding to fungal cells Dectin-1 is concentrated into a "phagocytic synapse" that permits activation of inflammatory signaling. We have further shown that Dectin-1 signaling leads to formation of phagosomes that recruit LC3, a protein that is well-known to participate in autophagy, but its role on traditional phagosomes is less clear. We have shown that LC3 recruitment to phagosomes enhances processing and presentation of antigens from these compartments on MHCII, and other investigators have shown that these phagosomes are more microbicidal. In addition, we and others have observed that Dectin-1 signaling drives activation of the inflammasome, a complex that facilitates processing and secretion of the pro- inflammatory cytokine IL-1?. This signal requires CARD9 and caspase-8 activity, features that appear to be unique to Dectin-1. In this project, we will define this model signaling pathway in three aims.
In aim one, we will define the mechanisms by which Dectin-1 signaling and LC3 influence phagosome maturation in order to favor efficient presentation of antigens in vitro and in vivo.
In aim two we will determine the mechanisms by which Dectin-1 signaling and phagocytosis lead to activation of an unusual Card9-related inflammasome for inflammatory cytokine production and explore the role of this process in activation of immune responses in vitro and in vivo.
In aim 3 we will explore the role of "LC3-associated phagocytosis" and Card9-related inflammasome activation during infection of mice with the prevalent human fungal pathogens Candida albicans and Aspergillus fumigatus.
Innate immune receptors recognize microbial pathogens and initiate local and systemic inflammatory responses that are essential for host defense. Dectin-1 is one such receptor, and it is important for recognizing fungal pathogens. In this project, we are characterizing the novel cellular and molecular mechanisms by which this receptor becomes activated and triggers appropriate immune responses.
|Ma, Jun; Becker, Courtney; Reyes, Christopher et al. (2014) Cutting edge: FYCO1 recruitment to dectin-1 phagosomes is accelerated by light chain 3 protein and regulates phagosome maturation and reactive oxygen production. J Immunol 192:1356-60|
|YÃ¡Ã±ez, Alberto; Hassanzadeh-Kiabi, Nargess; Ng, Madelena Y et al. (2013) Detection of a TLR2 agonist by hematopoietic stem and progenitor cells impacts the function of the macrophages they produce. Eur J Immunol 43:2114-25|
|Ma, Jun; Underhill, David M (2013) *-Glucan signaling connects phagocytosis to autophagy. Glycobiology 23:1047-51|
|Iliev, Iliyan D; Funari, Vincent A; Taylor, Kent D et al. (2012) Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 336:1314-7|
|Ma, Jun; Becker, Courtney; Lowell, Clifford A et al. (2012) Dectin-1-triggered recruitment of light chain 3 protein to phagosomes facilitates major histocompatibility complex class II presentation of fungal-derived antigens. J Biol Chem 287:34149-56|
|Goodridge, Helen S; Reyes, Christopher N; Becker, Courtney A et al. (2011) Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'. Nature 472:471-5|
|Goodridge, Helen S; Shimada, Takahiro; Wolf, Andrea J et al. (2009) Differential use of CARD9 by dectin-1 in macrophages and dendritic cells. J Immunol 182:1146-54|