Discovering a sialic acid independent ligand for paired receptors Siglec-5 and -14 (1003.5)

Siglec-5 and Siglec-14 are sialic acid (Sia)-binding immunoreceptors found on myeloid lineage cells. Despite having identical ligand binding domains due to gene conversion, Siglec-5 inhibits inflammatory responses after ligand engagement, but Siglec-14 activates it instead. This unusual combination defines Siglec-5 and -14 as paired receptors. Since sialoglycan ligands for Siglec-5 are widely distributed on host cell surfaces, this is hypothesized to be a self-recognition mechanism to prevent innate immune cells from attacking “self.” However, some bacterial pathogens take advantage of this self-recognition system by engaging Siglec-5, in order to suppress immune responses. Thus, it is hypothesized that Siglec-14 emerged to counteract these “hijacking” pathogens. Although this model of Siglec-14 evolution predicts uni-directional gene conversion between Siglec-5 and -14, the ligand binding domains of these receptors had undergone bi-directional gene conversion instead. Also Siglec-5 and -14 of some nonhuman primates have independently lost the ability to bind Sias due to a mutation in the Sia recognizing pocket. Thus, these receptors may have evolved to engage a Sia independent endogenous ligand. Preliminary evidence indicates that that such a ligand exists. Ongoing experiments are addressing whether this putative ligand-receptor interaction modulates the pro-inflammatory response. Grant Funding Source: Supported by NHLBI P01 HL057345