Sialic acids (Sias) presented at the distal ends of vertebrate glycan chains mediate many biological roles,including binding by intrinsic Sia-recognizing receptors called Siglecs (Sia-recognizing Ig-like lectins). Wehave hypothesized that the CD33-related subset of Siglecs (CD33rSiglecs) in primates and rodentsrecognize host Sias as 'self, thereby dampening the reactivity of immune cells. We also hypothesize thatSia-expressing bacterial pathogens take advantage of this mechanism to down-regulate innate immunereactivity against them. We earlier discovered a human-specific evolutionary loss of the commonmammalian Sia N-glycolylneuraminic acid (NeuSGc). This would have resulted in loss of optimalCD33rSiglec ligands. A variety of human-specific genetic changes and adjustments in these lectinsapparently then ensued, leaving the human immune system in an altered state relative to that of our greatape evolutionary relatives. The biological and pathological consequences of these differences are beingstudied by comparing humans and great apes, but many practical, ethical and fiscal issues limit thisapproach. We therefore propose to use transgenic mice to model and compare human and chimpanzeesialic acid and CD33rSiglec biology, elucidating functional consequences resulting from genetic changesduring human evolution. The overall hypothesis being tested is that the human propensity to developinflammatory diseases involving innate and adaptive immune cells, as well as infections by Sia-expressingbacteria are related to human-specific evolutionary changes in certain CD33rSiglecs. These include humanspecificchanges in Sia-binding properties of Siglec-9 on neutrophils and monocytes; in the bindingproperties, expression and function of Siglec-11 and -12 on macrophages; of Siglec-11 on human brainmicroglia, and the selective down-regulation of Siglec-5 on human T cells. We will use a variety ofgenetically modified mice to mimic the ancestral human condition of constitutive CD33rSiglec 'unmasking' inmyelomonocytic cells; the current functional states of human and chimpanzee Siglec-9; human-specificchanges in Siglec-11 and -12 on macrophages; human-specific Siglec-11 expression in microglia; and, theancestral great ape state of Siglec-5 expression on T lymphocytes. These studies will be done in wild-typemice, and in strains deficient in the relevant murine CD33rSiglecs. Appropriate studies of innate andadaptive immune responses as well as challenges with Sia-expressing bacterial pathogens will test theoriginal hypotheses. These studies involve collaborations with other program members and utilize all Coreservices in the program. Importantly, even if some of the taken approaches fail to accurately mirror humanevolution, the results will illuminate various general underlying principles regarding the biology ofCD33rSiglecs on innate and adaptive immune blood cells.
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