Grants and Contracts Details
Description
Human granulocytic anaplasmosis (HGA; formerly human granulocytic ehrlichiosis) is an emerging and
potentially fatal disease and the second most common tick-borne infection in the United States. The
etiologic agent is Anaplasma phagocytophilum, an obligate intracellular bacterium that displays a unique
tropism for neutrophils and neutrophil precursors. A. phagocytophilum adhesion to neutrophil surfaces
involves recognition of P-selectin glycoprotein ligand-1 (PSGL-1) and sialyl Lewis x (sLex), a tetrasaccharide
that modifies the N-terminus of PSGL-1 and other selectin ligands. Specifically, this recognition requires
interactions with a PSGL-1 N-terminal peptide and alpha 2,3-linked sialic acid and alpha 1,3-linked fucose of
sLex. We hypothesize that A. phagocytophilum uses multiple adhesins that cooperatively bind these
determinants. Studies of A. phagocytophilum and other Anaplasmataceae family members suggest the A.
phagocytophilum PSGL-1/ sLex-targeting adhesins are induced late in development and may require
glycosylation and multimerization into adhesin complexes for proper function. The objective of this proposal
is to identify and characterize the individual adhesins that recognize PSGL-1, sialic acid, and fucose. The
specific aims are: (1) identify candidate adhesins using affinity-based approaches; (2) identify adhesin
candidates as upregulated or glycosylated outer membrane proteins; (3) test binding of putative adhesins to
PSGL-1/ sLex glycoconjugates and cell surfaces. We have selected for an A. phagocytophilum adhesin
variant, the adhesion of which is PSGL-1- and sialic acid-independent, but remains fucose-dependent. This
variant will simplify identification of the fucose-specific adhesin and will aid adhesin hunting assays by
circumventing the reliance of wild-type A. phagocytophilum on cooperative binding. Accomplishing these
goals will shed light onto novel themes of bacteria-host cell interactions and will identify targets for treating or
preventing HGA. Furthermore, these studies may lead to the development of new treatments for inhibiting
cellular adhesion events associated with inflammatory disorders.
Status | Finished |
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Effective start/end date | 7/15/07 → 10/31/07 |
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