Anaplasma phagocytophilum Outer Membrane Protein A Interacts with Sialylated Glycoproteins To Promote Infection of Mammalian Host Cells

Ojogun, Nore; Kahlon, Amandeep Kaur; Ragland, Stephanie A.; Troese, Matthew J.; Mastronunzio, Juliana E.; Walker, Naomi J.; VieBrock, Lauren; Thomas, Russell J.; Borjesson, Dori L.; Fikrig, Erol; Carlyon, Jason A.

doi:10.1128/iai.00654-12

Cited by 58 publications

(157 citation statements)

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“…Given the demonstrated roles of A. phagocytophilum and E. chaffeensis OmpA proteins in promoting infection of mammalian host cells (17,19,21), we sought to determine if AmOmpA performs a similar adhesin function for A. marginale. An alignment of ApOmpA and AmOmpA revealed that the two exhibit 52.33% sequence identity (17).…”

Section: Resultsmentioning

confidence: 99%

“…Recombinant ApOmpA binds to host cells, confers adhesiveness and invasiveness to inert beads, and acts as a competitive agonist to inhibit A. phagocytophilum infection in vitro (17,18), confirming that it alone is sufficient to mediate binding and uptake. ApOmpA functionally depends on a lysine and a glycine in its essential linear binding domain that interacts with ␣2,3-sialic acid and ␣1,3-fucose of the Lewis antigen receptor, sialyl Lewis x (sLe x ; NeuAc␣2,3Gal␤1,4[Fuc␣1,3]GlcNac), on myeloid cells and 6-sulfo-sialyl Lewis x (6-sulfo-sLe x ; NeuAc␣2,3Gal␤1-4[Fuc␣1,3] HSO 3 3,6GlcNac) on endothelial cells (17,18). Antibodies raised against full-length ApOmpA or its 16-residue binding domain inhibit A. phagocytophilum infection of host cells (18).…”

mentioning

confidence: 94%

“…Indeed, we discovered that A. phagocytophilum OmpA (ApOmpA) is one of a trio of adhesins that cooperatively function to mediate optimal bacterial binding to and invasion of host cells (17,18,20,21). Recombinant ApOmpA binds to host cells, confers adhesiveness and invasiveness to inert beads, and acts as a competitive agonist to inhibit A. phagocytophilum infection in vitro (17,18), confirming that it alone is sufficient to mediate binding and uptake. ApOmpA functionally depends on a lysine and a glycine in its essential linear binding domain that interacts with ␣2,3-sialic acid and ␣1,3-fucose of the Lewis antigen receptor, sialyl Lewis x (sLe x ; NeuAc␣2,3Gal␤1,4[Fuc␣1,3]GlcNac), on myeloid cells and 6-sulfo-sialyl Lewis x (6-sulfo-sLe x ; NeuAc␣2,3Gal␤1-4[Fuc␣1,3] HSO 3 3,6GlcNac) on endothelial cells (17,18).…”

mentioning

confidence: 99%

“…OmpA is highly conserved among A. marginale sensu stricto strains and isolates, exhibiting 99.6 to 100% identity (14). Clues pertaining to the role of A. marginale OmpA (AmOmpA) are provided by recent studies demonstrating the importance of OmpA proteins to cellular invasion by A. phagocytophilum and Ehrlichia chaffeensis, two Anaplasmataceae members that cause potentially fatal infections of humans and animals (17)(18)(19). Indeed, we discovered that A. phagocytophilum OmpA (ApOmpA) is one of a trio of adhesins that cooperatively function to mediate optimal bacterial binding to and invasion of host cells (17,18,20,21).…”

mentioning

confidence: 99%

“…Clues pertaining to the role of A. marginale OmpA (AmOmpA) are provided by recent studies demonstrating the importance of OmpA proteins to cellular invasion by A. phagocytophilum and Ehrlichia chaffeensis, two Anaplasmataceae members that cause potentially fatal infections of humans and animals (17)(18)(19). Indeed, we discovered that A. phagocytophilum OmpA (ApOmpA) is one of a trio of adhesins that cooperatively function to mediate optimal bacterial binding to and invasion of host cells (17,18,20,21). Recombinant ApOmpA binds to host cells, confers adhesiveness and invasiveness to inert beads, and acts as a competitive agonist to inhibit A. phagocytophilum infection in vitro (17,18), confirming that it alone is sufficient to mediate binding and uptake.…”

mentioning

confidence: 99%

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Anaplasma marginale Outer Membrane Protein A Is an Adhesin That Recognizes Sialylated and Fucosylated Glycans and Functionally Depends on an Essential Binding Domain

et al. 2017

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Anaplasma marginale causes bovine anaplasmosis, a debilitating and potentially fatal tick-borne infection of cattle. Because A. marginale is an obligate intracellular organism, its adhesins that mediate entry into host cells are essential for survival. Here, we demonstrate that A. marginale outer membrane protein A (AmOmpA; AM854) contributes to the invasion of mammalian and tick host cells. AmOmpA exhibits predicted structural homology to OmpA of A. phagocytophilum (ApOmpA), an adhesin that uses key lysine and glycine residues to interact with ␣2,3-sialylated and ␣1,3-fucosylated glycan receptors, including 6-sulfo-sialyl Lewis x (6-sulfo-sLe x ). Antisera against AmOmpA or its predicted binding domain inhibits A. marginale infection of host cells. Residues G55 and K58 are contributory, and K59 is essential for recombinant AmOmpA to bind to host cells. Enzymatic removal of ␣2,3-sialic acid and ␣1,3-fucose residues from host cell surfaces makes them less supportive of AmOmpA binding. AmOmpA is both an adhesin and an invasin, as coating inert beads with it confers adhesiveness and invasiveness. Recombinant forms of AmOmpA and ApOmpA competitively antagonize A. marginale infection of host cells, but a monoclonal antibody against 6-sulfo-sLe x fails to inhibit AmOmpA adhesion and A. marginale infection. Thus, the two OmpA proteins bind related but structurally distinct receptors. This study provides a detailed understanding of AmOmpA function, identifies its essential residues that can be targeted by blocking antibody to reduce infection, and determines that it binds to one or more ␣2,3-sialylated and ␣1,3-fucosylated glycan receptors that are unique from those targeted by ApOmpA.

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