Saturday, May 4, 2024
5/4/2024
Pregnancy induced deacetylation of sialylated glycoproteins Abstract. Pregnancy confers susceptibility to severe infection caused by intracellular pathogens, including the prototypical perinatal bacterial pathogen, Listeria monocytogenes (Lm). Residence inside cells has traditionally been thought to be exploited by microbes to evade antibody-mediated immunity since IgG cannot cross the plasma membrane and directly enter cells. Our ongoing studies challenge this paradigm by showing vertically transferred maternal IgG antibodies efficiently protect neonates against Lm infection. The key molecular change enabling protection is deacetylation of terminal sialic acid residues in glycosylated anti-Lm IgG. Expression of the deacetylating enzyme sialic acid acetyl esterase (SIAE) increases during pregnancy. This enzyme is essential since anti-Lm antibodies in SIAE-deficient pregnant mice remain acetylated, and non- protective upon vertical transfer into neonates. Sialylated glycoproteins normally stimulate host cells by binding CD22, an inhibitory Siglec expressed by B cells. However, acetylation blocks CD22 binding, establishing the framework whereby differential acetylation versus deacetylation of sialylated IgG and other glycoproteins can profoundly impact immunity through CD22 binding, which in turn, controls activation and immune-modulatory function of B cells and other cell types with regulatory potential. Although these results significantly broaden the scope for how antibodies work, they also unveil important new knowledge gaps on whether deacetylated IgG similarly protects against infection outside the neonatal window, including during pregnancy with similarly increased susceptibility to Lm systemic infection, and after parturition when deacylated antibodies are still present at high levels. Other questions include the maternal cell types expressing SIAE responsible for antibody protective conversion, and the larger impacts on fetal tolerance and pregnancy outcomes controlled by deacetylation considering many fetal alloantigenic glycoproteins also contain sialylated N-linked glycans. Our overall hypothesis is that SIAE deacetylation unmasks a variety of sialylated glycoproteins as new CD22 ligands, which differentially modulate the suppressive properties of maternal immune cells, with context- dependent impacts on infection susceptibility and pregnancy outcomes. Shared susceptibility to Lm infection during pregnancy in humans and rodents will be exploited to further investigate how deacetylated antibodies work, in concert with fetal alloantigenic glycoproteins, through the following specific aims: Aim 1, determine whether deacetylated IgG protects against Lm systemic infection during pregnancy and after parturition; Aim 2, establish the SIAE-expressing maternal cell subset(s) responsible for IgG protective conversion; Aim 3, investigate how SIAE exposed CD22 ligands control fetal tolerance and pregnancy outcomes. Completion of these aims will not only unveil important insights as to how antibodies protect against intracellular infection, but also new information on the immune-pathogenesis of fetal wastage that occurs with Lm prenatal infection and exciting ways for boosting antimicrobial immunity in this vulnerable physiological window.
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