Sialylated antibody defense against intracellular infections
Abstract. Division of labor between humoral and cellular adaptive immune components for effective host
defense is a foundational immunological tenet. Antibodies are thought to offer limited protection against
intracellular pathogens since they cannot efficiently cross the plasma membrane to enter most cells, which
may explain the prevalence of intracellular infections in fetuses and newborns given their dependence on
vertically transferred maternal IgG for early life immunity. However, we recently demonstrated that pregnancy
enables antibody-mediated protection against the prototypical intracellular pathogen Listeria monocytogenes
(Lm). The key molecular change during pregnancy is deacetylation of sialic acid (Sia) located in the terminal
position of N-glycans on preconceptually primed Lm-specific IgG. Maternal deacetylated IgG then modulates
neonatal B cells via the Sia receptor CD22, which can only bind to deacetylated Sia. This establishes a
framework whereby differential acetylation versus deacetylation of sialylated IgG serves as a previously
unrecognized molecular “switch” that greatly impacts immunity through CD22, which in turn controls responder
B cell activation and immunomodulatory functions. While our findings reshape paradigms of antibody-mediated
host defense, they also unveil several important new gaps in knowledge, including mechanisms responsible for
addition of a six-atom, acetyl group to IgG Sia to purposefully “switch off” CD22-mediated protection. This
includes the enzymatic machinery required to add acetylated Sia to IgG N-glycans, as well as factors
controlling germinal center responses leading to production of acetylated IgG. Additionally, the subset of
neonatal CD22+ B lymphocytes that respond to “switched on” deacetylated IgG and how these B cells
modulate other immune cells are unclear. Our overall hypothesis is that overturning maternal B cell Sia
acetylation allows deacetylated IgG to bind to CD22 on neonatal Breg, suppressing their IL10 production, and
enabling protection against intracellular infection. Shared susceptibility to Lm infection between human and
rodent neonates will be exploited to further investigate how deacetylated IgG is formed and mediates
protection, through the following specific aims. Aim 1, define cell-specific control of antibody sialic acid
acetylation; Aim 2, interrogate how germinal center suppression drives antibody sialic acid acetylation; Aim 3,
investigate neonatal B cell IL10 inhibition of antibody-mediated protection. Aims 1 and 2, therefore, will
interrogate antibody secreting B cells as producers of “switched off” acetylated IgG, while Aim 3 will investigate
“switched on” deacetylated IgG modulation of IL10-poducing Breg. Completion of these aims will expand our
understanding of how to control antibody sialylation and acetylation to boost host defense against intracellular
infections, informing design of novel vaccine strategies and antibody-based therapeutics given the ubiquity of
antibody glycosylation.