<scp>d</scp> -Alanylation of Teichoic Acids Promotes Group A <i>Streptococcus</i> Antimicrobial Peptide Resistance, Neutrophil Survival, and Epithelial Cell Invasion

<jats:title>ABSTRACT</jats:title> <jats:p> Group A streptococcus (GAS) is a leading cause of severe, invasive human infections, including necrotizing fasciitis and toxic shock syndrome. An important element of the mammalian innate defense system against invasive bacterial infections such as GAS is the production of antimicrobial peptides (AMPs) such as cathelicidins. In this study, we identify a specific GAS phenotype that confers resistance to host AMPs. Allelic replacement of the <jats:italic>dltA</jats:italic> gene encoding <jats:sc>d</jats:sc> -alanine- <jats:sc>d</jats:sc> -alanyl carrier protein ligase in an invasive serotype M1 GAS isolate led to loss of teichoic acid <jats:sc>d</jats:sc> -alanylation and an increase in net negative charge on the bacterial surface. Compared to the wild-type (WT) parent strain, the GAS Δ <jats:italic>dltA</jats:italic> mutant exhibited increased susceptibility to AMP and lysozyme killing and to acidic pH. While phagocytic uptake of WT and Δ <jats:italic>dltA</jats:italic> mutants by human neutrophils was equivalent, neutrophil-mediated killing of the Δ <jats:italic>dltA</jats:italic> strain was greatly accelerated. Furthermore, we observed the Δ <jats:italic>dltA</jats:italic> mutant to be diminished in its ability to adhere to and invade cultured human pharyngeal epithelial cells, a likely proximal step in the pathogenesis of invasive infection. Thus, teichoic acid <jats:sc>d</jats:sc> -alanylation may contribute in multiple ways to the propensity of invasive GAS to bypass mucosal defenses and produce systemic infection. </jats:p>