Group B Streptococcus Engages an Inhibitory Siglec through Sialic Acid Mimicry to Blunt Innate Immune and Inflammatory Responses In Vivo

Yung-Chi Chang,Victor Nizet,Christine Tung,Jiquan Zhang,Joshua Olson,Ajit Varki,Paul R Crocker,Federico C Beasley,Michael R Wessels

doi:10.1371/journal.ppat.1003846

Abstract

Group B Streptococcus (GBS) is a common agent of bacterial sepsis and meningitis in newborns. The GBS surface capsule contains sialic acids (Sia) that engage Sia-binding immunoglobulin-like lectins (Siglecs) on leukocytes. Here we use mice lacking Siglec-E, an inhibitory Siglec of myelomonocytic cells, to study the significance of GBS Siglec engagement during in vivo infection. We found GBS bound to Siglec-E in a Sia-specific fashion to blunt NF-κB and MAPK activation. As a consequence, Siglec-E-deficient macrophages had enhanced pro-inflammatory cytokine secretion, phagocytosis and bactericidal activity against the pathogen. Following pulmonary or low-dose intravenous GBS challenge, Siglec-E KO mice produced more pro-inflammatory cytokines and exhibited reduced GBS invasion of the central nervous system. In contrast, upon high dose lethal challenges, cytokine storm in Siglec-E KO mice was associated with accelerated mortality. We conclude that GBS Sia mimicry influences host innate immune and inflammatory responses in vivo through engagement of an inhibitory Siglec, with the ultimate outcome of the host response varying depending upon the site, stage and magnitude of infection.

Highlights

Group B Streptococcus (GBS, S. agalactiae) is a Gram-positive encapsulated bacterium colonizing the vagina of 15–30% of healthy women
GBS binds to murine Sia-binding immunoglobulin-like lectins (Siglecs)-E in a sialic acid (Sia)-dependent manner Siglec-E has been shown to bind a wide range of sialylated lipid probes that have a2,3, a2,6, or a2,8 sialyl linkages in glycan arrays [32]
Corroborating what we found in the localized intranasal pneumonia model, reduced IL-10 transcript production in Siglec-E KO mice was observed after low-dose GBS infection (Figure 2E and 4F)

Summary

Introduction

Group B Streptococcus (GBS, S. agalactiae) is a Gram-positive encapsulated bacterium colonizing the vagina of 15–30% of healthy women. A decrease in the incidence of early-onset GBS disease in many developed countries has occurred following implementation of universal antenatal culture screening and use of intrapartum antibiotic prophylaxis (IAP) [6]. The use of IAP has not had a similar impact on the incidence of late-onset disease, which represents approximately one-third of total cases [6]. Up to 50% of late-onset GBS cases develop meningitis, which carries a very high incidence of neurocognitive sequelae – among survivors 13% had severe, 17% moderate and 18% mild disability at 5 years [7]. Less developed countries reporting no IAP use have an overall a 2.2-fold higher incidence of early-onset infection compared with those reporting any use. Invasive GBS infections occurring in nonpregnant adult populations, especially the elderly and immunecompromised, have been documented with increasing frequency [11,12,13]

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Conclusion