O-Acetylation of sialic acid on Group B<i>Streptococcus</i>inhibits neutrophil suppression and virulence

Weiman, Shannon; Uchiyama, Satoshi; Lin, Feng; Chaffin, Donald O.; Varki, Ajit; Nizet, Victor; Lewis, Amanda L.

doi:10.1042/bj20100232

Cited by 36 publications

(45 citation statements)

References 46 publications

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“…Site-specific mutation of a GBS O-acetylesterase has facilitated genetic control of O-acetylation levels (here referred to as GBS-hiOAc [80% of total surface sialic acids modified] and GBS-loOAc [ϳ2% of total surface sialic acids modified]) (29). Previous studies have shown that O-acetylation does not impact GBS complement evasion but does impede sialic acid-Siglec-9 engagement and thus attenuates bacterial evasion of human neutrophils (57,58). Murine neutrophils express a homolog of human Siglec-9 called Siglec-E.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously characterized a naturally occurring GBS capsule modification (sialic acid Oacetylation), which is expressed at low to moderate levels in all tested serotypes (30,58). Site-specific mutation of a GBS O-acetylesterase has facilitated genetic control of O-acetylation levels (here referred to as GBS-hiOAc [80% of total surface sialic acids modified] and GBS-loOAc [ϳ2% of total surface sialic acids modified]) (29).…”

Section: Resultsmentioning

confidence: 99%

“…GBS strains that overexpress wild-type NeuA (⌬neuA/pneuA or COH1 wild type/pneuA) express indistinguishable levels of sialic acids with minimal O-acetylation (GBS-loOAc), whereas a point mutation in NeuA leads to hyper-O-acetylation of sialic acids (⌬neuA/pneuA301; GBS-hiOAc). These strains have been extensively characterized (29,30,57,58). The acapsular GBS strain was previously described and compared in our experiments to the parent wild-type strain (64).…”

Section: Ethics Statementmentioning

confidence: 99%

“…Recent studies demonstrated that GBS surface sialic acids interact with host sialic acid binding immunoglobulin-like lectins (Siglecs), a family of surface receptors that are expressed on immune cells (5). Interactions between GBS sialic acids and human polymorphonuclear leukocyte (PMN) Siglec-9 lead to reduced PMN bactericidal functions and limit GBS killing, whereas modification of GBS sialic acids with high levels of O-acetylation impairs Siglec-9 binding and neutrophil suppression (6,57,58).…”

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confidence: 99%

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Immune Activation and Suppression by Group B Streptococcus in a Murine Model of Urinary Tract Infection

et al. 2011

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Group B streptococcus (GBS) is a common commensal of the gastrointestinal and vaginal mucosa and a leading cause of serious infections in newborns, the elderly, and immunocompromised populations. GBS also causes infections of the urinary tract. However, little is known about host responses to GBS urinary tract infection (UTI) or GBS virulence factors that participate in UTI. Here we describe a novel murine model of GBS UTI that may explain some features of GBS urinary tract association in the human host. We observed high titers and heightened histological signs of inflammation and leukocyte recruitment in the GBS-infected kidney. However, extensive inflammation and leukocyte recruitment were not observed in the bladder, suggesting that GBS may suppress bladder inflammation during cystitis. Acute GBS infection induced the localized expression of proinflammatory cytokines interleukin-1␣ (IL-1␣), macrophage inflammatory protein-1␣ (MIP-1␣), MIP-1␤, and IL-9, as well as IL-10, more commonly considered an anti-inflammatory cytokine. Using isogenic GBS strains with different capsule structures, we show that capsular sialic acid residues contribute to GBS urinary tract pathogenesis, while high levels of sialic acid O-acetylation attenuate GBS pathogenesis in the setting of UTI, particularly in direct competition experiments. In vitro studies demonstrated that GBS sialic acids participate in the suppression of murine polymorphonuclear leukocyte (PMN) bactericidal activities, in addition to reducing levels of IL-1␣, tumor necrosis factor alpha, IL-1␤, MIP-1␣, and KC produced by PMNs. These studies define several basic molecular and cellular events characterizing GBS UTI in an animal model, showing that GBS participates simultaneously in the activation and suppression of host immune responses in the urinary tract.Group B streptococcus (GBS) is the leading cause of bacterial sepsis and meningitis in human newborns and is increasingly associated with invasive infections in adult populations such as pregnant women, diabetics, and the elderly (11,16,48,65). GBS colonizes the gastrointestinal and vaginal mucosa of approximately 30% of individuals tested at a given time and nearly 2/3 of those tested at multiple intervals over a year (35). While GBS colonization occurs asymptomatically, localized infections of the skin, lungs, and urinary tract are associated with progression to serious systemic infections in individuals with a compromised or underdeveloped immune system (4,16,48,65). For example, vaginal colonization in late pregnancy is associated with vertical transmission of GBS in utero due to ascending amniotic infection or by aspiration of contaminated vaginal fluids during delivery. Pneumonia, sepsis, and meningitis are potential complications of GBS transmission to the neonate, reflecting an array of bacterial virulence factors that act to impede phagocytic clearance, resulting in host tissue injury (10). Much of what is known about GBS virulence has been defined in animal models of systemic infection (18,20,23,25,28,4...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Ethics Statementmentioning

confidence: 99%

mentioning

confidence: 99%

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Immune Activation and Suppression by Group B Streptococcus in a Murine Model of Urinary Tract Infection

et al. 2011

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“…For instance, acetylation can alter the molecular conformation (41) and increase the viscosity (42) of polysaccharides. Acetylation can also create and/or alter epitopes targeted by immune molecules, such as antibodies (16,43), lectins (10,44), and enzymes (45). Further, acetylation increases resistance to hypochlorite, an oxidizing agent produced in neutrophils (46).…”

Section: Discussionmentioning

confidence: 99%

Position of O-Acetylation within the Capsular Repeat Unit Impacts the Biological Properties of Pneumococcal Serotypes 33A and 33F

et al. 2017

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Streptococcus pneumoniae (pneumococcus) produces many capsule types that differ in their abilities to evade host immune recognition. To explain these serotypedependent protective capacities, many studies have investigated capsular thickness or the interaction of the capsule with complement proteins, but the effects of small chemical modifications of the capsule on its function have not been studied. One small chemical modification found frequently among pneumococcal capsules is O-acetylation. Pneumococcal serotype 33A has two membrane-bound O-acetyltransferase genes, wciG and wcjE. A 33A wcjE-deficient variant, 33F, occurs naturally and is increasing in prevalence in the wake of widespread conjugate vaccine use, but no wciG-deficient variants have been reported. To study the biological consequence of the loss of O-acetylation, we created wciG-deficient variants in both serotypes 33A and 33F, which we named 33X1 (ΔwciG) and 33X2 (ΔwciG ΔwcjE). Serotypes 33X1 and 33X2 express novel capsule types based on serological and biochemical analyses. We found that loss of WcjE-mediated O-acetylation appears not to affect cell wall shielding, since serotypes 33A and 33F exhibit comparable nonspecific opsonophagocytic killing, biofilm production, and adhesion to nasopharyngeal cells, though serotype 33F survived short-term drying better than serotype 33A. Loss of WciG-mediated O-acetylation in serotypes 33X1 and 33X2, however, resulted in a phenotype resembling that of nonencapsulated strains: increased cell wall accessibility, increased nonspecific opsonophagocytic killing, enhanced biofilm formation, and increased adhesion to nasopharyngeal cells. We conclude that WciG-mediated, but not WcjE-mediated, O-acetylation is important for producing protective capsules in 33A and that small chemical changes to the capsule can drastically affect its biological properties.KEYWORDS O-acetyltransferase, O-acetylation, capsular diversity, pneumococcal vaccine, capsular polysaccharide, serotype S treptococcus pneumoniae (pneumococcus) is an important human pathogen that can colonize the nasopharynx asymptomatically and disseminate opportunistically to cause pneumonia, meningitis, septicemia, and otitis media. The pneumococcus has a polysaccharide capsule, and 98 distinct capsular types (serotypes) have been identified based on chemical differences in their capsular repeat units (1-3). These chemical differences are mediated by genetic changes in the capsular polysaccharide synthesis (cps) operon (4) and result in different reactivities with anti-capsule antibodies. The capsule is essential for pneumococcal virulence (5), since it shelters pneumococci from complement fixation and opsonophagocytosis (6). However, differences in capsule type have been shown to affect complement fixation and virulence (7).

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Exploration of Sialic Acid Diversity and Biology Using Sialoglycan Microarrays

2013

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Sialic acids (Sias) are a group of α-keto acids with a nine-carbon backbone, which display many types of modifications in nature. The diversity of natural Sia presentations is magnified by a variety of glycosidic linkages to underlying glycans, the sequences and classes of such glycans, as well as the spatial organization of Sias with their surroundings. This diversity is closely linked to the numerous and varied biological functions of Sias. Relatively large libraries of natural and unnatural Sias have recently been chemically/chemoenzymatically synthesized and/or isolated from natural sources. The resulting sialoglycan microarrays have proved to be valuable tools for the exploration of diversity and biology of Sias. Here we provide an overview of Sia diversity in nature, the approaches used to generate sialoglycan microarrays, and the achievements and challenges arising.

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O-Acetylation of sialic acid on Group BStreptococcusinhibits neutrophil suppression and virulence

Cited by 36 publications

References 46 publications

Immune Activation and Suppression by Group B Streptococcus in a Murine Model of Urinary Tract Infection

Immune Activation and Suppression by Group B Streptococcus in a Murine Model of Urinary Tract Infection

Position of O-Acetylation within the Capsular Repeat Unit Impacts the Biological Properties of Pneumococcal Serotypes 33A and 33F

Exploration of Sialic Acid Diversity and Biology Using Sialoglycan Microarrays

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