Low Invasiveness of Pneumococcal Serotype 11A Is Linked to Ficolin-2 Recognition of O-acetylated Capsule Epitopes and Lectin Complement Pathway Activation

Brady, Allison M.; Calix, Juan J.; Yu, Jigui; Geno, K. Aaron; Cutter, Gary; Nahm, Moon H.

doi:10.1093/infdis/jiu195

Cited by 46 publications

(87 citation statements)

References 51 publications

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“…L-ficolin was also reported to bind several pneumococcal strains, like serotypes 2, 3, 6B, 11 (A, D, and F), 18 and 35 (A and C) (12,28,35,36). To our knowledge, we report in this study for the first time that serum and recombinant L-ficolins bind to unencapsulated pneumococcal strain (R6) and confirm the recently reported interaction with serotype 2 D39 encapsulated strain (12).…”

Section: Discussionsupporting

confidence: 88%

“…However, it cannot be excluded that some pneumococcal CPS might also be recognized by L-ficolin depending on the serotype considered because putative L-ficolin ligands such as N-acetylglucosamine, galactose, and PCho can be displayed by the CPS structures (39,40). In this respect, interaction of L-ficolin with O-acetylated epitopes of serotype 11A CPS has been reported very recently (36).…”

Section: Discussionmentioning

confidence: 99%

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Human L-Ficolin Recognizes Phosphocholine Moieties of Pneumococcal Teichoic Acid

Vassal-Stermann

Lacroix

Gout

et al. 2014

The Journal of Immunology

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International audienceHuman L-ficolin is a soluble protein of the innate immune system able to sense pathogens through its fibrinogen (FBG) recognition domains and to trigger activation of the lectin complement pathway through associated serine proteases. L-Ficolin has been previously shown to recognize pneumococcal clinical isolates, but its ligands and especially its molecular specificity remain to be identified. Using solid-phase binding assays, serum and recombinant L-ficolins were shown to interact with serotype 2 pneumococcal strain D39 and its unencapsulated R6 derivative. Incubation of both strains with serum triggered complement activation, as measured by C4b and C3b deposition, which was decreased by using ficolin-depleted serum. Recombinant L-ficolin and its FBG-like recognition domain bound to isolated pneumococcal cell wall extracts, whereas binding to cell walls depleted of teichoic acid (TA) was decreased. Both proteins were also shown to interact with two synthetic TA compounds, each comprising part structures of the complete lipoteichoic acid molecule with two PCho residues. Competition studies and direct interaction measurements by surface plasmon resonance identified PCho as a novel L-ficolin ligand. Structural analysis of complexes of the FBG domain of L-ficolin and PCho revealed that the phosphate moiety interacts with amino acids previously shown to define an acetyl binding site. Consequently, binding of L-ficolin to immobilized acetylated BSA was inhibited by PCho and synthetic TA. Binding of serum L-ficolin to immobilized synthetic TA and PCho-conjugated BSA triggered activation of the lectin complement pathway, thus further supporting the hypothesis of L-ficolin involvement in host antipneumococcal defense

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Human L-Ficolin Recognizes Phosphocholine Moieties of Pneumococcal Teichoic Acid

Vassal-Stermann

Lacroix

Gout

et al. 2014

The Journal of Immunology

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“…Flow cytometric serotyping assays were performed as previously described (10), with the modification that HBC buffer (Hanks' balanced salt solution [HBSS]-bovine serum albumin-calcium buffer; 1ϫ HBSS without magnesium or calcium, 0.5% bovine serum albumin, 2.2 mM CaCl 2 [26]) was used instead of FACS buffer. Briefly, bacterial stocks were washed in HBC, incubated with 1:10,000 dilutions of antisera, washed by centrifugation, stained with a phycoerythrin-conjugated anti-rabbit immunoglobulin secondary antibody (catalog no.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Novel Pneumococcal Serotype 35D, a Natural WciG-Deficient Variant of Serotype 35B

2017

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Pneumococcus (Streptococcus pneumoniae) remains a significant cause of morbidity and mortality, especially among those at the extremes of age. Its capsular polysaccharide is essential for systemic virulence. Over 90 serologically distinct pneumococcal capsular polysaccharides (serotypes) are recognized, but they are unequal in prevalence. Because antibodies against the capsule are protective, polysaccharide conjugate vaccines, which are constructed against the most prevalent serotypes, have caused great reductions in pneumococcal disease caused by these serotypes. In response, however, the relative prevalences of serotypes have shifted. Certain previously rare serotypes, such as serotype 35B, are increasing in prevalence. Serotype 35B is thus a likely future vaccine candidate, but due to their previous rarity, serotype 35B strains have not been scrutinized for underlying heterogeneity. We studied putative serotype 35B clinical isolates to assess the uniformity of their serological reactions. While most isolates exhibited the accepted serology of serotype 35B, one isolate failed to bind to critical serotyping reagents. We determined that the genetic basis for this aberrant serology was the presence of inactivating mutations in the O-acetyltransferase gene wciG. Complementation studies in a wciG deletion strain verified that the mutant WciG was nonfunctional, and the serology of the mutant could be restored through complementation with a construct encoding a functional WciG. Nuclear magnetic resonance studies confirmed that the capsule of the WciG-deficient isolate lacked O-acetylation but was otherwise identical to serotype 35B. As this isolate expresses a unique serology with unique biochemistry and a stable genetic basis, we named its novel capsule serotype 35D.KEYWORDS O-acetylation, Streptococcus pneumoniae, capsular polysaccharide, serogroup 35, serotype 35B, serotype 35D S treptococcus pneumoniae (pneumococcus) is an important human pathogen that can express many different polysaccharide capsules that protect the organism from opsonophagocytic killing (1). As antibodies to the capsule are protective, currently available vaccines against pneumococcus are designed to elicit antibodies to the capsule and have been highly successful in reducing the incidence of invasive pneumococcal disease (IPD). A pneumococcal polysaccharide-protein conjugate vaccine (PCV) with polysaccharide from the seven most commonly observed serotypes (PCV7) was introduced in the United States in 2000 and reduced the incidence of IPD in children younger than 5 by over 75% (2); the updated 13-valent PCV (PCV13) has reduced the incidence of IPD by an additional 64% in this age group in the United States (3). However, the protection by these vaccines is serotype specific, and their widespread implementation has brought shifts in the serotypes found in both nasopharyngeal carriage and IPD (see, e.g., reference 4).

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“…They are the targets of many serotyping reagents, innate immune molecules (e.g., ficolin-2 [14,18] and siglecs [19]), and vaccine-elicited antibodies (20). Pneumococcal cps loci harbor many acetyltransferase genes (11), and several serogroups contain serotype pairs: one with a functional transferase and the other with nonfunctional transferase.…”

Section: -H 1-c 2-h 2-c 3-h 3-c 4-h 4-c 5-h 5-c 6-h 6-c 35c (Smentioning

confidence: 99%

“…However, biochemical studies showed that serotype 42 capsular polysaccharide (CPS) has two O-acetylations on its 3-linked ␤-galactofuranose (Galf) (12,13), while a commercial serotype 35C capsule preparation contained no O-acetylation (13). In addition, both serotypes are known to bind ficolin-2, which targets O-acetyl groups in some pneumococcal serotypes (14). Taken together, these data suggest that our understanding of these serotypes is incomplete.…”

mentioning

confidence: 99%

WciG O -Acetyltransferase Functionality Differentiates Pneumococcal Serotypes 35C and 42

et al. 2017

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Streptococcus pneumoniae expresses capsular polysaccharides (CPSs) to protect itself from opsonophagocytic killing. The genes responsible for capsules synthesized by the Wzy-dependent mechanism, which accounts for 96 of the 98 known pneumococcal capsule types, are in a chromosomal region known as the cps locus. The nucleotide sequence in this region has been determined for all serotypes. In contrast, not all CPS structures have been defined. The structure of the serotype 35C polysaccharide was recently reported, but the presence of O-acetyltransferase genes in the serotype 35C cps locus suggested that it could be incomplete, as the reported structure contains no O-acetylation. In addition, the genetic distinction of serotype 35C from the closely related serotype 42 was unclear, as their reported cps loci are nearly identical. To clarify these discrepancies, we obtained serotype 35C and 42 clinical and reference isolates and studied their serological and genetic properties, as well as the structures of CPSs purified from reference isolates. We demonstrated that the Oacetyltransferase WciG was functional in serotype 35C but nonfunctional in serotype 42 due to a deletion in wciG. Serotype 35C was O-acetylated at the 5-and 6-positions of 3-␤-galactofuranose, as well as the 2-position of 6-␤-galactofuranose. However, serotype 42 has only O-acetylation at 3-␤-galactofuranose, an observation consistent with its loss of WciG functionality, which is associated with O-acetylation at the 2-position and subsequent reaction with typing antiserum 35a. These findings provide a comprehensive view of the genetic, biochemical structural, and serological bases of serotypes 35C and 42.

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Low Invasiveness of Pneumococcal Serotype 11A Is Linked to Ficolin-2 Recognition of O-acetylated Capsule Epitopes and Lectin Complement Pathway Activation

Abstract: Ficolin-2 mediates serum protection by recognizing specific O-acetylated epitopes of pneumococcal capsule polysaccharides, exemplifying a novel host-microbe interaction that innately offers serotype-specific immunity to IPD.

Cited by 46 publications

References 51 publications

Human L-Ficolin Recognizes Phosphocholine Moieties of Pneumococcal Teichoic Acid

Human L-Ficolin Recognizes Phosphocholine Moieties of Pneumococcal Teichoic Acid

Discovery of Novel Pneumococcal Serotype 35D, a Natural WciG-Deficient Variant of Serotype 35B

WciG O -Acetyltransferase Functionality Differentiates Pneumococcal Serotypes 35C and 42

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