The Pneumococcal Serotype 15C Capsule Is Partially O-Acetylated and Allows for Limited Evasion of 23-Valent Pneumococcal Polysaccharide Vaccine-Elicited Anti-Serotype 15B Antibodies

Abstract

As a species, Streptococcus pneumoniae (the pneumococcus) utilizes a diverse array of capsular polysaccharides to evade the host. In contrast to large variations in sugar composition and linkage formation, O-acetylation is a subtle capsular modification that nonetheless has a large impact on capsular shielding and recognition of the capsule by vaccine-elicited antibodies. Serotype 15B, which is included in the 23-valent pneumococcal polysaccharide vaccine (PPV23), carries the putative O-acetyltransferase gene wciZ. The coding sequence of wciZ contains eight consecutive TA repeats [(TA) 8 ]. Replication slippage is thought to result in the addition or loss of TA repeats, subsequently causing frameshift and truncation of WciZ to yield a nonacetylated serotype, 15C. Using sensitive serological tools, we show that serotype 15C isolates whose wciZ contains seven or nine TA repeats retain partial O-acetylation, while serotype 15C isolates whose wciZ contains six TA repeats have barely detectable O-acetylation. We confirmed by inhibition enzyme-linked immunosorbent assay that (TA) 7 serotype 15C is ϳ0.1% as acetylated as serotype 15B, while serotype 15X is nonacetylated. To eliminate the impact of genetic background, we created isogenic serotype 15B, (TA) 7 serotype 15C, and 15BΔwciZ (15X) strains and found that reduction or absence of WciZ-mediated O-acetylation did not affect capsular shielding from phagocytes, biofilm formation, adhesion to nasopharyngeal cells, desiccation tolerance, or murine colonization. Sera from PPV23-immunized persons opsonized serotype 15B significantly but only slightly better than serotypes 15C and 15X; thus, PPV23 may not result in expansion of serotype 15C.KEYWORDS O-acetyltransferase, O-acetylation, capsule diversity, pneumococcal vaccine, capsular polysaccharide, serotyping, replication slippage S treptococcus pneumoniae (the pneumococcus), a Gram-positive human pathogen, mediates pneumonia and invasive diseases such as septicemia and meningitis and colonizes 6 to 76% of the world's pediatric population (1-3). Pneumococcal diseases are the leading cause of death in children under 5 years old (4), and pneumococcal capsular polysaccharide is the organism's most significant virulence factor as it shields the pneumococcus from various chemical and immune assaults (5). As a result, nonencapsulated pneumococci rarely cause pneumonia or invasive pneumococcal disease (6-8). Pneumococcal capsular types differ in their shielding abilities; therefore, some capsule types are more virulent than others (9, 10). Our previous studies have indicated that small chemical modifications of the capsular repeat unit result in differential shielding of closely related serotypes (11,12).An important capsular modification is O-acetylation: an uncharged, but polar, acetyl

Invasive Pneumococcal Disease in Adults in Portugal: The Importance of Serotypes 8 and 3 (2015–2018)

“…Serotypes were classified into vaccine serotypes, i.e., those included in PCV7 (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F), PCV13 (all PCV7 serotypes plus 1, 3, 5, 6A, 7F, and 19A, the later also referred to as addPCV13), PCV15 (all PCV13 serotypes plus 22F and 33F, the later also referred to as addPCV15), PCV20 (all PCV15 serotypes plus 8, 10A, 11A, 12F, and 15B, the later also referred to as addPCV20), and PPV23 (all PCV20 serotypes, except serotype 6A, plus serotypes 2, 9N, 17F and 20, the later also referred to as addPPV23), or as non-vaccine serotypes (NVTs). Given the high frequency of spontaneous switching between serotypes 15B and 15C, we decided to group isolates with these serotypes into a single group and to assume that PCV20 and PPV23 protect against both these serotypes [ 14 ]. Additionally, given the difficulties in phenotypically distinguishing isolates of serotypes 25A and 38, as well as isolates with serotypes 29 and 35B, these also grouped together into 25A/38 and 29/35B, respectively.…”

Bacterial polysaccharides as major surface antigens: interest in O-acetyl substitutions

“…89 In contrast, a recent investigation of the specificity of recognition of sera from a larger number of Pneumovax  immunized individuals, concluded on a rather slight difference of the opsonophagocytic activity of the induced sera in favor of type 15B in comparison to type 15C. 85 Interestingly, by use 5 of antibodies specifically targeting WciZ-mediated O-acetylation the same study revealed that the CPS from S. pneumoniae 15B and 15C were O-acetylated at the same location, albeit to a much lesser extent for the later (Fig. 9B).…”

“…It was found that wciZ coded by (TA) 7 or (TA) 9 wciZ retaining partial activity, whereas type 15C strains with (TA) 6 wciZ had barely detectable CPS O-acetylation levels. 85 In support to the assumption that the influence of O-acetylation on CPS biological properties is 15 polysaccharide-dependent, 75 it was suggested that CPS O-acetylation had little effect on the biological properties of CPS in the case of S. pneumoniae types 15B and 15C and allowed for only limited evasion of Pneumovax  -elicited anti-serotype 15B antibodies. 85 Whereas Pneumovax ® comprises type 15B, no member of pneumococci group 15 was included in Prevnar.…”

“…85 In support to the assumption that the influence of O-acetylation on CPS biological properties is 15 polysaccharide-dependent, 75 it was suggested that CPS O-acetylation had little effect on the biological properties of CPS in the case of S. pneumoniae types 15B and 15C and allowed for only limited evasion of Pneumovax  -elicited anti-serotype 15B antibodies. 85 Whereas Pneumovax ® comprises type 15B, no member of pneumococci group 15 was included in Prevnar. However, issues of possible serotype replacement with non-20 vaccine serotypes have emerged after Prevnar introduction, and concern arose with serotypes 15A, 15B and 15C.…”

Allergic airway sensitization impairs antibacterial IgG antibody responses during bacterial respiratory tract infections

“…Capsule-specific antibodies are essential mediators of clearance and control during pneumococcal infections alongside other innate immune activators (ie, ficolin-2). [18][19][20] The increased microbial lung burden and susceptibility of asthmatic patients to infections suggest that further study of this population's immune response is warranted. M pneumoniae and S pneumoniae are convenient model organisms with which to explore the airway allergic immune response in mice.…”