Sugar-Coated Killer: Serotype 3 Pneumococcal Disease

Abstract

Capsular polysaccharide (CPS), which surrounds the bacteria, is one of the most significant and multifaceted contributors to Streptococcus pneumoniae virulence. Capsule prevents entrapment in mucus during colonization, traps water to protect against desiccation, can serve as an energy reserve, and protects the bacterium against complement-mediated opsonization and immune cell phagocytosis. To date, 100 biochemically and serologically distinct capsule types have been identified for S. pneumoniae; 20 to 30 of which have well-defined propensity to cause opportunistic human infection. Among these, serotype 3 is perhaps the most problematic as serotype 3 infections are characterized as having severe clinical manifestations including empyema, bacteremia, cardiotoxicity, and meningitis; consequently, with a fatality rate of 30%-47%. Moreover, serotype 3 resists antibody-mediated clearance despite its inclusion in the current 13-valent conjugate vaccine formulation. This review covers the role of capsule in pneumococcal pathogenesis and the importance of serotype 3 on human disease. We discuss how serotype 3 capsule synthesis and presentation on the bacterial surface is distinct from other serotypes, the biochemical and physiological properties of this capsule type that facilitate its ability to cause disease, and why existing vaccines are unable to confer protection. We conclude with discussion of the clonal properties of serotype 3 and how these have changed since introduction of the 13-valent vaccine in 2000.

Keywords: Streptococcus pneumoniae; capsule production; invasive pneumococcal disease; serotype 3; synthase-dependent pathway; vaccine escape; wzy-dependent pathway.

Figure 1

S. pneumoniae isolates expressing most capsule types make (A) small round colonies similar to doughnuts on blood agar plate, but (B) serotype 3 and 37 pneumococci develop characteristically large mucoid colonies. From Song et al. (2013).

Figure 2

A pictorial explanation of Wzy-mediated CPS synthesis. Repeated patterns of monosaccharides are transported to and added to undecaprenylphosphate (Und-p). The polysaccharide strip is then flipped across the membrane by Wzx flippase and repeat segments are added onto the non-reducing end by Wzy polymerase. Once the desired length is reached, polysaccharide chains are exported from the cell membrane to the peptidoglycan by unknown means, where they bind covalently via glycosidic bond.

Figure 3

Representation of synthase-mediated CPS production. Synthesis begins when a glucose monosaccharide is transferred to an integral phosphatidylglycerol. Addition of a glucuronic acid is catalyzed by the synthase. This method repeats until concentrations of either sugar runs too low for synthesis to continue. The phosphatidylglycerol then dissociates from the synthase and disperses within the external cell membrane.

Figure 4

A summary of the topics covered within this review. To the left are virulence factors commonly seen and utilized by pneumococcal serotypes. On the right are virulence factors increased in serotype 3 strains. These include but are not limited to electronegativity and capsule production/shedding. Electronegativity has a variety of effects on virulence as demonstrated above. Higher electronegativity acts as a repellent of immune cells and mucin, allowing for increased escape of immune responses and nasopharyngeal colonization by mucin evasion. Increases in capsular polysaccharide shedding in serotype 3 have been hypothesized to overwhelm the immune responses by sequestering antibodies and minimizing the deposit of antibody on the cell surface.