All ETDs from UAB

Advisory Committee Chair

Moon H Nahm

Advisory Committee Members

William H Benjamin

Lynn E Dobrunz

Kevin F Dybvig

Susan K Hollingshead

Janet Yother

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The facultative pathogen Streptococcus pneumoniae is capable of producing a polysaccharide (PS) capsule that prevents bacterial recognition and clearance by the host immune system. Over 90 antigenically distinct capsule serotypes have been identified. Because anti-capsule antibodies can mediate bacterial clearance, capsule diversity is critical to S. pneumoniae survival. However, the mechanisms of capsule evolution remain unclear. Due to the complex interaction of capsule synthesis (cps) genes, it is commonly thought that pneumococcal serotypes evolve once and that all clinically relevant serotypes are genetically derived from a single founding clone. In this dissertation we demonstrate a novel mechanism of capsule evolution involving two recently discovered serotypes, 11A and 11E, which were previously classified as a single serotype according to conventional serotyping methods. Serotype 11E arises from serotype 11A progenitors by loss-of-function mutations to the cps gene wcjE, which mediates ß-galactose 6-O-acetylation on the 11A capsular PS. However, all isolates expressing serotype 11E contain unique and unrelated loss-of-function mutations to wcjE, revealing the recurrent and independent evolution of this serotype. Analysis of over 400 serotype 11A and 11E strains isolated from nasopharynx (asymptomatic carriage) or from disease sites (i.e, blood, conjunctiva and middle ear) revealed that serotype 11E strains are significantly more likely to occur among blood isolates compared to nasopharyngeal isolates (OR=103.82[21.08-511.32]). Furthermore, no two 11E isolates identified in these studies (n=15) share a similar mutation to wcjE, suggesting that serotype 11E is not transmitted between hosts. We propose that wcjE-mediated O-acetylation may biologically favor nasopharyngeal carriage and transmission, while loss of wcjE function potentially predisposes for invasion or is selected for during invasion to deeper tissue. We describe the "dead end" evolution of serotype 11E, where the ability of the serotype to persist within a host and cause disease is uncoupled from host-to-host transmission. Furthermore, in accordance with epidemiological reports that serotype "11A" is uncommonly associated with invasive disease despite being among the most prevalent serotypes found among colonized individuals, we present evidence for the first specific capsule glycoepitope (i.e., wcjE-mediated ß-galactose-6-O-acetylation) that appears to be associated with pneumococcal tissue specificity.

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