Abstract
Streptococcus pneumoniae is an important cause of otitis media and invasive disease. Since introduction of the heptavalent pneumococcal conjugate vaccine, there has been an increase in replacement disease due to serotype 19A clonal complex (CC)199 isolates. The goals of this study were to 1) describe genetic diversity among nineteen CC199 isolates from carriage, middle ear, blood, and cerebrospinal fluid, 2) compare CC199 19A (n = 3) and 15B/C (n = 2) isolates in the chinchilla model for pneumococcal disease, and 3) identify accessory genes associated with tissue-specific disease among a larger collection of S. pneumoniae isolates. CC199 isolates were analyzed by comparative genome hybridization. One hundred and twenty-seven genes were variably present. The CC199 phylogeny split into two main clades, one comprised predominantly of carriage isolates and another of disease isolates. Ability to colonize and cause disease did not differ by serotype in the chinchilla model. However, isolates from the disease clade were associated with faster time to bacteremia compared to carriage clade isolates. One 19A isolate exhibited hypervirulence. Twelve tissue-specific genes/regions were identified by correspondence analysis. After screening a diverse collection of 326 isolates, spr0282 was associated with carriage. Four genes/regions, SP0163, SP0463, SPN05002 and RD8a were associated with middle ear isolates. SPN05002 also associated with blood and CSF, while RD8a associated with blood isolates. The hypervirulent isolate's genome was sequenced using the Solexa paired-end sequencing platform and compared to that of a reference serotype 19A isolate, revealing the presence of a novel 20 kb region with sequence similarity to bacteriophage genes. Genetic factors other than serotype may modulate virulence potential in CC199. These studies have implications for the long-term effectiveness of conjugate vaccines. Ideally, future vaccines would target common proteins to effectively reduce carriage and disease in the vaccinated population.
Highlights
Streptococcus pneumoniae asymptomatically colonizes the upper respiratory tract of approximately half of all healthy children and is a leading cause of acute otitis media, pneumonia and meningitis globally [1]–[3]
The Comparative genome hybridization (CGH) results identified four regions of diversity (RD), using the criteria specified by previous studies investigating pneumococcal genomic diversity [23]
The regions of diversity differed from those previously described by Silva et al RD2 identified within CC199 isolates did not contain SP0114 and SP0115 and was approximately 0.7 kb smaller; RD24, identified within CC199 isolates, was slightly larger due to the addition of SP1947
Summary
Streptococcus pneumoniae asymptomatically colonizes the upper respiratory tract of approximately half of all healthy children and is a leading cause of acute otitis media, pneumonia and meningitis globally [1]–[3]. Our comprehension of the epidemiology, pathogenesis, and virulence factors of S. pneumoniae has improved in recent years, the basis for whether colonization with a specific strain establishes asymptomatic colonization or produces local or invasive diseases requires further elucidation. Encapsulated strains of S. pneumoniae express one of at least 93 distinct capsular polysaccharides [4], [5]. Non-vaccine serotypes have increased in prevalence [8]– [11]. Studies show a significant increase in the number of otitis media and invasive disease cases due to serotype 19A [8], [12]–
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