Evidence for Soft Selective Sweeps in the Evolution of Pneumococcal Multidrug Resistance and Vaccine Escape

Abstract

The multidrug-resistant Streptococcus pneumoniae Taiwan19F-14, or PMEN14, clone was first observed with a 19F serotype, which is targeted by the heptavalent polysaccharide conjugate vaccine (PCV7). However, “vaccine escape” PMEN14 isolates with a 19A serotype became an increasingly important cause of disease post-PCV7. Whole genome sequencing was used to characterize the recent evolution of 173 pneumococci of, or related to, PMEN14. This suggested that PMEN14 is a single lineage that originated in the late 1980s in parallel with the acquisition of multiple resistances by close relatives. One of the four detected serotype switches to 19A generated representatives of the sequence type (ST) 320 isolates that have been highly successful post-PCV7. A second produced an ST236 19A genotype with reduced resistance to β-lactams owing to alteration of pbp1a and pbp2x sequences through the same recombination that caused the change in serotype. A third, which generated a mosaic capsule biosynthesis locus, resulted in serotype 19A ST271 isolates. The rapid diversification through homologous recombination seen in the global collection was similarly observed in the absence of vaccination in a set of isolates from the Maela refugee camp in Thailand, a collection that also allowed variation to be observed within carriage through longitudinal sampling. This suggests that some pneumococcal genotypes generate a pool of standing variation that is sufficiently extensive to result in “soft” selective sweeps: The emergence of multiple mutants in parallel upon a change in selection pressure, such as vaccine introduction. The subsequent competition between these mutants makes this phenomenon difficult to detect without deep sampling of individual lineages.

Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

“…The majority of these assays are solely PCR based (40)(41)(42)(43), although sequencing approaches and microarrays have also been used (45,46). Several recent studies have also compared phenotypic drug susceptibility testing results with predictions based on whole-genome sequencing (WGS) data for a variety of bacterial pathogens (47), including S. pneumoniae (48,49). Our CDC-based laboratory has developed a promising WGS-based "typing pipeline" for rapid and automated predictions of pneumococcal serotypes, MICs, genotypes, and additional features (50).…”

“…Despite these observations, most ␤-lactam-resistant strains appear to have unaltered murM genes (125). For example, the highly ␤-lactam-resistant emergent PMEN-14 clone and the closely related and highly successful serotype 19A switch variants of this clonal complex have a nonmosaic murM gene that is identical to that found in certain sensitive strains (49).…”

“…Recombinational exchange events at the cps loci have been shown to have occurred often between pneumococcal strains (49,98,155,156), providing a mechanism of immune escape from serotype-specific antibody. The first account of pneumococcal serotype switching was described in 1928 (157), leading to the discovery of the transforming substance in 1944 (158).…”

Community-Acquired Pneumonia in Children Caused by Pneumococci of MLSB- and M-Phenotype: Clinical Cases

“…Во многих случаях резистентность S. pneumoniae к антибактериальным препаратам имеет клональную специфичность [19]. В последние годы отмечается воз-растание роли пневмококков, относящихся к глобально распространенным клональным комплексам, в возник-новении многих инфекционных заболеваний, включая и внебольничную пневмонию [20].…”

“…Особую роль играют представители мультирезистент-ного клона Taiwan 19F -14 (PMEN 14) [19], к которым отно-сятся и пневмококки серотипа 19А (ST 320), выявленные у наших пациентов. Полученные данные свидетельствуют о наличии у обнаруженных нами пневмококков двух механизмов резистентности к макролидным антибиоти-кам, что не позволяет рекомендовать макролиды в каче-стве стартовой антибактериальной терапии.…”