Transcriptome Remodeling Contributes to Epidemic Disease Caused by the Human Pathogen Streptococcus pyogenes

Abstract

For over a century, a fundamental objective in infection biology research has been to understand the molecular processes contributing to the origin and perpetuation of epidemics. Divergent hypotheses have emerged concerning the extent to which environmental events or pathogen evolution dominates in these processes. Remarkably few studies bear on this important issue. Based on population pathogenomic analysis of 1,200 Streptococcus pyogenes type emm89 infection isolates, we report that a series of horizontal gene transfer events produced a new pathogenic genotype with increased ability to cause infection, leading to an epidemic wave of disease on at least two continents. In the aggregate, these and other genetic changes substantially remodeled the transcriptomes of the evolved progeny, causing extensive differential expression of virulence genes and altered pathogen-host interaction, including enhanced immune evasion. Our findings delineate the precise molecular genetic changes that occurred and enhance our understanding of the evolutionary processes that contribute to the emergence and persistence of epidemically successful pathogen clones. The data have significant implications for understanding bacterial epidemics and for translational research efforts to blunt their detrimental effects. IMPORTANCEThe confluence of studies of molecular events underlying pathogen strain emergence, evolutionary genetic processes mediating altered virulence, and epidemics is in its infancy. Although understanding these events is necessary to develop new or improved strategies to protect health, surprisingly few studies have addressed this issue, in particular, at the comprehensive population genomic level. Herein we establish that substantial remodeling of the transcriptome of the human-specific pathogen Streptococcus pyogenes by horizontal gene flow and other evolutionary genetic changes is a central factor in precipitating and perpetuating epidemic disease. The data unambiguously show that the key outcome of these molecular events is evolution of a new, more virulent pathogenic genotype. Our findings provide new understanding of epidemic disease.

Population and Whole Genome Sequence Based Characterization of Invasive Group A Streptococci Recovered in the United States during 2015

“…According to our data, the clade 3 strain is T serotype 13 (corresponding to the tee89 gene) and associated with the decline of the T serotype 11 (corresponding to the tee11 gene) clade 1 emm89 strain (5) that expressed capsule and contained the less active nga promoter Pnga1. Although only two T11 (tee11) isolates (recovered in 1995 and 2000) and one T13 (tee89) isolate (recovered in 2000) were sequenced in this study prior to 2015, where all 185 isolates were sequenced, our data are entirely consistent with the previous reports and publicly available WGS data that include a large number (870) of these isolates recovered from 1995 to 2013 (4,5,36). Compare Fig.…”

“…Recently, it was observed that infections due to emm AC cluster (or pattern A-C) strains peaked in the winter (first quarter, from January to March), while E cluster (4,5) associating the emergence of emm89 with the appearance of the acapsular clade 3 strain containing the upregulated nga operon promoter Pnga3 and a different tee gene (36). According to our data, the clade 3 strain is T serotype 13 (corresponding to the tee89 gene) and associated with the decline of the T serotype 11 (corresponding to the tee11 gene) clade 1 emm89 strain (5) that expressed capsule and contained the less active nga promoter Pnga1.…”

“…In particular, the association of the three major iGAS lineages (emm1/ST28, emm89/ST101, emm12/ST36) with an upregulated nga operon is compelling, especially when this feature directly correlated with the marked emergence of emm89 in ABCs isolates over the past decade (4,5,36). Individual strain parameters may provide greater understanding of GAS tissue tropism and disease manifestations.…”

Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis

“…Advances in DNA sequencing and related technologies have facilitated genome-wide dissection of genetic events involved in colonization (6), immune evasion (7), virulence (8)(9)(10), and the evolution and spread of highly virulent S. pyogenes clones (11)(12)(13). To advance our understanding of S. pyogenes molecular-pathogenesis events occurring during invasive infection, we performed whole-genome sequencing of 2,954 isolates recovered from a nonhuman primate model of necrotizing fasciitis.…”

High degree of virulence gene diversity in Streptococcus pyogenes isolated in Central Italy

“…Genetic changes in emm89 strains have recently generated clonal lineages responsible for invasive infections in different parts of the globe [12,13]. The high prevalence of noninvasive emm89 type strains in our collection confirmed the increasing expansion of this emm type together with its propensity to switch to more virulent variants, which is of concern and claims the continuous monitoring of its diffusion into the population [14].The analysis of the recorded patterns of virulence genes revealed the presence of major clones as already described in previous studies [4,15,16].…”