Editors' ChoiceInfectious Disease

Enemies Among Us

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Science Translational Medicine  06 Apr 2011:
Vol. 3, Issue 77, pp. 77ec48
DOI: 10.1126/scitranslmed.3002457

Streptococcal pharyngitis, or “strep throat,” is caused by Group A Streptococcus (GAS) and is one of the most common causes of bacterial disease in childhood. Yet, it has long been understood by pediatricians that GAS causes a spectrum of clinical illness, ranging from asymptomatic colonization to pharyngitis to, rarely, a more invasive disease. To date, epidemiologic studies have linked specific virulence factors related to the emm gene locus with more invasive strains; however, the full molecular basis and reservoir for such strains is not well characterized. In the largest analysis of GAS to date, Shea et al. define distinct genomic patterns associated with pharyngitis-causing and invasive strains and suggest that these polymorphisms may accumulate to establish a more invasive phenotype.

High-throughput DNA sequencing technologies allow the comparison of entire genomes across large populations. To better define genomic differences between relatively benign and invasive strains of GAS, Shea et al. performed genome-wide sequencing on 86 pharyngeal isolates and 215 invasive strains from the same geographical locale. First, after analysis of genetic polymorphisms, they report that invasive and pharyngitis-causing strains are both genetically diverse, decreasing the likelihood that invasive strains are a distinct subset of GAS. However, the distribution of polymorphisms differed greatly between the strains. For instance, the polymorphisms found in the pharyngitis-causing strains led to deletion or down-regulation of two gene regions (hasA and hasB) that are essential for hyaluronic acid synthesis, a key component that protects the bacteria from being eaten by immune cells. Strikingly, the changes in the has gene segment were inducible in a nonhuman primate model within 35 days after inoculation with the parent strain, suggesting that the host environment differentially affects the strains. For the invasive strains, polymorphisms were mapped to regions important for invasive potential, including both the covR gene and the covR transcriptional regulator, resulting in the potential for increased expression of virulence factors.

Lastly, to determine whether the invasive strains were a genetically distinct subset of pharyngitis-causing strains, Shea et al. analyzed the genetic population structure of the isolates. Surprisingly, the invasive strains clustered tightly together with pharyngitis-causing strains, eliminating the likelihood that one specific strain is the bad actor that continually propagates among patients. Rather, it is likely that invasive strains may arise from any lineage in the pharyngitis-causing strain reservoir given the right environmental conditions. In this regard, the authors suggest pressures put on GAS by the patient's body may act on specific genomic regions, ultimately allowing the bacteria to “accumulate” polymorphisms that enhance or decrease its invasive potential. A better understanding of which selective pressures lead to a more benign or invasive phenotype will be critical in disarming the enemies among us.

P. R. Shea et al., Distinct signatures of diversifying selection revealed by genome analysis of respiratory tract and invasive bacterial populations. Proc. Natl. Acad. Sci. U.S.A. 108, 5039–5044 (2011). [Abstract]

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