Within-Host Evolution of Staphylococcus aureus during Asymptomatic Carriage

Abstract

Background Staphylococcus aureus is a major cause of healthcare associated mortality, but like many important bacterial pathogens, it is a common constituent of the normal human body flora. Around a third of healthy adults are carriers. Recent evidence suggests that evolution of S. aureus during nasal carriage may be associated with progression to invasive disease. However, a more detailed understanding of within-host evolution under natural conditions is required to appreciate the evolutionary and mechanistic reasons why commensal bacteria such as S. aureus cause disease. Therefore we examined in detail the evolutionary dynamics of normal, asymptomatic carriage. Sequencing a total of 131 genomes across 13 singly colonized hosts using the Illumina platform, we investigated diversity, selection, population dynamics and transmission during the short-term evolution of S. aureus.Principal FindingsWe characterized the processes by which the raw material for evolution is generated: micro-mutation (point mutation and small insertions/deletions), macro-mutation (large insertions/deletions) and the loss or acquisition of mobile elements (plasmids and bacteriophages). Through an analysis of synonymous, non-synonymous and intergenic mutations we discovered a fitness landscape dominated by purifying selection, with rare examples of adaptive change in genes encoding surface-anchored proteins and an enterotoxin. We found evidence for dramatic, hundred-fold fluctuations in the size of the within-host population over time, which we related to the cycle of colonization and clearance. Using a newly-developed population genetics approach to detect recent transmission among hosts, we revealed evidence for recent transmission between some of our subjects, including a husband and wife both carrying populations of methicillin-resistant S. aureus (MRSA).SignificanceThis investigation begins to paint a picture of the within-host evolution of an important bacterial pathogen during its prevailing natural state, asymptomatic carriage. These results also have wider significance as a benchmark for future systematic studies of evolution during invasive S. aureus disease.

Molecular tracing of the emergence, diversification, and transmission of S. aureus sequence type 8 in a New York community

“…This method takes advantage of the above-noted features of a consistent mutation rate across the population, very low levels of possible recombination, and no evidence of hypermutators. To estimate the genome variability during asymptomatic colonization, we first analyzed individuals who were colonized with ST8 isolates at multiple body sites (24). Multiple positive swabs were available for 21 individuals, ranging from two to five sites (throat, axilla, groin), yielding 55 isolates.…”

Lysibodies are IgG Fc fusions with lysin binding domains targetingStaphylococcus aureuswall carbohydrates for effective phagocytosis

“…For example, AtlA lysibody and ClyS lysibody bound all strains of S. aureus tested as well as several coagulase-negative staphylococci, whereas PlySs2 lysibody bound streptococci and enterococci in addition to staphylococci. The protein targets of monoclonal antibodies, on the other hand, are often variable even at the species level and may not always be expressed (44)(45)(46)(47). This may limit the strain coverage of certain monoclonal antibodies and could also result in the selection of escape mutants during the course of treatment.…”

Inactivation of Transcriptional Regulators during Within-Household Evolution of Escherichia coli

“…It is also possible that transmission from one host to another, besides creating bottleneck effects, could intensify the pressure for adaptive diversification because of differences in the gut environment due to between-host differences in diet, immunity status, or microbiota composition. Over time, the clonal diversity of same-strain descendants within a given host could reach a high-level equilibrium that is maintained by frequency-dependent or other types of positive selection, at least over the short term (76).…”