Biology subjects

Lipsitch, M.

Publications and source records attributed to Lipsitch, M..

21 records · Page 2Linked to original sources

bioRxiv2017

Host population structure and treatment frequency maintain balancing selection on drug resistance

It is a truism that antimicrobial drugs select for resistance, but explaining pathogen- and population-specific variation in patterns of resistance remains an open problem. Like other common commensals, Streptococcus pneumoniae has demonstrated persistent coexistence of drug-sensitive and drug-resistant strains. Theoretically, this outcome is unlikely. We modeled the dynamics of competing strains of S. pneumoniae to investigate the impact of transmission dynamics and treatment-induced selective pressures on the probability of stable coexistence. We find that the outcome of competition is extremely sensitive to structure in the host population, although coexistence can arise from age-assortative transmission models with age-varying rates of antibiotic use. Moreover, we find that the selective pressure from antibiotics arises not so much from the rate of antibiotic use per se but from the frequency of treatment: frequent antibiotic therapy disproportionately impacts the fitness of sensitive strains. This same phenomenon explains why serotypes with longer durations of carriage tend to be more resistant. These dynamics may apply to other potentially pathogenic, microbial commensals and highlight how population structure, which is often omitted from models, can have a large impact.

evolutionary biology↗

bioRxiv2017

Weak epistasis may drive adaptation in recombining bacteria

The impact of epistasis on the evolution of multilocus traits depends on recombination. Population genetic theory has been largely developed for eukaryotes, many of which recombine so frequently that epistasis between polymorphisms has not been considered to play a large role in adaptation and has been compared to the fleeting influence of non-heritable effects. Many bacteria also recombine, some to the degree that their populations are described as panmictic or freely recombining. However, whether this recombination is sufficient to limit the ability of selection to act on epistatic contributions to fitness is unknown. We create a sensitive method to quantify homologous recombination in five bacterial pathogens and use these parameter estimates in a multilocus model of bacterial evolution with additive and epistatic effects. We find that even for highly recombining species (e.g. Streptococcus pneumoniae or Helicobacter pylori), selection may act on the cumulative effects of weak (as well as strong) interactions between distant mutations since homologous recombination typically transfers only short segments. Furthermore, whether selection acts more efficiently on physically proximal loci depends on the average recombination tract length. Epistasis may thus play an important role in the adaptive evolution of bacteria and, unlike in eukaryotes, does not need to be strong, involve near loci, or require specific metapopulation dynamics.

evolutionary biology↗

bioRxiv2017

Exploring The Role Of Competition Induced By Non-Vaccine Serotypes For Herd Protection

The competitive pressure from non-vaccine serotypes may have helped pneumococcal conjugate vaccines (PCVs) to limit vaccine serotype (VT) prevalence. We aim to investigate if, consequently, the indirect protection of higher valency vaccines could fall short of the profound effects of current formulations.\n\nWe compare three previously described pneumococcal models harmonized to simulate 20 serotypes with a combined pre-vaccination prevalence in <5y old children of 40%. We simulate vaccines of increasing valency by adding serotypes in order of their competitiveness and explore their ability to reduce VT carriage by 95% within 10 years after introduction.\n\nAll models predict that additional valency will reduce indirect vaccine effects and hence the overall vaccine impact on carriage both in children and adults. Consequently, the minimal effective coverage (efficacy against carriage * vaccine coverage) needed to eliminate vaccine type carriage increases with increasing valency. One model predicts this effect to be modest while the other two predict that high-valency vaccines may struggle to eliminate VT pneumococci unless vaccine efficacy against carriage can be substantially improved. Similar results were obtained when settings of higher transmission intensity and different PCV formulations were explored.\n\nFailure to eliminate carriage as a result of increased valency could lead to overall decreased impact of vaccination if the disease burden caused by the added serotypes is low. Hence a comparison of vaccine formulations of varying valency, and pan-valent formulations in particular, should consider the invasiveness of targeted serotypes, as well as efficacy against carriage.

ecology↗