Biology subjects

Sebastian Bonhoeffer

Publications and source records attributed to Sebastian Bonhoeffer.

3 recordsLinked to original sources

bioRxiv2016

Assessing the public health impact of tolerance-based therapies with mathematical models

Disease tolerance is a defense strategy against infections that aims at maintaining host health even at high pathogen replication or load. Tolerance mechanisms are currently intensively studied with the long-term goal of exploiting them therapeutically. Because tolerance-based treatment imposes less selective pressure on the pathogen it has been hypothesised to be \"evolution-proof\". However, the primary public health goal is to reduce the incidence and mortality associated with a disease. From this perspective, tolerance-based treatment bears the risk of increasing the prevalence of the disease, which may lead to increased mortality. We assessed the promise of tolerance-based treatment strategies using mathematical models. Conventional treatment was implemented as an increased recovery rate, while tolerance-based treatment was assumed to reduce the disease-related mortality of infected hosts without affecting recovery. We investigated the endemic phase of two types of infections: acute and chronic. Additionally, we considered the effect of pathogen resistance against conventional treatment. We show that, for low coverage of tolerance-based treatment, chronic infections can cause even more deaths than without treatment. Overall, we found that conventional treatment always outperforms tolerance-based treatment, even when we allow the emergence of pathogen resistance. Our results cast doubt on the potential benefit of tolerance-based over conventional treatment. Any clinical application of tolerance-based treatment of infectious diseases has to consider the associated detrimental epidemiological feedback.\n\nAuthor summaryConventional therapies improve patient health by eliminating the pathogen, or, at least, reducing its burden. Recently, alternative therapies that exploit host tolerance mechanisms have received attention from the medical community as a promising strategy. These treatments aim at reducing the level of illness due to the infection, rather than eliminating the pathogen directly. Using a mathematical model, we show that although these treatments are beneficial at the individual level, they can have undesired public health consequences. In particular we show that tolerance-based treatment gives more time for the disease to spread in the population, which in turn increase its prevalence. Moreover, in the case of a low coverage of the treatment of a chronic infection, the overall mortality can increase.

Epidemiology↗

bioRxiv2016

Potential pitfalls in estimating viral load heritability

In HIV patients, the set-point viral load (SPVL) is the most widely used predictor of disease severity. Yet SPVL varies over several orders of magnitude between patients. The heritability of SPVL quantifies how much of the variation in SPVL is due to transmissible viral genetics. There is currently no clear consensus on the value of SPVL heritability, as multiple studies have reported apparently discrepant estimates. Here we illustrate that the discrepancies in estimates are most likely due to differences in the estimation methods, rather than the study populations. Importantly, phylogenetic estimates run the risk of being strongly confounded by unrealistic model assumptions. Care must be taken when interpreting and comparing the different estimates to each other.

Evolutionary Biology↗

bioRxiv2016

Population heterogeneity in mutation rate increases mean fitness and the frequency of higher order mutants

Mutation rate is a crucial evolutionary parameter that has typically been treated as a constant in population genetic analyses. However, mutation rate is likely to vary among co-existing individuals within a population, due to genetic polymorphisms, heterogeneous environmental influences, and random physiological fluctuations. We explore the consequences of such mutation rate heterogeneity in a model allowing an arbitrary distribution of mutation rate among individuals, either with or without inheritance. We find that variation of mutation rate about the mean results in a higher probability of producing zero or many simultaneous mutations on a genome. Moreover, it increases the frequency of higher order mutants even under ongoing mutation and selection. We gain a quantitative understanding of how this frequency depends on moments of the mutation rate distribution and selection coefficients. In particular, in a two-locus model, heterogeneity leads to a relative increase in double mutant frequency proportional to the squared coefficient of variation of the mutation rate. Relative effect sizes increase with the number of loci. Finally, this clustering of deleterious mutations into fewer individuals results in a higher population mean fitness. Our results imply that mutation rate heterogeneity allows a population to maintain a higher level of adaptedness to its current environment, while simultaneously harboring greater genetic diversity in the standing variation, which could be crucial for future adaptation to a new environment. Our results also have implications for interpreting mutation rate estimates and mutant frequencies in data.

Genetics↗