Biology subjects

McLeod, D. V.

Publications and source records attributed to McLeod, D. V..

7 recordsLinked to original sources

bioRxiv2025

Viral evolution during primary infection in immunocompromised hosts

The immune response to viral infection is a delicate balance. By perturbing this balance, immunodeficiencies are expected to influence within-host viral evolution. Indeed, the presence of immunocompromised hosts has been argued to be a source of novel viral variants in some infectious diseases, including SARS-CoV-2. However, these arguments rest upon between-host models and so the role of immunodeficiencies on within-host evolution in primary infections is poorly understood. Using a mechanistic immunological model, here we consider how different immunodeficiencies shape the orchestration of the immune response during primary infection. We study how this alters the viral fitness landscape, thus speeding and slowing viral evolution. We show that during acute infections, while immunodeficiencies in neutrophils and interferon initially speed viral evolution, by the time the infection is cleared, mutations are at lower frequencies than in immunocompetent hosts. In persistent infections, we show that while T cell deficiencies slow viral evolution, interleukin-6 and macrophage deficiencies speed viral evolution. Finally, we show that positive epistatic interactions arising due to the immunological response will accelerate the evolution of viral mutations affecting the ability of virions to evade different aspects of the immune response and to enter host cells.

immunology↗

bioRxiv2025

Horizontal gene transfer, segregation loss and the speed of microbial adaptation

Microbial adaptation is driven by the circulation of mobile genetic elements (MGEs) among bacteria. On the one hand, MGEs can be viewed as selfish genes that spread like infectious diseases in a host population. On the other hand, the horizontal transfer and the loss of these MGEs is often viewed as a form of sexual reproduction that reshuffles genetic diversity in a way that may sometimes be adaptive for bacteria cells. Here, we show how these two perspectives can be reconciled using a single unified framework capturing the dynamics of multiple, interacting MGEs. We apply this framework to study how interactions between MGEs affecting rates of horizontal gene transfer and segregation loss shape the short- and long-term evolutionary dynamics of MGEs and the bacteria population. We show these interactions produce non-random MGE associations that can speed up or slow down microbial adaptation depending on the evolutionary conflicts between MGEs as well as between MGEs and their bacterial hosts. Moreover, we show how these interactions affect the evolutionary potential of the bacteria population. We discuss the implications of these predictions for the community response to environmental stressors such as antibiotic treatment or vaccination campaigns as well as the evolution of accessory genomes.

evolutionary biology↗

bioRxiv2023

A multilocus perspective on the evolutionary dynamicsof multistrain pathogens

Many human pathogens, including malaria, dengue, influenza, Streptococcus pneumoniae, and cytomegalovirus, coexist as multiple genetically distinct strains. Understanding how these multistrain pathogens evolve is of critical importance for forecasting epidemics and predicting the consequences of vaccination. One factor believed to play an important role is naturally acquired immunity. Consequently, a large body of research has sought to predict how acquired immunity molds the genomics of pathogen populations (i.e., what shapes pathogen strain structure). The diversity of existing models has resulted in conflicting evolutionary predictions, and has sparked an ongoing debate about which predictions are most broadly applicable. Here, we adopt a multilocus population genetics perspective that unifies the predictions of existing models. We identify three key factors that determine the role of naturally acquired immunity in the evolution of pathogen strain structure: (i) the strength and specificity of immune protections, (ii) the dynamic immunological landscape, and (iii) the number of loci coding for the antigens of the pathogen. Isolating and discussing these three factors clarifies the relationship among previous models of multistrain dynamics, and establishes a solid theoretical foundation for the study of the evolutionary epidemiology of multistrain pathogens.

evolutionary biology↗

bioRxiv2021

Multilocus adaptation to vaccination

Pathogen adaptation to public health interventions, such as vaccination, may take tortuous routes and involve multiple mutations at distinct locations in the pathogen genome, acting on distinct phenotypic traits. Despite its importance for public health, how these multilocus adaptations jointly evolve is poorly understood. Here we consider the joint evolution of two adaptations: the pathogens ability to escape the vaccine-induced immune response and adjustments to the pathogens virulence and transmissi-bility. We elucidate the role played by epistasis and recombination, with an emphasis on the different protective effects of vaccination. We show that vaccines reducing transmission and/or increasing clearance generate positive epistasis between the vaccine-escape and virulence alleles, favouring strains that carry both mutations, whereas vaccines reducing virulence mortality generate negative epistasis, favouring strains that carry either mutation, but not both. High rates of recombination can affect these predictions. If epistasis is positive, frequent recombination can lead to the sequential fixation of the two mutations and prevent the transient build-up of more virulent escape strains. If epistasis is negative, frequent recombination between loci can create an evolutionary bistability, such that whichever adaptation is more accessible tends to be favoured in the long-term. Our work provides a timely alternative to the variant-centered perspective on pathogen adaptation and captures the effect of different types of vaccines on the interference between multiple adaptive mutations.

evolutionary biology↗

bioRxiv2020

Mosaic vaccination: how distributing different vaccines across a population could improve epidemic control

Although vaccination has been remarkably effective against some pathogens, for others, rapid antigenic evolution results in vaccination conferring only weak and/or short-lived protection. Consequently, considerable effort has been invested in developing more evolutionarily robust vaccines, either by targeting highly conserved components of the pathogen (universal vaccines) or by including multiple immunological targets within a single vaccine (multi-epitope vaccines). An unexplored third possibility is to vaccinate individuals with one of a number of qualitatively different vaccines, creating a mosaic of individual immunity in the population. Here we explore whether a mosaic vaccination strategy can deliver superior epidemiological outcomes to conventional vaccination, in which all individuals receive the same vaccine. We suppose vaccine doses can be distributed between distinct vaccine targets (e.g., different surface proteins against which an immune response can be generated) and/or immunologically-distinct variants at these targets (e.g., strains); the pathogen can undergo antigenic evolution at both targets. Using simple mathematical models, we show that mosaic vaccination often outperforms conventional vaccination, leading to fewer infected individuals, improved vaccine efficacy, and lower individual risks over the course of the epidemic.

evolutionary biology↗

bioRxiv2020

Epigenetic inheritance and the evolution of infectious diseases

Genes with identical DNA sequences may show differential expression because of epigenetic marks. These marks in pathogens are key to their virulence and are being evaluated as targets for medical treatment. Where epigenetic marks were created in response to past conditions (epigenetically inherited), they represent a form of memory, the impact of which has not been considered in the evolution of infectious diseases. We fill this gap by exploring the evolution of virulence in pathogens that inherit epigenetic information on the sex of their previous host. We show that memories of past hosts can also provide clues about the sex of present and future hosts when women and men differ in their immunity to infection and/or their interactions with the sexes. These biological and social differences between the sexes are pervasive in humans. We show that natural selection can favour the evolution of greater virulence in infections originating from one sex. Furthermore, natural selection can favour the evolution of greater virulence in infections across sexes (or within sexes). Our results explain certain patterns of virulence in diseases like measles, chickenpox and polio that have puzzled medical researchers for decades. In particular, they address why girls infected by boys (or boys infected by girls) are more likely to die from the infection than girls infected by girls (or boys infected by boys). We propose epigenetic therapies to treat infections by tampering with the memories of infecting pathogens. Counterintuitively, we predict that successful therapies should target pathogens genes that inhibit virulence, rather than those enhancing virulence. Our findings imply that pathogens can carry memories of past environments other than sex (e.g. those related to socioeconomic status) that may condition their virulence and could signify an important new direction in personalised medicine.

evolutionary biology↗

bioRxiv2020

Understanding the evolution of multiple drug resistance in structured populations

The evolution of multidrug resistance (MDR) is a pressing public health concern. Yet many aspects, such as the role played by population structure, remain poorly understood. Here we argue that studying MDR evolution by focusing upon the dynamical equations for linkage disequilibrium (LD) can greatly simplify the calculations, generate more insight, and provide a unified framework for understanding the role of population structure. We demonstrate how a general epidemiological model of MDR evolution can be recast in terms of the LD equations. These equations reveal how the different forces generating and propagating LD operate in a dynamical setting at both the population and metapopulation levels. We then apply these insights to show how the LD perspective: (i) explains equilibrium patterns of MDR, (ii) provides a simple interpretative framework for transient evolutionary dynamics, and (iii) can be used to assess the consequences of different drug prescription strategies for MDR evolution.

evolutionary biology↗