Sylvain Gandon

• PhD
• Research Director at Centre d'Écologie Fonctionnelle et Évolutive, French National Centre for Scientific Research

Microbial host populations evolve traits conferring specific resistance to viral predators via various defense mechanisms, while viruses reciprocally evolve traits to evade these defenses. Such co-evolutionary dynamics often involve diversification promoted by negative frequency-dependent selection. However, microbial traits conferring competitive...

The experimental validation of theoretical predictions is a crucial step in demonstrating the predictive power of a model. While quantitative validations are common in infectious diseases epidemiology, experimental microbiology primarily focuses on the evaluation of a qualitative match between model predictions and experiments. In this study, we de...

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 importan...

Highlights d Methylation-associated defense system (MADS) is a complex bacterial innate immune system d MADS function relies on nuclease, ATPase, kinase, and methyltransferase domains d MADS is distributed across gram-positive and gram-negative bacteria d MADS and CRISPR-Cas interplay provides strong and durable protection against phages

The experimental validation of theoretical predictions is a significant step in the demonstration of the predictive power of a model. In a previous study, we monitored the evolution of the temperate phage λ spreading in continuous cultures of Escherichia coli. This experimental work confirmed the influence of the epidemiological dynamics on the evo...

Bacteria contain a wide variety of innate and adaptive immune systems which provide protection to the host against invading genetic material, including bacteriophages (phages). It is becoming increasingly clear that bacterial immune systems are frequently lost and gained through horizontal gene transfer (HGT). However, how and when new immune syste...

Beneficial mutations drive the within-host adaptation of viral populations and can prolong the duration of host infection. Yet, most mutations are not adaptive and the increase of the mean fitness of viral populations is hampered by deleterious and lethal mutations. Because of this ambivalent role of mutations, it is unclear if a higher mutation ra...

Mutations allowing pathogens to escape host immunity promote the spread of infectious diseases in heterogeneous host populations and can lead to major epidemics. Understanding the conditions that slow down this evolution is key for the development of durable control strategies against pathogens. Here, we use theory and experiments to compare the ef...

Pathogen adaptation to multiple selective pressures challenges our ability to control their spread. Here we analyze the evolutionary dynamics of pathogens spreading in a heterogeneous host population where selection varies periodically in space. We study both the transient dynamics taking place at the front of the epidemic and the long-term evoluti...

Many vector-borne diseases are affected by the seasonality of the environment. Yet, seasonality can act on distinct steps of the life cycle of the pathogen and it is often difficult to predict the influence of the periodic fluctuations of the environment on the basic reproduction ratio R0 of vector-borne pathogens. Here, we analyse a general vector...

Worldwide inequalities in vaccine availability are expected to affect the spread and spatial distribution of infectious diseases. It is unclear, however, how spatial variation in vaccination coverage can affect the long-term evolution of pathogens. Here we use an analytical model and numerical simulations to analyse the influence of different imper...

Understanding the evolution of multistrain pathogens 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, and this has motivated a large-body of research seeking to understand how acquired immunity can mold the genomics of pa...

Organisms have evolved a range of constitutive (always active) and inducible (elicited by parasites) defence mechanisms, but we have limited understanding of what drives the evolution of these orthogonal defence strategies. Bacteria and their phages offer a tractable system to study this: Bacteria can acquire constitutive resistance by mutation of...

Phages are promising tools to fight antibiotic-resistant bacteria, and as for now, phage therapy is essentially performed in combination with antibiotics. Interestingly, combined treatments including phages and a wide range of antibiotics lead to an increased bacterial killing, a phenomenon called phage-antibiotic synergy (PAS), suggesting that ant...

Since its emergence in late 2019, the SARS-CoV-2 virus has spread globally, causing the ongoing COVID-19 pandemic. In the fall of 2020, the Alpha variant (lineage B.1.1.7) was detected in England and spread rapidly, outcompeting the previous lineage. Yet, very little is known about the underlying modifications of the infection process that can expl...

Urbanization is a worldwide phenomenon tremendously modifying environmental features. By affecting the reservoirs of pathogens and the body and immune conditions of hosts, it is expected that urbanization alters the epidemiological dynamics and diversity of diseases. Cities could act as a shield against the parasite load or as a parasite burden, de...

Organisms have evolved a range of constitutive (always active) and inducible (elicited by parasites) defence mechanisms, but we have limited understanding of what drives the evolution of these orthogonal defence strategies. Bacteria and their phages offer a tractable system to study this: bacteria can acquire constitutive resistance by mutation of...

The constant arms race between bacteria and their phages has resulted in a large diversity of bacterial defence systems 1,2 , with many bacteria carrying several systems 3,4 . In response, phages often carry counter-defence genes 5–9 . If and how bacterial defence mechanisms interact to protect against phages with counter-defence genes remains uncl...

Population bottlenecks are commonplace in experimental evolution, specifically in serial passaging experiments where microbial populations alternate between growth and dilution. Natural populations also experience such fluctuations caused by seasonality, resource limitation, or host-to-host transmission for pathogens. Yet, how unlimited growth with...

Worldwide inequalities in vaccine availability are expected to affect the spread and spatial distribution of infectious diseases. It is unclear, however, how spatial variation in vaccination coverage can affect the long-term evolution of pathogens. Here we use an analytical model and numerical simulations to analyse the influence of different imper...

Many vector-borne diseases are affected by the seasonality of the environment. Yet, seasonality can act on distinct steps of the life-cycle of the pathogen and it is often difficult to predict the influence of the periodic fluctuations of the environment on the persistence of vector-borne pathogens. Here we analyse a general vector-borne disease mo...

Phages are promising tools to fight antibiotic-resistant bacteria, and as for now, phage therapy is essentially performed in combination with antibiotics. Interestingly, combined treatments including phages and a wide range of antibiotics lead to an increased bacterial killing, a phenomenon called phage-antibiotic synergy (PAS), suggesting that ant...

Following the initiation of the unprecedented global vaccination campaign against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), attention has now turned to the potential impact of this large-scale intervention on the evolution of the virus. In this Essay, we summarize what is currently known about pathogen evolution in the context o...

Since its emergence in late 2019, the SARS-CoV-2 virus has spread globally, causing the ongoing COVID-19 pandemic. In the fall of 2020, the Alpha variant (lineage B.1.1.7) was detected in England and rapidly spread and outcompeted the previous lineage. Yet, very little is known about the underlying modifications of the infection process that can ex...

The diversity of resistance challenges the ability of pathogens to spread and to exploit host populations. Yet, how this host diversity evolves over time remains unclear because it depends on the interplay between intraspecific competition among host genotypes and coevolution with pathogens. Here we study experimentally the effect of coevolving pha...

Vaccination is expected to reduce disease prevalence and to halt the spread of epidemics. But pathogen adaptation may erode the efficacy of vaccination and challenge our ability to control disease spread. Here we examine the influence of the speed of vaccination rollout on the overall risk of pathogen adaptation to vaccination. We extend the framew...

The acquisition of multiple resistance to drugs is often viewed as a slow process resulting from the incremental accumulation of resistance to single drugs. We challenge this view with the analysis of the evolution of drug resistance in a pathogen spreading in a heterogeneous host population where drug use varies periodically in space. We study bot...

Population bottlenecks are commonplace in experimental evolution, specifically in serial passaging experiments where microbial populations alternate between growth and dilution. Natural populations also experience such fluctuations caused by seasonality, resource limitation, or host-to-host transmission for pathogens. Yet, how unlimited growth with...

Mutations allowing pathogens to escape host immunity promote the spread of infectious diseases in heterogeneous host populations and can lead to major epidemics. Understanding the conditions favoring these evolutionary emergences is key for the development of durable control strategies against pathogens. Here we compare the durability of three diff...

Coevolution between bacteriophages (phages) and their bacterial hosts occurs through changes in resistance and counter-resistance mechanisms. To assess phage–host evolution in wild populations, we isolated 195 Vibrio crassostreae strains and 243 vibriophages during a 5-month time series from an oyster farm and combined these isolates with existing...

What is the influence of periodic environmental fluctuations on life‐history evolution? We present a general theoretical framework to understand and predict the long‐term evolution of life‐history traits under a broad range of ecological scenarios. Specifically, we investigate how periodic fluctuations affect selection when the population is also s...

Pathogen adaptation to public health interventions such as vaccination may take tortuous routes and involve multiple mutations at different locations in the pathogen genome, acting on distinct phenotypic traits. Yet how these multi-locus adaptations jointly evolve is poorly understood. Here we consider the joint evolution of two adaptations: pathog...

Significance The ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) raises an important question: who should we vaccinate first? Answering this question requires an analysis of both the short-term (epidemiological) and the long-term (evolutionary) consequences of targeted vaccination strategies. We analyze the speed of...

The diversity of resistance fuels host adaptation to infectious diseases and challenges the ability of pathogens to exploit host populations. Yet, how this host diversity evolves over time remains unclear because it depends on the interplay between intraspecific competition and coevolution with pathogens. Here we study the effect of a coevolving ph...

With the unprecedented global vaccination campaign against SARS-CoV-2 attention has now turned to the potential evolutionary consequences of this large-scale intervention. In this perspective we summarize what is currently known about evolution in the context of vaccination from research on other pathogen species, with an eye towards the future evo...

Many viruses cause both lytic infections, where they release viral particles, and dormant infections, where they await future opportunities to reactivate.1 The benefits of each transmission mode depend on the density of susceptible hosts in the environment.2-4 Some viruses infecting bacteria use molecular signaling to respond plastically to changes...

The limited supply of vaccines against SARS-CoV-2 raises the question of targeted vaccination. Older and more sensitive hosts should be vaccinated first to minimize the disease burden. But what are the evolutionary consequences of targeted vaccination? We clarify the consequences of different vaccination strategies through the analysis of the speed...

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,...

Pathogen adaptation to public health interventions, such as vaccination, may take tortuous routes and involve a multitude of genetic mutations acting on distinct phenotypic traits. For example, pathogens can escape the vaccine-induced immune response, or adjust their virulence so as to increase transmission in vaccinated hosts. Despite its importan...

A Correction to this paper has been published: https://doi.org/10.1038/s41396-020-00846-1

Coevolution between bacteriophage (or phage) and their bacterial host is thought to be key for the coexistence of these antagonists. Recent studies have revealed the major role of mobile genetic elements in the emergence of phage resistant hosts but how phage escape these defenses in the wild remained to be explored. Here we show a striking paralle...

The malaria parasite Plasmodium relictum is one of the most widespread species of avian malaria. As is the case in its human counterparts, bird Plasmodium undergoes a complex life cycle infecting two hosts: the arthropod vector and the vertebrate host. In this study, we examined transcriptomes of P. relictum (SGS1) during crucial timepoints within...

What is the influence of periodic environmental fluctuations on life-history evolution? We present a general theoretical framework to understand and predict the long-term evolution of life-history traits under a broad range of ecological scenarios. Indeed, this analysis yields time-varying selection gradients that help dissect the influence of the...

The mutation responsible for Duffy negativity, which impedes Plasmodium vivax infection, has reached high frequencies in certain human populations. Conversely, mutations capable of blocking the more lethal P. falciparum have not succeeded in malarious zones. Here we present an evolutionary-epidemiological model of malaria which demonstrates that if...

CRISPR-Cas immune systems are widespread in bacteria and archaea, but not ubiquitous. Previous work has demonstrated that CRISPR immunity is associated with an infection-induced fitness cost, which may help explain the patchy distribution observed. However, the mechanistic basis of this cost has remained unclear. Using Pseudomonas aeruginosa PA14 a...

Inference using mathematical models of infectious disease dynamics is a powerful tool to analyse epidemiological data and elucidate pathogen life cycles. Key epidemiological parameters can be estimated from demographic time series by computing the likelihood of alternative models of pathogen transmission. Here we use this inference approach to anal...

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,...

The malaria parasite Plasmodium relictum is one of the most widespread species of avian malaria. As is the case in its human counterparts, bird Plasmodium undergoes a complex life cycle infecting two hosts: the arthropod vector and the vertebrate host. In this study, we examine the transcriptome of P. relictum (SGS1) during crucial timepoints withi...

Many infectious diseases exhibit seasonal dynamics driven by periodic fluctuations of the environment. Predicting the risk of pathogen emergence at different points in time is key for the development of effective public health strategies. Here we study the impact of seasonality on the probability of emergence of directly transmitted pathogens under...

There is no doubt that the novel coronavirus SARS-CoV-2 that causes COVID-19 is mutating and thus has the potential to adapt during the current pandemic. Whether this evolution will lead to changes in the transmission, the duration, or the severity of the disease is not clear. This has led to considerable scientific and media debate, from raising a...

The Price equation has found widespread application in many areas of evolutionary biology, including the evolutionary epidemiology of infectious diseases. In this paper, we illustrate the utility of this approach to modelling disease evolution by first deriving a version of Price’s equation that can be applied in continuous time and to populations...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

On infection of their host, temperate viruses that infect bacteria (bacteriophages; hereafter referred to as phages) enter either a lytic or a lysogenic cycle. The former results in lysis of bacterial cells and phage release (resulting in horizontal transmission), whereas lysogeny is characterized by the integration of the phage into the host genom...

Lay Summary: Competition often occurs among diverse parasites within a single host, but control efforts could change its strength. We examined how the interplay between competition and control could shape the evolution of parasite traits like drug resistance and disease severity.

Selection of the fittest can promote individual competitiveness but often results in the erosion of group performance. Recently, several authors revisited this idea in crop production and proposed new practices based on selection for cooperative phenotypes, i.e. phenotypes that increase crop yield through decreased competitiveness. These recommenda...

At the start of life, the origin of a primitive genome required individual replicators, or genes, to act like enzymes and cooperatively copy each other. The evolutionary stability of such enzymatic cooperation poses a problem, because it would have been susceptible to parasitic replicators that did not act like enzymes but could still benefit from...

Dès 1917, dans l’article où il décrit ses premières observations et propose le nom de bactériophage, Félix d’Hérelle rapporte une première utilisation de ces virus pour traiter des infections bactériennes, donnant ainsi naissance à la phagothérapie. Le développement de cette application a montré qu’il était possible de mettre en place des traitemen...

Les bactériophages tiennent une place prépondérante dans le monde vivant. Du point de vue épistémologique, ils participent à la compréhension du vivant via trois aspects fondamentaux : (i) les mécanismes moléculaires les plus intimes du fonctionnement des infections virales et de celui des cellules elles-mêmes (biologie moléculaire) ; (ii) le fonct...

Adaptation in spatially heterogeneous environments results from the balance between local selection, mutation and migration. We study the interplay among these different evolutionary forces and demography in a classical two-habitat scenario with asexual reproduction. We develop a new theoretical approach that goes beyond the Adaptive Dynamics frame...

Bacteriophages encoding anti-CRISPR proteins (Acrs) must cooperate to overcome phage resistance mediated by the bacterial immune system CRISPR-Cas, where the first phage blocks CRISPR-Cas immunity in order to allow a second Acr phage to successfully replicate. However, in nature, bacteria are frequently not pre-immunized, and phage populations are...

Many infectious diseases exhibit seasonal dynamics driven by periodic fluctuations of the environment. Predicting the risk of pathogen emergence at different points in time is key for the development of effective public health strategies. Here we study the impact of seasonality on the probability of emergence of directly transmitted pathogens under...

The ability of the agent of plague, Yersinia pestis, to form a biofilm blocking the gut of the flea has been considered to be a key evolutionary step in maintaining flea‐borne transmission. However, blockage decreases dramatically the life expectancy of fleas, challenging the adaptive nature of blockage. Here, we develop an epidemiological model of...

The durability of host resistance is challenged by the ability of pathogens to escape the defence of their hosts. Understanding the variability in the durability of host resistance is of paramount importance for designing more effective control strategies against infectious diseases. Here, we study the durability of various clustered regularly inte...

Background Some Plasmodium species have the ability to modify the behaviour of their mosquito vectors. This is thought to be an adaptive strategy that maximizes the parasite’s transmission. Methods The effect of Plasmodium relictum infections on the blood feeding behaviour of Culex pipiens quinquefasciatus mosquitoes was monitored. Results Plasmo...

Many bacteria encode CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats; CRISPR-associated) adaptive immune systems to protect themselves against their viruses (phages). To overcome resistance, phages have evolved anti-CRISPR proteins (Acr), which naturally vary in their potency to suppress the host immune system and avoid phage...

The aim of vaccination is to prevent or limit the risk of pathogen infections for individual hosts but large vaccination coverage often has dramatic epidemiological consequences at the scale of the whole host population. This massive perturbation of the ecology and transmission of the pathogen can also have important evolutionary effects. In partic...

The theory of life-history evolution provides a powerful framework to understand the evolutionary dynamics of pathogens. It assumes, however, that host populations are large and that one can neglect the effects of demographic stochasticity. Here, we expand the theory to account for the effects of finite population size on the evolution of pathogen...

The emergence and re-emergence of pathogens remains a major public health concern. Unfortunately, when and where pathogens will (re-)emerge is notoriously difficult to predict, as the erratic nature of those events is reinforced by the stochastic nature of pathogen evolution during the early phase of an epidemic. For instance, mutations allowing pa...

Increased phage inoculum size (V0) and intermediate proportions of resistant hosts (fR) maximize the probability of evolutionary emergence in the Streptococcus thermophilus DGCC 7710–phage 2972 system. The proportion of populations (96 total) infected with either V0 ≈ 2 (red), V0 ≈ 20 (green), or V0 ≈ 200 (blue) phages, in which emergence (A, solid...

Raw data of the experiments presented in Figs 3, 4 and 5, S9, S10, and S11 Figs. The file contains five tabs and the data in each tab have been used to generate one (or two) figure(s). (1) Tab Fig 3. The table is composed of four columns: “Phages” indicates the number of phages initially inoculated, “Fraction” indicates the proportion of replicates...

Supplementary information. In this supplementary file, we provide (1) an explicit derivation of the probability of evolutionary emergence and additional theoretical results, and (2) more details on the experimental part of the project. (PDF)

The three alternative outcomes following the inoculation of the host population by a pathogen. The figure (A) is a schematic representation of the host population before and after the emergence. The dots represent uninfected hosts (pink), hosts infected with the wild-type pathogen (blue), and hosts infected with the escape mutant (red) that can inf...

Effect of the pathogen inoculum size (V0) on pathogen emergence when there is a single type of resistant host (n = 1) for different values of the fraction of resistant hosts (fR). In this figure, we plot P0,1 against V0 (dashed lines) and ∑V0=0∞e-E[V0]E[V0]V0V0!P0,1 against E[V0] (full line) under the assumption that the number of phages inoculated...

Effect of the cost of escape mutations (c) on evolutionary emergence. The shaded area refers to the fraction of pathogen emergence caused by pathogen adaptation (when c = 0.01) and is maximized for an intermediate value of the fraction of resistant hosts. The dashed curves represent the theoretical prediction when we track the change of the frequen...

Results from individual-based simulations (burst-death life cycle with fixed proportions of resistant hosts): Probability of emergence versus the proportion of resistant bacteria when a single propagule (V0 = 1) is introduced in a well-mixed population (ϕ = 0) with a single type of resistance (n = 1). Results are shown in the absence (u0,1 = 0, cro...

Proportion (1 − P0) of the 96 replicates in which phage escape mutants were generated in the absence of selection (Luria-Delbrück experiment) after plating the phage against 40 different BIM of Pseudomonas aeruginosa. In Figs 4 and 5, we used eight different BIMs (indicated in the gray rectangle, see S2 Table), on which our estimation of the phage...

Definitions of the main parameters of the model. (DOCX)

Spacer sequences of the eight BIMs of Pseudomonas aeruginosa used in our study (see S9 Fig). BIM, bacteriophage-insensitive mutant. (DOCX)

Summary figure. In this study, we explore the effects of three main components of the composition of the host population on the evolutionary emergence of pathogens. (TIF)

Effect of the proportion of resistant hosts (fR) on pathogen emergence when there is a single type of resistant host (n = 1) and for two values of the phage inoculum size (V0 = 1 and 10) when ϕ = 0.3. (A) Probability of pathogen emergence without (u0,1 = 0, dashed curve) or with (u0,1 = 0.01, full curve) mutations. The shaded area refers to the fra...

Results from individual-based simulations (burst-death life cycle with fixed proportions of resistant hosts): Probability of emergence versus the proportion of resistant bacteria when a single propagule (V0 = 1) is introduced in a well-mixed population (ϕ = 0). Results are shown on a log scale in the absence of mutation (u0,1 = 0, crosses, dotted l...

Results from individual-based simulations (birth–death life cycle with evolving proportions of resistant hosts). Upper panels (A and B): The probability of emergence versus the initial proportion of resistant bacteria in a well-mixed population (ϕ = 0) with a single type of resistance (n = 1). Results are shown in the absence (u0,1 = 0, crosses) or...

High proportion of resistant hosts minimizes the probability of emergence in the Pseudomonas aeruginosa UCBPP-PA14–phage DMS3vir system. Probability of emergence (i.e., when the amplification of the phage is detected) for increasing values of the proportion of a single resistant bacterium (fR). In contrast, Fig 4 presents the probability of evoluti...

Fitness landscape of the phage in a bacterial population with n = 4 different types of resistance. The figure (A) presents the network of 16 different strains with an increasing number of escape mutations. Arrows indicate possible mutation steps. The figure (B) presents the infectivity of five of these 16 different strains against each of the five...

The ability of the agent of plague, Yersinia pestis , to form a biofilm blocking the gut of the flea has been considered to be a key evolutionary step in maintaining flea-borne transmission. However, blockage decreases dramatically the life expectancy of fleas, challenging the adaptive nature of blockage. Here we develop an epidemiological model of...

Some phages encode anti-CRISPR (acr) genes, which antagonize bacterial CRISPR-Cas immune systems by binding components of its machinery, but it is less clear how deployment of these acr genes impacts phage replication and epidemiology. Here, we demonstrate that bacteria with CRISPR-Cas resistance are still partially immune to Acr-encoding phage. As...

Temporal variations in the activity of arthropod vectors can dramatically affect the epidemiology and evolution of vector-borne pathogens. Here, we explore the "Hawking hypothesis", which states that these pathogens may evolve the ability to time investment in transmission to match the activity of their vectors. First, we use a theoretical model to...

Adaptation in spatially heterogeneous environments results from the balance between local selection, mutation and migration. We study the interplay among these different evolutionary forces and demography in a classical two habitat scenario with asexual reproduction. We develop a new theoretical approach that fills a gap between the restrictive ass...

Table S1. Description of statistical models used.