Outside-Host Growth of Pathogens Attenuates Epidemiological Outbreaks

Opportunist saprotrophic pathogens differ from obligatory pathogens due to their capability in host-independent growth in environmental reservoirs. Thus, the outside-host environment potentially influences host-pathogen dynamics. Despite the socio-economical importance of these pathogens, theory on their dynamics is practically missing. We analyzed a novel epidemiological model that couples outside-host density-dependent growth to host-pathogen dynamics. Parameterization was based on columnaris disease, a major hazard in fresh water fish farms caused by saprotrophic Flavobacterium columnare. Stability analysis and numerical simulations revealed that the outside-host growth maintains high proportion of infected individuals, and under some conditions can drive host extinct. The model can show stable or cyclic dynamics, and the outside-host growth regulates the frequency and intensity of outbreaks. This result emerges because the density-dependence stabilizes dynamics. Our analysis demonstrates that coupling of outside-host growth and traditional host-pathogen dynamics has profound influence on disease prevalence and dynamics. This also has implications on the control of these diseases.     

Loss of Competition in the Outside Host Environment Generates Outbreaks of Environmental Opportunist Pathogens

Environmentally transmitted pathogens face ecological interactions (e.g., competition, predation, parasitism) in the outside-host environment and host immune system during infection. Despite the ubiquitousness of environmental opportunist pathogens, traditional epidemiology focuses on obligatory pathogens incapable of environmental growth. Here we ask how competitive interactions in the outside-host environment affect the dynamics of an opportunist pathogen. We present a model coupling the classical SI and Lotka–Volterra competition models. In this model we compare a linear infectivity response and a sigmoidal infectivity response. An important assumption is that pathogen virulence is traded off with competitive ability in the environment. Removing this trade-off easily results in host extinction. The sigmoidal response is associated with catastrophic appearances of disease outbreaks when outside-host species richness, or overall competition pressure, decreases. This indicates that alleviating outside-host competition with antibacterial substances that also target the competitors can have unexpected outcomes by providing benefits for opportunist pathogens. These findings may help in developing alternative ways of controlling environmental opportunist pathogens.     

Outside-host phage therapy as a biological control against environmental infectious diseases

Background

Environmentally growing pathogens present an increasing threat for human health, wildlife and food production. Treating the hosts with antibiotics or parasitic bacteriophages fail to eliminate diseases that grow also in the outside-host environment. However, bacteriophages could be utilized to suppress the pathogen population sizes in the outside-host environment in order to prevent disease outbreaks. Here, we introduce a novel epidemiological model to assess how the phage infections of the bacterial pathogens affect epidemiological dynamics of the environmentally growing pathogens. We assess whether the phage therapy in the outside-host environment could be utilized as a biological control method against these diseases. We also consider how phage-resistant competitors affect the outcome, a common problem in phage therapy. The models give predictions for the scenarios where the outside-host phage therapy will work and where it will fail to control the disease. Parameterization of the model is based on the fish columnaris disease that causes significant economic losses to aquaculture worldwide. However, the model is also suitable for other environmentally growing bacterial diseases.

Results

Transmission rates of the phage determine the success of infectious disease control, with high-transmission phage enabling the recovery of the host population that would in the absence of the phage go asymptotically extinct due to the disease. In the presence of outside-host bacterial competition between the pathogen and phage-resistant strain, the trade-off between the pathogen infectivity and the phage resistance determines phage therapy outcome from stable coexistence to local host extinction.

Conclusions

We propose that the success of phage therapy strongly depends on the underlying biology, such as the strength of trade-off between the pathogen infectivity and the phage-resistance, as well as on the rate that the phages infect the bacteria. Our results indicate that phage therapy can fail if there are phage-resistant bacteria and the trade-off between pathogen infectivity and phage resistance does not completely inhibit the pathogen infectivity. Also, the rate that the phages infect the bacteria should be sufficiently high for phage-therapy to succeed.

     

Environmental Variation Generates Environmental Opportunist Pathogen Outbreaks

Many socio-economically important pathogens persist and grow in the outside host environment and opportunistically invade host individuals. The environmental growth and opportunistic nature of these pathogens has received only little attention in epidemiology. Environmental reservoirs are, however, an important source of novel diseases. Thus, attempts to control these diseases require different approaches than in traditional epidemiology focusing on obligatory parasites. Conditions in the outside-host environment are prone to fluctuate over time. This variation is a potentially important driver of epidemiological dynamics and affect the evolution of novel diseases. Using a modelling approach combining the traditional SIRS models to environmental opportunist pathogens and environmental variability, we show that epidemiological dynamics of opportunist diseases are profoundly driven by the quality of environmental variability, such as the long-term predictability and magnitude of fluctuations. When comparing periodic and stochastic environmental factors, for a given variance, stochastic variation is more likely to cause outbreaks than periodic variation. This is due to the extreme values being further away from the mean. Moreover, the effects of variability depend on the underlying biology of the epidemiological system, and which part of the system is being affected. Variation in host susceptibility leads to more severe pathogen outbreaks than variation in pathogen growth rate in the environment. Positive correlation in variation on both targets can cancel the effect of variation altogether. Moreover, the severity of outbreaks is significantly reduced by increase in the duration of immunity. Uncovering these issues helps in understanding and controlling diseases caused by environmental pathogens.     

The Influence of Infective Dose on the Virulence of a Generalist Pathogen in Rainbow Trout (Oncorhynchus mykiss) and Zebra Fish (Danio rerio)

Pathogen density and genetic diversity fluctuate in the outside-host environment during and between epidemics, affecting disease emergence and the severity and probability of infections. Although the importance of these factors for pathogen virulence and infection probability has been acknowledged, their interactive effects are not well understood. We studied how an infective dose in an environmentally transmitted opportunistic fish pathogen, Flavobacterium columnare, affects its virulence both in rainbow trout, which are frequently infected at fish farms, and in zebra fish, a host that is not naturally infected by F. columnare. We used previously isolated strains of confirmed high and low virulence in a single infection and in a co-infection. Infection success (measured as host morbidity) correlated positively with dose when the hosts were exposed to the high-virulence strain, but no response for the dose increase was found when the hosts were exposed to the low-virulence strain. Interestingly, the co-infection resulted in poorer infection success than the single infection with the high-virulence strain. The rainbow trout were more susceptible to the infection than the zebra fish but, in both species, the effects of the doses and the strains were qualitatively similar. We suggest that as an increase in dose can lead to increased host morbidity, both the interstrain interactions and differences in infectivity in different hosts may influence the severity and consequently the evolution of disease. Our results also confirm that the zebra fish is a good laboratory model to study F. columnare infection.     

The acquisition of hypovirulence in host-pathogen systems with three trophic levels

A major focus of research on the dynamics of host-pathogen interactions has been the evolution of pathogen virulence, which is defined as the loss in host fitness due to infection. It is usually assumed that changes in pathogen virulence are the result of selection to increase pathogen fitness. However, in some cases, pathogens have acquired hypovirulence by themselves becoming infected with hyperparasites. For example, the chestnut blight fungus Cryphonectria parasitica has become hypovirulent in some areas by acquiring a double-stranded RNA hyperparasite that debilitates the pathogen, thereby reducing its virulence to the host. In this article, we develop and analyze a mathematical model of the dynamics of host-pathogen interactions with three trophic levels. The system may be dominated by either uninfected (virulent) or hyperparasitized (hypovirulent) pathogens, or by a mixture of the two. Hypovirulence may allow some recovery of the host population, but it can also harm the host population if the hyperparasite moves the transmission rate of the pathogen closer to its evolutionarily stable strategy. In the latter case, the hyperparasite is effectively a mutualist of the pathogen. Selection among hyperparasites will often minimize the deleterious effects, or maximize the beneficial effects, of the hyperparasite on the pathogen. Increasing the frequency of multiple infections of the same host individual promotes the acquisition of hypovirulence by increasing the opportunity for horizontal transmission of the hyperparasite. This effect opposes the usual theoretical expectation that multiple infections promote the evolution of more virulent pathogens via selection for rapid growth within hosts.     

Environmental variation enables invasions of environmental opportunist pathogens

Emerging infectious diseases are a persistent threat to humans and food production but the mechanisms promoting the emergence of novel pathogens are not fully understood. The widely discussed explanations for pathogen emergence include range shifts, coincidental evolution of virulence, and host immunity variation. Here we propose a novel mechanism of virulence evolution that relies on environmental variability. Our model combines an environmental community experiencing random or periodic variability, to a classical SIR epidemiological model. We assume that environmentally growing, potentially infective variants arise at low frequency from a resident, non‐infective (benign microbial) strain through random variation on genetic material. We found that environmental perturbations commonly promote establishment of sporadic infections or persistent epidemics, by creating transient periods of low competition, which can in turn be exploited by an infective strain. Given the ubiquitous nature of potentially pathogenic environmental micro‐organisms and environmental variability, this mechanism provides a plausible explanation for emerging diseases.     

Lipidomics of host-pathogen interactions

The cell biology of intracellular pathogens (viruses, bacteria, eukaryotic parasites) has provided us with molecular information of host-pathogen interactions. As a result it is becoming increasingly evident that lipids play important roles at various stages of host-pathogen interactions. They act in first line recognition and host cell signaling during pathogen docking, invasion and intracellular trafficking. Lipid metabolism is a housekeeping function in energy homeostasis and biomembrane synthesis during pathogen replication and persistence. Lipids of enormous chemical diversity play roles as immunomodulatory factors. Thus, novel biochemical analytics in combination with cell and molecular biology are a promising recipe for dissecting the roles of lipids in host-pathogen interactions.     

Coincidental Loss of Bacterial Virulence in Multi-Enemy Microbial Communities

The coincidental virulence evolution hypothesis suggests that outside-host selection, such as predation, parasitism and resource competition can indirectly affect the virulence of environmentally-growing bacterial pathogens. While there are some examples of coincidental environmental selection for virulence, it is also possible that the resource acquisition and enemy defence is selecting against it. To test these ideas we conducted an evolutionary experiment by exposing the opportunistic pathogen bacterium Serratia marcescens to the particle-feeding ciliate Tetrahymena thermophila, the surface-feeding amoeba Acanthamoeba castellanii, and the lytic bacteriophage Semad11, in all possible combinations in a simulated pond water environment. After 8 weeks the virulence of the 384 evolved clones were quantified with fruit fly Drosophila melanogaster oral infection model, and several other life-history traits were measured. We found that in comparison to ancestor bacteria, evolutionary treatments reduced the virulence in most of the treatments, but this reduction was not clearly related to any changes in other life-history traits. This suggests that virulence traits do not evolve in close relation with these life-history traits, or that different traits might link to virulence in different selective environments, for example via resource allocation trade-offs.     

Virulence evolution at the front line of spreading epidemics

Understanding and predicting the spatial spread of emerging pathogens is a major challenge for the public health management of infectious diseases. Theoretical epidemiology shows that the speed of an epidemic is governed by the life‐history characteristics of the pathogen and its ability to disperse. Rapid evolution of these traits during the invasion may thus affect the speed of epidemics. Here we study the influence of virulence evolution on the spatial spread of an epidemic. At the edge of the invasion front, we show that more virulent and transmissible genotypes are expected to win the competition with other pathogens. Behind the front line, however, more prudent exploitation strategies outcompete virulent pathogens. Crucially, even when the presence of the virulent mutant is limited to the edge of the front, the invasion speed can be dramatically altered by pathogen evolution. We support our analysis with individual‐based simulations and we discuss the additional effects of demographic stochasticity taking place at the front line on virulence evolution. We confirm that an increase of virulence can occur at the front, but only if the carrying capacity of the invading pathogen is large enough. These results are discussed in the light of recent empirical studies examining virulence evolution at the edge of spreading epidemics.     

Parasite Replication and the Evolutionary Epidemiology of Parasite Virulence

Parasite virulence evolution is shaped by both within-host and population-level processes yet the link between these differing scales of infection is often neglected. Population structure and heterogeneity in both parasites and hosts will affect how hosts are exploited by pathogens and the intensity of infection. Here, it is shown how the degree of relatedness among parasites together with epidemiological parameters such as pathogen yield and longevity influence the evolution of virulence. Furthermore, the role of kin competition and the degree of cheating within highly structured parasite populations also influences parasite fitness and infectivity patterns. Understanding how the effects of within-host processes scale up to affect the epidemiology has importance for understanding host-pathogen interactions.     

Virulence evolution in emerging infectious diseases

Models of virulence evolution generally consider the outcome of competition between resident and mutant parasite strains at or near endemic equilibrium. Less studied is what happens during the initial phases of invasion and adaptation. Understanding initial adaptive dynamics is particularly important in the context of emerging diseases in wildlife and humans, for which rapid and accurate intervention may be of the essence. To address the question of virulence evolution in emerging diseases, we employ a simple stochastic modeling framework. As is intuitive, the pathogen strains most likely to emerge are those with the highest net reproductive rates (R0). We find, however, that stochastic events shape the properties of emerging pathogens in sometimes unexpected ways. First, the mean virulence of emerging pathogens is expected to be larger in dense host populations and/or when transmission is high, due to less restrictive conditions for the spread of the pathogen. Second, a positive correlation between average virulence and transmissibility emerges due to a combination of drift and selection. We conclude that at least in the initial phases of adaptation, special assumptions about constraints need not be invoked to explain some virulence-transmission correlations and that virulence management practices should consider how residual variation in transmission and virulence can be selected to reduce the prevalence and/or virulence of emerging infectious diseases.     

Imperfect vaccines and the evolution of pathogens causing acute infections in vertebrates

A study by Gandon et al. (2001) considered the potential ways pathogens may evolve in response to vaccination with imperfect vaccines. In this paper, by focusing on acute infections of vertebrate hosts, we examine whether imperfect vaccines that do not completely block a pathogen's replication (antigrowth) or transmission (antitransmission) may lead to evolution of more or less virulent pathogen strains. To address this question, we use models of the within-host dynamics of the pathogen and the host's immune responses. One advantage of the use of this within-host approach is that vaccination can be easily incorporated in the models and the trade-offs between pathogen transmissibility, host recovery, and virulence that drive evolution of pathogens in these models can be easily estimated. We find that the use of either antigrowth or antitransmission vaccines leads to the evolution of pathogens with an increased within-host growth rate; infection of unvaccinated hosts with such evolved pathogens results in high host mortality and low pathogen transmission. Vaccination of only a fraction of hosts with antigrowth vaccines may prevent pathogens from evolving high virulence due to pathogen adaptation to unvaccinated hosts and thus protection of vaccinated hosts from pathogen-induced disease. In contrast, antitransmission vaccines may be beneficial only if they are effective enough to cause pathogen extinction. Our results suggest that particular mechanisms of action of vaccines and their efficacy are crucial in predicting longterm evolutionary consequences of the use of imperfect vaccines.     

Virulence and community dynamics of fungal species with vertical and horizontal transmission on a plant with multiple infections

The virulence evolution of multiple infections of parasites from the same species has been modeled widely in evolution theory. However, experimental studies on this topic remain scarce, particularly regarding multiple infections by different parasite species. Here, we characterized the virulence and community dynamics of fungal pathogens on the invasive plant Ageratina adenophora to verify the predictions made by the model. We observed that A. adenophora was highly susceptible to diverse foliar pathogens with mixed vertical and horizontal transmission within leaf spots. The transmission mode mainly determined the pathogen community structure at the leaf spot level. Over time, the pathogen community within a leaf spot showed decreased Shannon diversity; moreover, the vertically transmitted pathogens exhibited decreased virulence to the host A. adenophora, but the horizontally transmitted pathogens exhibited increased virulence to the host. Our results demonstrate that the predictions of classical models for the virulence evolution of multiple infections are still valid in a complex realistic environment and highlight the impact of transmission mode on disease epidemics of foliar fungal pathogens. We also propose that seedborne fungi play an important role in structuring the foliar pathogen community from multiple infections within a leaf spot.     

我国淡水鱼类柱形病病原菌柱状黄杆菌的遗传多样性

为认识我国淡水鱼类烂鳃病的病原以及柱形病在我国的发生情况,实验从发生烂鳃病的病鱼中分离细菌性病原,经过生理生化特性分析以及是否在含托普霉素的Shieh培养基中生长并形成黄色假根状菌落,是否产生降解明胶和硫酸软骨素的酶类等特性的鉴定,并结合16SrDNA序列分析,证实柱状黄杆菌(Flavobacterium columnare)是所分离的烂鳃病的病原。同时,研究也证实20世纪曾经命名为烂鳃(Gill-rot)病病原的鱼害黏球菌(Myxococcus piscicola Lu,Nie & Ko,1975)是柱状黄杆菌的同物异名。利用分离到的16株柱状黄杆菌的16SrDNA序列,以及已经发表的柱状黄杆菌的相关序列,构建了系统发育树,发现柱状黄杆菌的菌株聚成3枝,与柱状黄杆菌的三种基因组型(Genomovar)相对应。其中当时命名为鱼害黏球菌的强毒株G4与分别分离自日本和美国的两株聚为一枝。另外两枝包括的菌株较多,它们中的一些菌株来源于相同的鱼类宿主,如鲤形目的种类;但是,这两枝也包括一些特有的株,如从欧洲和美国的鲑形目鱼类上分离的柱状黄杆菌聚为一枝,这一枝还包括我国曾经命名为鱼害黏球菌的G18弱毒株。从我国隶属于鲈形目的鳜鱼和鲟形目的中华鲟上分离到的柱状黄杆菌则聚为另外一枝。作者认为对不同基因组型菌株的致病性和致病机理的研究将可能从根本上认识鱼类柱形病的流行规律。       

Linking anthropogenic resources to wildlife–pathogen dynamics: a review and meta‐analysis

Urbanisation and agriculture cause declines for many wildlife, but some species benefit from novel resources, especially food, provided in human‐dominated habitats. Resulting shifts in wildlife ecology can alter infectious disease dynamics and create opportunities for cross‐species transmission, yet predicting host–pathogen responses to resource provisioning is challenging. Factors enhancing transmission, such as increased aggregation, could be offset by better host immunity due to improved nutrition. Here, we conduct a review and meta‐analysis to show that food provisioning results in highly heterogeneous infection outcomes that depend on pathogen type and anthropogenic food source. We also find empirical support for behavioural and immune mechanisms through which human‐provided resources alter host exposure and tolerance to pathogens. A review of recent theoretical models of resource provisioning and infection dynamics shows that changes in host contact rates and immunity produce strong non‐linear responses in pathogen invasion and prevalence. By integrating results of our meta‐analysis back into a theoretical framework, we find provisioning amplifies pathogen invasion under increased host aggregation and tolerance, but reduces transmission if provisioned food decreases dietary exposure to parasites. These results carry implications for wildlife disease management and highlight areas for future work, such as how resource shifts might affect virulence evolution.     

Vector-Borne Pathogen and Host Evolution in a Structured Immuno-Epidemiological System

Vector-borne disease transmission is a common dissemination mode used by many pathogens to spread in a host population. Similar to directly transmitted diseases, the within-host interaction of a vector-borne pathogen and a host’s immune system influences the pathogen’s transmission potential between hosts via vectors. Yet there are few theoretical studies on virulence–transmission trade-offs and evolution in vector-borne pathogen–host systems. Here, we consider an immuno-epidemiological model that links the within-host dynamics to between-host circulation of a vector-borne disease. On the immunological scale, the model mimics antibody-pathogen dynamics for arbovirus diseases, such as Rift Valley fever and West Nile virus. The within-host dynamics govern transmission and host mortality and recovery in an age-since-infection structured host-vector-borne pathogen epidemic model. By considering multiple pathogen strains and multiple competing host populations differing in their within-host replication rate and immune response parameters, respectively, we derive evolutionary optimization principles for both pathogen and host. Invasion analysis shows that the \({\mathcal {R}}_0\) maximization principle holds for the vector-borne pathogen. For the host, we prove that evolution favors minimizing case fatality ratio (CFR). These results are utilized to compute host and pathogen evolutionary trajectories and to determine how model parameters affect evolution outcomes. We find that increasing the vector inoculum size increases the pathogen \({\mathcal {R}}_0\), but can either increase or decrease the pathogen virulence (the host CFR), suggesting that vector inoculum size can contribute to virulence of vector-borne diseases in distinct ways.     

Social immunity modulates competition between coinfecting pathogens

Coinfections with multiple pathogens can result in complex within‐host dynamics affecting virulence and transmission. While multiple infections are intensively studied in solitary hosts, it is so far unresolved how social host interactions interfere with pathogen competition, and if this depends on coinfection diversity. We studied how the collective disease defences of ants – their social immunity – influence pathogen competition in coinfections of same or different fungal pathogen species. Social immunity reduced virulence for all pathogen combinations, but interfered with spore production only in different‐species coinfections. Here, it decreased overall pathogen sporulation success while increasing co‐sporulation on individual cadavers and maintaining a higher pathogen diversity at the community level. Mathematical modelling revealed that host sanitary care alone can modulate competitive outcomes between pathogens, giving advantage to fast‐germinating, thus less grooming‐sensitive ones. Host social interactions can hence modulate infection dynamics in coinfected group members, thereby altering pathogen communities at the host level and population level.     

Intensive aquaculture selects for increased virulence and interference competition in bacteria

Although increased disease severity driven by intensive farming practices is problematic in food production, the role of evolutionary change in disease is not well understood in these environments. Experiments on parasite evolution are traditionally conducted using laboratory models, often unrelated to economically important systems. We compared how the virulence, growth and competitive ability of a globally important fish pathogen, Flavobacterium columnare, change under intensive aquaculture. We characterized bacterial isolates from disease outbreaks at fish farms during 2003–2010, and compared F. columnare populations in inlet water and outlet water of a fish farm during the 2010 outbreak. Our data suggest that the farming environment may select for bacterial strains that have high virulence at both long and short time scales, and it seems that these strains have also evolved increased ability for interference competition. Our results are consistent with the suggestion that selection pressures at fish farms can cause rapid changes in pathogen populations, which are likely to have long-lasting evolutionary effects on pathogen virulence. A better understanding of these evolutionary effects will be vital in prevention and control of disease outbreaks to secure food production.     

Life history trade-offs and relaxed selection can decrease bacterial virulence in environmental reservoirs

Pathogen virulence is usually thought to evolve in reciprocal selection with the host. While this might be true for obligate pathogens, the life histories of opportunistic pathogens typically alternate between within-host and outside-host environments during the infection-transmission cycle. As a result, opportunistic pathogens are likely to experience conflicting selection pressures across different environments, and this could affect their virulence through life-history trait correlations. We studied these correlations experimentally by exposing an opportunistic bacterial pathogen Serratia marcescens to its natural protist predator Tetrahymena thermophila for 13 weeks, after which we measured changes in bacterial traits related to both anti-predator defence and virulence. We found that anti-predator adaptation (producing predator-resistant biofilm) caused a correlative attenuation in virulence. Even though the direct mechanism was not found, reduction in virulence was most clearly connected to a predator-driven loss of a red bacterial pigment, prodigiosin. Moreover, life-history trait evolution was more divergent among replicate populations in the absence of predation, leading also to lowered virulence in some of the 'predator absent' selection lines. Together these findings suggest that the virulence of non-obligatory, opportunistic bacterial pathogens can decrease in environmental reservoirs through life history trade-offs, or random accumulation of mutations that impair virulence traits under relaxed selection.