Heterogeneity,Mixing, and the Spatial Scales of Mosquito-Borne Pathogen Transmission

The Ross-Macdonald model has dominated theory for mosquito-borne pathogen transmission dynamics and control for over a century. The model, like many other basic population models, makes the mathematically convenient assumption that populations are well mixed; i.e., that each mosquito is equally likely to bite any vertebrate host. This assumption raises questions about the validity and utility of current theory because it is in conflict with preponderant empirical evidence that transmission is heterogeneous. Here, we propose a new dynamic framework that is realistic enough to describe biological causes of heterogeneous transmission of mosquito-borne pathogens of humans, yet tractable enough to provide a basis for developing and improving general theory. The framework is based on the ecological context of mosquito blood meals and the fine-scale movements of individual mosquitoes and human hosts that give rise to heterogeneous transmission. Using this framework, we describe pathogen dispersion in terms of individual-level analogues of two classical quantities: vectorial capacity and the basic reproductive number, . Importantly, this framework explicitly accounts for three key components of overall heterogeneity in transmission: heterogeneous exposure, poor mixing, and finite host numbers. Using these tools, we propose two ways of characterizing the spatial scales of transmission—pathogen dispersion kernels and the evenness of mixing across scales of aggregation—and demonstrate the consequences of a model''s choice of spatial scale for epidemic dynamics and for estimation of , both by a priori model formulas and by inference of the force of infection from time-series data.     

Elucidating relationships between P.falciparum prevalence and measures of genetic diversity with a combined genetic-epidemiological model of malaria

There is an abundance of malaria genetic data being collected from the field, yet using these data to understand the drivers of regional epidemiology remains a challenge. A key issue is the lack of models that relate parasite genetic diversity to epidemiological parameters. Classical models in population genetics characterize changes in genetic diversity in relation to demographic parameters, but fail to account for the unique features of the malaria life cycle. In contrast, epidemiological models, such as the Ross-Macdonald model, capture malaria transmission dynamics but do not consider genetics. Here, we have developed an integrated model encompassing both parasite evolution and regional epidemiology. We achieve this by combining the Ross-Macdonald model with an intra-host continuous-time Moran model, thus explicitly representing the evolution of individual parasite genomes in a traditional epidemiological framework. Implemented as a stochastic simulation, we use the model to explore relationships between measures of parasite genetic diversity and parasite prevalence, a widely-used metric of transmission intensity. First, we explore how varying parasite prevalence influences genetic diversity at equilibrium. We find that multiple genetic diversity statistics are correlated with prevalence, but the strength of the relationships depends on whether variation in prevalence is driven by host- or vector-related factors. Next, we assess the responsiveness of a variety of statistics to malaria control interventions, finding that those related to mixed infections respond quickly (∼months) whereas other statistics, such as nucleotide diversity, may take decades to respond. These findings provide insights into the opportunities and challenges associated with using genetic data to monitor malaria epidemiology.     

复杂性-稳定性研究: 数学模型的进展

对自然生态系统的观察给人们以复杂的群落更稳定的直观印象, 但数学模型却得出了截然相反的结论。这一“悖论”使得复杂性-稳定性研究自20世纪70年代以来成为长期的热点。本文对这一领域的数学模型研究进行简要综述。首先对这一论题进行概念剖析, 然后将各类模型分为线性和非线性两大类, 前者即群落矩阵法, 后者包括相互作用矩阵法、复杂网络数值模拟法和食物网构件动力学法。它们分别基于不同的群落构建方法和稳定性判断标准, 探求各物种是如何相互作用并实现共存的。总体而言, 在随机构建的群落模型中, 多样性和连接度的增长不利于系统稳定; 而在更接近真实自然群落的模型中, 相互作用方式、网络拓扑结构、相互作用强度分布等方面的机制提供了稳定效应, 按此组织的生态网络可达到很高的复杂度。然而, 复杂性-稳定性的研究还远未结束, 当前的模型仍不足以反映自然群落中的复杂相互作用, 稳定性的概念也有待拓展。对这一议题的深入研究在生态学理论和生态系统管理实践方面都具有重大价值。     

Pathogen persistence in the environment and insect-baculovirus interactions: disease-density thresholds, epidemic burnout, and insect outbreaks

Classical epidemic theory focuses on directly transmitted pathogens, but many pathogens are instead transmitted when hosts encounter infectious particles. Theory has shown that for such diseases pathogen persistence time in the environment can strongly affect disease dynamics, but estimates of persistence time, and consequently tests of the theory, are extremely rare. We consider the consequences of persistence time for the dynamics of the gypsy moth baculovirus, a pathogen transmitted when larvae consume foliage contaminated with particles released from infectious cadavers. Using field-transmission experiments, we are able to estimate persistence time under natural conditions, and inserting our estimates into a standard epidemic model suggests that epidemics are often terminated by a combination of pupation and burnout rather than by burnout alone, as predicted by theory. Extending our models to allow for multiple generations, and including environmental transmission over the winter, suggests that the virus may survive over the long term even in the absence of complex persistence mechanisms, such as environmental reservoirs or covert infections. Our work suggests that estimates of persistence times can lead to a deeper understanding of environmentally transmitted pathogens and illustrates the usefulness of experiments that are closely tied to mathematical models.     

Persistence of Pathogens with Short Infectious Periods in Seasonal Tick Populations: The Relative Importance of Three Transmission Routes

Background

The flaviviruses causing tick-borne encephalitis (TBE) persist at low but consistent levels in tick populations, despite short infectious periods in their mammalian hosts and transmission periods constrained by distinctly seasonal tick life cycles. In addition to systemic and vertical transmission, cofeeding transmission has been proposed as an important route for the persistence of TBE-causing viruses. Because cofeeding transmission requires ticks to feed simultaneously, the timing of tick activity may be critical to pathogen persistence. Existing models of tick-borne diseases do not incorporate all transmission routes and tick seasonality. Our aim is to evaluate the influence of seasonality on the relative importance of different transmission routes by using a comprehensive mathematical model.

Methodology/Principal Findings

We developed a stage-structured population model that includes tick seasonality and evaluated the relative importance of the transmission routes for pathogens with short infectious periods, in particular Powassan virus (POWV) and the related “deer tick virus,” emergent encephalitis-causing flaviviruses in North America. We used the next generation matrix method to calculate the basic reproductive ratio and performed elasticity analyses. We confirmed that cofeeding transmission is critically important for such pathogens to persist in seasonal tick populations over the reasonable range of parameter values. At higher but still plausible rates of vertical transmission, our model suggests that vertical transmission can strongly enhance pathogen prevalence when it operates in combination with cofeeding transmission.

Conclusions/Significance

Our results demonstrate that the consistent prevalence of POWV observed in tick populations could be maintained by a combination of low vertical, intermediate cofeeding and high systemic transmission rates. When vertical transmission is weak, nymphal ticks support integral parts of the transmission cycle that are critical for maintaining the pathogen. We also extended the model to pathogens that cause chronic infections in hosts and found that cofeeding transmission could contribute to elevating prevalence even in these systems. Therefore, the common assumption that cofeeding transmission is not relevant in models of chronic host infection, such as Lyme disease, could lead to underestimating pathogen prevalence.     

Disentangling host,pathogen, and environmental determinants of a recently emerged wildlife disease: lessons from the first 15 years of amphibian chytridiomycosis research

The amphibian fungal disease chytridiomycosis, which affects species across all continents, recently emerged as one of the greatest threats to biodiversity. Yet, many aspects of the basic biology and epidemiology of the pathogen, Batrachochytrium dendrobatidis (Bd), are still unknown, such as when and from where did Bd emerge and what is its true ecological niche? Here, we review the ecology and evolution of Bd in the Americas and highlight controversies that make this disease so enigmatic. We explore factors associated with variance in severity of epizootics focusing on the disease triangle of host susceptibility, pathogen virulence, and environment. Reevaluating the causes of the panzootic is timely given the wealth of data on Bd prevalence across hosts and communities and the recent discoveries suggesting co‐evolutionary potential of hosts and Bd. We generate a new species distribution model for Bd in the Americas based on over 30,000 records and suggest a novel future research agenda. Instead of focusing on pathogen “hot spots,” we need to identify pathogen “cold spots” so that we can better understand what limits the pathogen''s distribution. Finally, we introduce the concept of “the Ghost of Epizootics Past” to discuss expected patterns in postepizootic host communities.     

Seroprevalence of dengue,Zika, chikungunya and Ross River viruses across the Solomon Islands

Across the Pacific, and including in the Solomon Islands, outbreaks of arboviruses such as dengue, chikungunya, and Zika are increasing in frequency, scale and impact. Outbreaks of mosquito-borne disease have the potential to overwhelm the health systems of small island nations. This study mapped the seroprevalence of dengue, Zika, chikungunya and Ross River viruses in 5 study sites in the Solomon Islands. Serum samples from 1,021 participants were analysed by ELISA. Overall, 56% of participants were flavivirus-seropositive for dengue (28%), Zika (1%) or both flaviviruses (27%); and 53% of participants were alphavirus-seropositive for chikungunya (3%), Ross River virus (31%) or both alphaviruses (18%). Seroprevalence for both flaviviruses and alphaviruses varied by village and age of the participant. The most prevalent arboviruses in the Solomon Islands were dengue and Ross River virus. The high seroprevalence of dengue suggests that herd immunity may be a driver of dengue outbreak dynamics in the Solomon Islands. Despite being undetected prior to this survey, serology results suggest that Ross River virus transmission is endemic. There is a real need to increase the diagnostic capacities for each of the arboviruses to support effective case management and to provide timely information to inform vector control efforts and other outbreak mitigation interventions.     

Can Wolbachia be used to control malaria?

Malaria is a mosquito-borne infectious disease caused by Plasmodium parasites transmitted by the infectious bite of Anopheles mosquitoes. Vector control of malaria has predominantly focused on targeting the adult mosquito through insecticides and bed nets. However, current vector control methods are often not sustainable for long periods so alternative methods are needed. A novel biocontrol approach for mosquito-borne diseases has recently been proposed, it uses maternally inherited endosymbiotic Wolbachia bacteria transinfected into mosquitoes in order to interfere with pathogen transmission. Transinfected Wolbachia strains in Aedes aegypti mosquitoes, the primary vector of dengue fever, directly inhibit pathogen replication, including Plasmodium gallinaceum, and also affect mosquito reproduction to allow Wolbachia to spread through mosquito populations. In addition, transient Wolbachia infections in Anopheles gambiae significantly reduce Plasmodium levels. Here we review the prospects of using a Wolbachia-based approach to reduce human malaria transmission through transinfection of Anopheles mosquitoes.     

Humidity – The overlooked variable in the thermal biology of mosquito-borne disease

Vector-borne diseases cause significant financial and human loss, with billions of dollars spent on control. Arthropod vectors experience a complex suite of environmental factors that affect fitness, population growth and species interactions across multiple spatial and temporal scales. Temperature and water availability are two of the most important abiotic variables influencing their distributions and abundances. While extensive research on temperature exists, the influence of humidity on vector and pathogen parameters affecting disease dynamics are less understood. Humidity is often underemphasized, and when considered, is often treated as independent of temperature even though desiccation likely contributes to declines in trait performance at warmer temperatures. This Perspectives explores how humidity shapes the thermal performance of mosquito-borne pathogen transmission. We summarize what is known about its effects and propose a conceptual model for how temperature and humidity interact to shape the range of temperatures across which mosquitoes persist and achieve high transmission potential. We discuss how failing to account for these interactions hinders efforts to forecast transmission dynamics and respond to epidemics of mosquito-borne infections. We outline future research areas that will ground the effects of humidity on the thermal biology of pathogen transmission in a theoretical and empirical framework to improve spatial and temporal prediction of vector-borne pathogen transmission.     

Ross River virus disease clinical presentation,pathogenesis and current therapeutic strategies

Ross River virus (RRV) is an arthitogenic alphavirus capable of causing outbreaks of debilitating musculoskeletal inflammatory disease in humans. RRV is the most common mosquito-borne disease in Australia, with outbreaks of RRV generally occurring during seasonal wet and warm conditions. Patients with Ross River virus disease (RRVD) typically present with fever, polyarthralgia, myalgia and a maculopapular erythematous rash. Treatment of the disease is usually palliative with no licensed vaccines or antiviral therapies currently available. In an effort to better inform therapeutic design, much progress has been made to understand the pathogenesis of RRVD. Progress has been largely driven by clinical evaluations supported by research using established murine models of RRVD, able to accurately replicate human disease. In this review we describe RRVD pathogenesis and the role of the host immune response, with particular focus on insights from studying animal models. We also discuss prospects for effective vaccines, preclinical development of therapeutic strategies and raise important questions for future RRV research.     

Superinfection and the evolution of resistance to antimalarial drugs

A major issue in the control of malaria is the evolution of drug resistance. Ecological theory has demonstrated that pathogen superinfection and the resulting within-host competition influences the evolution of specific traits. Individuals infected with Plasmodium falciparum are consistently infected by multiple parasites; however, while this probably alters the dynamics of resistance evolution, there are few robust mathematical models examining this issue. We developed a general theory for modelling the evolution of resistance with host superinfection and examine: (i) the effect of transmission intensity on the rate of resistance evolution; (ii) the importance of different biological costs of resistance; and (iii) the best measure of the frequency of resistance. We find that within-host competition retards the ability and slows the rate at which drug-resistant parasites invade, particularly as the transmission rate increases. We also find that biological costs of resistance that reduce transmission are less important than reductions in the duration of drug-resistant infections. Lastly, we find that random sampling of the population for resistant parasites is likely to significantly underestimate the frequency of resistance. Considering superinfection in mathematical models of antimalarial drug resistance may thus be important for generating accurate predictions of interventions to contain resistance.     

Antigenic Diversity,Transmission Mechanisms,and the Evolution of Pathogens

Pathogens have evolved diverse strategies to maximize their transmission fitness. Here we investigate these strategies for directly transmitted pathogens using mathematical models of disease pathogenesis and transmission, modeling fitness as a function of within- and between-host pathogen dynamics. The within-host model includes realistic constraints on pathogen replication via resource depletion and cross-immunity between pathogen strains. We find three distinct types of infection emerge as maxima in the fitness landscape, each characterized by particular within-host dynamics, host population contact network structure, and transmission mode. These three infection types are associated with distinct non-overlapping ranges of levels of antigenic diversity, and well-defined patterns of within-host dynamics and between-host transmissibility. Fitness, quantified by the basic reproduction number, also falls within distinct ranges for each infection type. Every type is optimal for certain contact structures over a range of contact rates. Sexually transmitted infections and childhood diseases are identified as exemplar types for low and high contact rates, respectively. This work generates a plausible mechanistic hypothesis for the observed tradeoff between pathogen transmissibility and antigenic diversity, and shows how different classes of pathogens arise evolutionarily as fitness optima for different contact network structures and host contact rates.     

Interplay between order-parameter and system parameter dynamics: considerations on perceptual-cognitive-behavioral mode-mode transitions exhibiting positive and negative hysteresis and on response times

A mathematical model is presented for the emergence of perceptual-cognitive-behavioral modes in psychophysical experiments in which participants are confronted with two alternatives. The model is based on the theory of self-organization and, in particular, the order parameter concept such that the emergence of a mode is conceptualized as an instability leading to the emergence of an appropriately defined order parameter. The order parameter model is merged with a second model that describes adaptation in terms of a system parameter dynamics. It is shown that the two-component model predicts hysteretic mode-mode transitions when control parameters are increased or decreased beyond critical values. The two-component model can account for both positive and negative hysteresis effects due to the interaction between order parameter and system parameter dynamics. Moreover, the model-based analysis reveals that response time curves look rather flat when response times are relatively decoupled from the mode-mode transition phenomenon. In general, response time curves exhibit a peaked close to the mode-mode transition point. In this context, the possibility is discussed that such peaked response time curves belong to the class of critical phenomena of self-organizing systems. In order to illustrate the relevance of peaked response time curves for future research and research reported in the past, results from a perceptual judgment experiment are reported, in which participants judged their ability to stand on a tilted slope for various angles of inclination. Response time curves were found that exhibited a peak around the mode-mode-transition points between “yes” and “no” responses.     

秦冠苹果品种对苹果黑星病的组织学抗性研究

为揭示苹果抗病品种秦冠在组织细胞学水平上抗苹果黑星病的特征,本研究采用扫描和透射电镜技术,将苹果黑星菌Venturia inaequalis接种侵染寄主后,系统观察抗病品种秦冠和感病品种嘎啦的叶片组织和细胞结构变化。扫描电镜观察结果表明,黑星菌分生孢子悬浮液接种秦冠和嘎啦叶片48 h后,病菌沿叶脉生长扩展,其菌丝可从叶片气孔或直接侵入。透射电镜观察结果表明,秦冠叶片的角质层厚度明显高于嘎啦,其中秦冠角质层平均厚度为1.75 μm,嘎啦为1.06 μm。透射电镜观察结果表明,黑星菌菌丝在寄主叶肉细胞间扩展,导致嘎啦栅栏组织细胞萎缩,排列松散,叶绿体变形受损,细胞内出现较大淀粉粒和胞内物质外渗流失,并在后期发展成大量细胞坏死;而秦冠虽症状类似,但受损程度明显小于嘎啦。以上结果表明,秦冠在组织细胞学上对苹果黑星病具有抗侵染、抗扩展和延缓病程发展的作用,可作为苹果黑星病抗性育种材料加以利用。     

A network-patch methodology for adapting agent-based models for directly transmitted disease to mosquito-borne disease

Mosquito-borne diseases cause significant public health burden and are widely re-emerging or emerging. Understanding, predicting, and mitigating the spread of mosquito-borne disease in diverse populations and geographies are ongoing modelling challenges. We propose a hybrid network-patch model for the spread of mosquito-borne pathogens that accounts for individual movement through mosquito habitats, extending the capabilities of existing agent-based models (ABMs) to include vector-borne diseases. The ABM are coupled with differential equations representing ‘clouds’ of mosquitoes in patches accounting for mosquito ecology. We adapted an ABM for humans using this method and investigated the importance of heterogeneity in pathogen spread, motivating the utility of models of individual behaviour. We observed that the final epidemic size is greater in patch models with a high risk patch frequently visited than in a homogeneous model. Our hybrid model quantifies the importance of the heterogeneity in the spread of mosquito-borne pathogens, guiding mitigation strategies.     

Weather Regulates Location,Timing, and Intensity of Dengue Virus Transmission between Humans and Mosquitoes

BackgroundDengue is one of the most aggressively expanding mosquito-transmitted viruses. The human burden approaches 400 million infections annually. Complex transmission dynamics pose challenges for predicting location, timing, and magnitude of risk; thus, models are needed to guide prevention strategies and policy development locally and globally. Weather regulates transmission-potential via its effects on vector dynamics. An important gap in understanding risk and roadblock in model development is an empirical perspective clarifying how weather impacts transmission in diverse ecological settings. We sought to determine if location, timing, and potential-intensity of transmission are systematically defined by weather.Conclusions/SignificanceLocal duration in limited areas of temperature-humidity weather-space identifies potential locations, timing, and magnitude of transmission. The weather-space profile of transmission-potential provides needed data that define a systematic and highly-sensitive weather-disease connection, demonstrating separate but coupled roles of temperature and humidity. New insights regarding natural regulation of human-mosquito transmission across diverse ecological settings advance our understanding of risk locally and globally for dengue and other mosquito-borne diseases and support advances in public health policy/operations, providing an evidence-base for modeling, predicting risk, and surveillance-prevention planning.     

Mosquito Population Regulation and Larval Source Management in Heterogeneous Environments

An important question for mosquito population dynamics, mosquito-borne pathogen transmission and vector control is how mosquito populations are regulated. Here we develop simple models with heterogeneity in egg laying patterns and in the responses of larval populations to crowding in aquatic habitats. We use the models to evaluate how such heterogeneity affects mosquito population regulation and the effects of larval source management (LSM). We revisit the notion of a carrying capacity and show how heterogeneity changes our understanding of density dependence and the outcome of LSM. Crowding in and productivity of aquatic habitats is highly uneven unless egg-laying distributions are fine-tuned to match the distribution of habitats’ carrying capacities. LSM reduces mosquito population density linearly with coverage if adult mosquitoes avoid laying eggs in treated habitats, but quadratically if eggs are laid in treated habitats and the effort is therefore wasted (i.e., treating 50% of habitat reduces mosquito density by approximately 75%). Unsurprisingly, targeting (i.e. treating a subset of the most productive pools) gives much larger reductions for similar coverage, but with poor targeting, increasing coverage could increase adult mosquito population densities if eggs are laid in higher capacity habitats. Our analysis suggests that, in some contexts, LSM models that accounts for heterogeneity in production of adult mosquitoes provide theoretical support for pursuing mosquito-borne disease prevention through strategic and repeated application of modern larvicides.     

Influence of contact definitions in assessment of the relative importance of social settings in disease transmission risk

Background

Realistic models of disease transmission incorporating complex population heterogeneities require input from quantitative population mixing studies. We use contact diaries to assess the relative importance of social settings in respiratory pathogen spread using three measures of person contact hours (PCH) as proxies for transmission risk with an aim to inform bipartite network models of respiratory pathogen transmission.

Methods and Findings

Our survey examines the contact behaviour for a convenience sample of 65 adults, with each encounter classified as occurring in a work, retail, home, social, travel or “other” setting. The diary design allows for extraction of PCH-interaction (cumulative time in face-face conversational or touch interaction with contacts) – analogous to the contact measure used in several existing surveys – as well as PCH-setting (product of time spent in setting and number of people present) and PCH-reach (product of time spent in setting and number of people in close proximity). Heterogeneities in day-dependent distribution of risk across settings are analysed using partitioning and cluster analyses and compared between days and contact measures. Although home is typically the highest-risk setting when PCH measures isolate two-way interactions, its relative importance compared to social and work settings may reduce when adopting a more inclusive contact measure that considers the number and duration of potential exposure events.

Conclusions

Heterogeneities in location-dependent contact behaviour as measured by contact diary studies depend on the adopted contact definition. We find that contact measures isolating face-face conversational or touch interactions suggest that contact in the home dominates, whereas more inclusive contact measures indicate that home and work settings may be of higher importance. In the absence of definitive knowledge of the contact required to facilitate transmission of various respiratory pathogens, it is important for surveys to consider alternative contact measures.     

Fatal or Harmless: Extreme Bistability Induced by Sterilizing,Sexually Transmitted Pathogens

Models of sexually transmitted infections have become a fixture of mathematical epidemiology. A common attribute of all these models is treating reproduction and mating, and hence pathogen transmission, as uncoupled events. This is fine for humans, for example, where only a tiny fraction of sexual intercourses ends up with having a baby. But it can be a deficiency for animals in which mating and giving birth are tightly coupled, and mating thus mediates both reproduction and pathogen transmission. Here, we model dynamics of sterilizing, sexually transmitted infections in such animals, assuming structural consistency between the processes of reproduction and pathogen transmission. We show that highly sterilizing, sexually transmitted pathogens trigger bistability in the host population. In particular, the host population can end up in two extreme alternative states, disease-free persistence and pathogen-driven extinction, depending on its initial state. Given that sterilizing, sexually transmitted infections that affect animals are abundant, our results might implicate an effective pest control tactic that consists of releasing the corresponding pathogens, possibly after genetically enhancing their sterilization power.