精准医学与微生物感染——实施精准感染病学的探讨

2015年3月,习近平主席亲自指示科技部召开了国家首次精准医学战略专家座谈会。鉴于我国在病原微生物学、免疫学、疫苗学及感染病学中的成就,本文从病因和机体免疫应答方面分析了我国开展精准感染病学的优势并提出主要切入点。通过对免疫基因组学的研究,结合环境因素及生活习惯的综合研究,将对控制感染性疾病作出创新性贡献,这具有全球性的重要价值。     

Emerging and Reemerging Infectious Diseases: Biocomplexity as an Interdisciplinary Paradigm

Understanding factors responsible for reemergence of diseases believed to have been controlled and outbreaks of previously unknown infectious diseases is one of the most difficult scientific problems facing society today. Significant knowledge gaps exist for even the most studied emerging infectious diseases. Coupled with failures in the response to the resurgence of infectious diseases, this lack of information is embedded in a simplistic view of pathogens and disconnected from a social and ecological context, and assumes a linear response of pathogens to environmental change. In fact, the natural reservoirs and transmission rates of most emerging infectious diseases primarily are affected by environmental factors, such as seasonality or meteorological events, typically producing nonlinear responses that are inherently unpredictable. A more realistic view of emerging infectious diseases requires a holistic perspective that incorporates social as well as physical, chemical, and biological dimensions of our planet’s systems. The notion of biocomplexity captures this depth and richness, and most importantly, the interactions of human and natural systems. This article provides a brief review and a synthesis of interdisciplinary approaches and insights employing the biocomplexity paradigm and offers a social–ecological approach for addressing and garnering an improved understanding of emerging infectious diseases. Drawing on findings from studies of cholera and other examples of emerging waterborne, zoonotic, and vectorborne diseases, a “blueprint” for the proposed interdisciplinary research framework is offered which integrates biological processes from the molecular level to that of communities and regional systems, incorporating public health infrastructure and climate aspects.     

The structural simplification of an epidemiological compartment model

It is shown how a multicompartmental infectious disease model can be systematically examined for reduction of structural complexity. For steadystate situations, four basic rules are proposed for eliminating components of flow-lines, whole flow-lines, and compartments, plus combining compartments. An application to a typhoid fever model allows calculations to be done on a pocket calculator. The approach could be particularly important in developing countries.     

Skin as a potential source of infectious foot and mouth disease aerosols

This review examines whether exfoliated, virus-infected animal skin cells could be an important source of infectious foot and mouth disease virus (FMDV) aerosols. Infectious material rafting on skin cell aerosols is an established means of transmitting other diseases. The evidence for a similar mechanism for FMDV is: (i) FMDV is trophic for animal skin and FMDV epidermis titres are high, even in macroscopically normal skin; (ii) estimates for FMDV skin cell aerosol emissions appear consistent with measured aerosol emission rates and are orders of magnitude larger than the minimum infectious dose; (iii) the timing of infectious FMDV aerosol emissions is consistent with the timing of high FMDV skin concentrations; (iv) measured FMDV aerosol sizes are consistent with skin cell aerosols; and (v) FMDV stability in natural aerosols is consistent with that expected for skin cell aerosols. While these findings support the hypothesis, this review is insufficient, in and of itself, to prove the hypothesis and specific follow-on experiments are proposed. If this hypothesis is validated, (i) new FMDV detection, management and decontamination approaches could be developed and (ii) the relevance of skin cells to the spread of viral disease may need to be reassessed as skin cells may protect viruses against otherwise adverse environmental conditions.     

Genetic management of infectious diseases: a heterogeneous epidemio-genetic model illustrated with S. aureus mastitis

Given that individuals are genetically heterogeneous in their degree of resistance to infection, a model is proposed to formulate appropriate choices that will limit the spread of an infectious disease. The model is illustrated with data on S. aureus mastitis and is based on parameters characterizing the spread of the disease (contact rate, probability of infection after contact, and rate of recovery after infection), the demography (replacement and culling rates) and the genetic composition (degree of relationship and heritability of the disease trait) of the animal population. To decrease infection pressure, it is possible to apply non-genetic procedures that increase the culling (e.g., culling of chronically infected cows) and recovery (e.g., antibiotic therapy) rates of infected cows. But the contribution of the paper is to show that genetic management of infectious disease is also theoretically possible as a control measure complementary to non-genetic actions. Indeed, the probability for an uninfected individual to become infected after contact with an infected one is partially related to their degree of kinship: the more closely they are related, the more likely they are to share identical genes like those associated to the non-resistance to infection. Different prospective genetic management procedures are proposed to decrease the contact rate between infected and uninfected relatives and keep the number of secondary cases generated by one infected animal below 1.     

Neanderthal genomics suggests a pleistocene time frame for the first epidemiologic transition

High quality Altai Neanderthal and Denisovan genomes are revealing which regions of archaic hominin DNA have persisted in the modern human genome. A number of these regions are associated with response to infection and immunity, with a suggestion that derived Neanderthal alleles found in modern Europeans and East Asians may be associated with autoimmunity. As such Neanderthal genomes are an independent line of evidence of which infectious diseases Neanderthals were genetically adapted to. Sympathetically, human genome adaptive introgression is an independent line of evidence of which infectious diseases were important for AMH coming in to Eurasia and interacting with Neanderthals. The Neanderthals and Denisovans present interesting cases of hominin hunter‐gatherers adapted to a Eurasian rather than African infectious disease package. Independent sources of DNA‐based evidence allow a re‐evaluation of the first epidemiologic transition and how infectious disease affected Pleistocene hominins. By combining skeletal, archaeological and genetic evidence from modern humans and extinct Eurasian hominins, we question whether the first epidemiologic transition in Eurasia featured a new package of infectious diseases or a change in the impact of existing pathogens. Coupled with pathogen genomics, this approach supports the view that many infectious diseases are pre‐Neolithic, and the list continues to expand. The transfer of pathogens between hominin populations, including the expansion of pathogens from Africa, may also have played a role in the extinction of the Neanderthals and offers an important mechanism to understand hominin–hominin interactions well back beyond the current limits for aDNA extraction from fossils alone. Am J Phys Anthropol 160:379–388, 2016. © 2016 Wiley Periodicals, Inc.     

Modeling relapse in infectious diseases

An integro-differential equation is proposed to model a general relapse phenomenon in infectious diseases including herpes. The basic reproduction number R(0) for the model is identified and the threshold property of R(0) established. For the case of a constant relapse period (giving a delay differential equation), this is achieved by conducting a linear stability analysis of the model, and employing the Lyapunov-Razumikhin technique and monotone dynamical systems theory for global results. Numerical simulations, with parameters relevant for herpes, are presented to complement the theoretical results, and no evidence of sustained oscillatory solutions is found.     

Meeting report: How to get wrong things right--a discussion over current and future pandemic infectious diseases

Infectious diseases have played a substantial part in shaping the history of humanity. In a discussion at a recent EMBL-EMBO science and society symposium entitled 'The future of our species', several experts discussed how infectious diseases are still influencing our world today. Here we present examples from recent and current infectious disease epidemics followed by a discussion of the local, national and international response to these. Special emphasis is laid on how the change of our environment can augment the world-wide spread of infectious diseases and the role of education in limiting this spread. An urgent need for improved coordinative efforts in globally combating infectious diseases is called for and examples are highlighted.     

The role of ABO blood groups and secretor status in host defences

Epidemiological studies on the associations between ABO blood group antigens, secretor status and susceptibility to infectious agents are summarized. Evidence for association of non-secretion with some autoimmune diseases for which infectious aetiologies have been proposed is also given. Several hypotheses are proposed to explain the host-parasite interactions underlying the epidemiological observations, and evidence to support or refute them is presented.     

Binding between Prion Protein and Aβ Oligomers Contributes to the Pathogenesis of Alzheimer's Disease

A plethora of evidence suggests that protein misfolding and aggregation are underlying mechanisms of various neurodegenerative diseases, such as prion diseases and Alzheimer's disease(AD). Like prion diseases, AD has been considered as an infectious disease in the past decades as it shows strain specificity and transmission potential. Although it remains elusive how protein aggregation leads to AD, it is becoming clear that cellular prion protein(PrP~C ) plays an important role in AD pathogenesis. Here, we briefly reviewed AD pathogenesis and focused on recent progresses how PrP~C contributed to AD development. In addition, we proposed a potential mechanism to explain why infectious agents, such as viruses, conduce AD pathogenesis. Microbe infections cause Aβ deposition and upregulation of PrP~C , which lead to high affinity binding between Aβ oligomers and PrP~C . The interaction between PrP~C and Aβ oligomers in turn activates the Fyn signaling cascade, resulting in neuron death in the central nervous system(CNS). Thus, silencing PrP~C expression may turn out be an effective treatment for PrP~C dependent AD.     

气候变化对传染病爆发流行的影响研究进展

全球气候变化已影响到传染病发生、传播与变化的各个环节,从病原体及其携带者、传播途径和人体自身抵抗力等方面直接或间接影响传染病的发病趋势,从而对人类健康造成了巨大的威胁。所以加强对气候变化与传染病间关系、预测预报研究,对进一步认识、预防和控制传染病的爆发流行具有重要意义。本文首先阐述了全球气候变化对生物物种的地理分布和人类健康的影响,气候变化改变了生物物种的地理分布范围,增加了某些物种的潜在分布区域,并造成生物物侯期的改变;同时,极端气候事件成为导致种群数量波动的一个重要驱动力。气候变化对人类健康有直接和间接影响,它使得传染病发病率增加、传染病分布范围扩大、人群对疾病易感性增强。文章重点评述了气候变化对疟疾、登革热、霍乱、流行性乙型脑炎、流感、SARS、肠道传染病、鼠疫、血吸虫病等常见传染病流行机制和传播过程的影响研究进展。评述了传染病和气象因子关系分析中常用的定性和定量分析方法,传统的研究多以定性分析为主,方法较单一;目前,利用流行病学资料与同期的气象因子进行单因素相关分析、多元回归分析是常用的研究方法;主成分回归分析、逐步判别分析、灰色关联分析法、RS和GIS等方法近年来逐渐得到应用;数学建模、实验室生物学仿真实验方法是今后需强化的方向。提出了该研究领域国内外研究普遍存在和亟待解决的问题,针对目前的研究现状和存在的问题,提出了未来的研究重点和发展方向。     

核酸适配体在感染性疾病诊治中的研究进展

临床上，感染性疾病由于诊断不明或诊断时间较长导致严重后果的情况并不罕见。近年来，由于新型病原体感染报道层出不穷，现有病原体出现耐药也十分普遍，导致感染性疾病的诊断和治疗仍是临床上亟待解决的难题。核酸适配体是通过体外反复筛选或指数富集配体系统进化(systematic evolution of ligands by exponential enrichment，SELEX)技术筛选出来的一类具有特异性识别能力的寡核苷酸序列，具有靶向结合目标分子的能力，可用于病原体检测和新型治疗性药物的开发。适配体已在感染性疾病诊治中显现良好的应用前景，进一步推进相关研究有望为感染性疾病的诊治提供新的途径。     

A 25 nm virion is the likely cause of transmissible spongiform encephalopathies

The transmissible spongiform encephalopathies (TSEs) such as endemic sheep scrapie, sporadic human Creutzfeldt-Jakob disease (CJD), and epidemic bovine spongiform encephalopathy (BSE) may all be caused by a unique class of "slow" viruses. This concept remains the most parsimonious explanation of the evidence to date, and correctly predicted the spread of the BSE agent to vastly divergent species. With the popularization of the prion (infectious protein) hypothesis, substantial data pointing to a TSE virus have been largely ignored. Yet no form of prion protein (PrP) fulfills Koch's postulates for infection. Pathologic PrP is not proportional to, or necessary for infection, and recombinant and "amplified" prions have failed to produce significant infectivity. Moreover, the "wealth of data" claimed to support the existence of infectious PrP are increasingly contradicted by experimental observations, and cumbersome speculative notions, such as spontaneous PrP mutations and invisible strain-specific forms of "infectious PrP" are proposed to explain the incompatible data. The ability of many "slow" viruses to survive harsh environmental conditions and enzymatic assaults, their stealth invasion through protective host-immune defenses, and their ability to hide in the host and persist for many years, all fit nicely with the characteristics of TSE agents. Highly infectious preparations with negligible PrP contain nucleic acids of 1-5 kb, even after exhaustive nuclease digestion. Sedimentation as well as electron microscopic data also reveal spherical infectious particles of 25-35 nm in diameter. This particle size can accommodate a viral genome of 1-4 kb, sufficient to encode a protective nucleocapsid and/or an enzyme required for its replication. Host PrP acts as a cellular facilitator for infectious particles, and ultimately accrues pathological amyloid features. A most significant advance has been the development of tissue culture models that support the replication of many different strains of agent and can produce high levels of infectivity. These models provide new ways to rapidly identify intrinsic viral and strain-specific molecules so important for diagnosis, prevention, and fundamental understanding.     

When amyloids become prions

The conformational diseases, linked to protein aggregation into amyloid conformations, range from non-infectious neurodegenerative disorders, such as Alzheimer''s disease (AD), to highly infectious ones, such as human transmissible spongiform encephalopathies (TSEs). They are commonly known as prion diseases. However, since all amyloids could be considered prions (from those involved in cell-to-cell transmission to those responsible for real neuronal invasion), it is necessary to find an underlying cause of the different capacity to infect that each of the proteins prone to form amyloids has. As proposed here, both the intrinsic cytotoxicity and the number of nuclei of aggregation per cell could be key factors in this transmission capacity of each amyloid.     

对两用生物技术发展现状与生物安全的思考

生命科技的蓬勃发展与全球化步伐的持续加速,为人类社会带来了诸多福祉。然而,生物技术的两用特征和传染病严峻的流行趋势带来了一系列生物安全隐患,引发了世界性的生物安全问题。随着国际形势的日趋复杂,生物安全这一非传统安全问题已成为国家安全体系的重要组成部分。本文通过分析典型两用生物技术的潜在威胁及新发突发传染病的发展趋势,指出我国生物安全领域面临的挑战性问题。同时结合研究发达国家在战略、政策与技术方面应对生物安全的重要举措,从战略布局、科技创新、团队建设、政策支持等方面为我国在两用生物技术的生物安全领域的发展提出建议。     

A susceptible-infected model of early detection of respiratory infection outbreaks on a background of influenza

The threat of biological warfare and the emergence of new infectious agents spreading at a global scale have highlighted the need for major enhancements to the public health infrastructure. Early detection of epidemics of infectious diseases requires both real-time data and real-time interpretation of data. Despite moderate advancements in data acquisition, the state of the practice for real-time analysis of data remains inadequate. We present a nonlinear mathematical framework for modeling the transient dynamics of influenza, applied to historical data sets of patients with influenza-like illness. We estimate the vital time-varying epidemiological parameters of infections from historical data, representing normal epidemiological trends. We then introduce simulated outbreaks of different shapes and magnitudes into the historical data, and estimate the parameters representing the infection rates of anomalous deviations from normal trends. Finally, a dynamic threshold-based detection algorithm is devised to assess the timeliness and sensitivity of detecting the irregularities in the data, under a fixed low false-positive rate. We find that the detection algorithm can identify such designated abnormalities in the data with high sensitivity with specificity held at 97%, but more importantly, early during an outbreak. The proposed methodology can be applied to a broad range of influenza-like infectious diseases, whether naturally occurring or a result of bioterrorism, and thus can be an integral component of a real-time surveillance system.     

Human mobility patterns predict divergent epidemic dynamics among cities

The epidemic dynamics of infectious diseases vary among cities, but it is unclear how this is caused by patterns of infectious contact among individuals. Here, we ask whether systematic differences in human mobility patterns are sufficient to cause inter-city variation in epidemic dynamics for infectious diseases spread by casual contact between hosts. We analyse census data on the mobility patterns of every full-time worker in 48 Canadian cities, finding a power-law relationship between population size and the level of organization in mobility patterns, where in larger cities, a greater fraction of workers travel to work in a few focal locations. Similarly sized cities also vary in the level of organization in their mobility patterns, equivalent on average to the variation expected from a 2.64-fold change in population size. Systematic variation in mobility patterns is sufficient to cause significant differences among cities in infectious disease dynamics—even among cities of the same size—according to an individual-based model of airborne pathogen transmission parametrized with the mobility data. This suggests that differences among cities in host contact patterns are sufficient to drive differences in infectious disease dynamics and provides a framework for testing the effects of host mobility patterns in city-level disease data.     

The macroecology of infectious diseases: a new perspective on global‐scale drivers of pathogen distributions and impacts

Identifying drivers of infectious disease patterns and impacts at the broadest scales of organisation is one of the most crucial challenges for modern science, yet answers to many fundamental questions remain elusive. These include what factors commonly facilitate transmission of pathogens to novel host species, what drives variation in immune investment among host species, and more generally what drives global patterns of parasite diversity and distribution? Here we consider how the perspectives and tools of macroecology, a field that investigates patterns and processes at broad spatial, temporal and taxonomic scales, are expanding scientific understanding of global infectious disease ecology. In particular, emerging approaches are providing new insights about scaling properties across all living taxa, and new strategies for mapping pathogen biodiversity and infection risk. Ultimately, macroecology is establishing a framework to more accurately predict global patterns of infectious disease distribution and emergence.     

Quantum dots and prion proteins

A diagnostics of infectious diseases can be done by the immunologic methods or by the amplification of nucleic acid specific to contagious agent using polymerase chain reaction. However, in transmissible spongiform encephalopathies, the infectious agent, prion protein (PrP^Sc), has the same sequence of nucleic acids as a naturally occurring protein. The other issue with the diagnosing based on the PrP^Sc detection is that the pathological form of prion protein is abundant only at late stages of the disease in a brain. Therefore, the diagnostics of prion protein caused diseases represent a sort of challenges as that hosts can incubate infectious prion proteins for many months or even years. Therefore, new in vivo assays for detection of prion proteins and for diagnosis of their relation to neurodegenerative diseases are summarized. Their applicability and future prospects in this field are discussed with particular aim at using quantum dots as fluorescent labels.     

A Hybrid EM and Monte Carlo EM Algorithm and Its Application to Analysis of Transmission of Infectious Diseases

Summary In epidemics of infectious diseases such as influenza, an individual may have one of four possible final states: prior immune, escaped from infection, infected with symptoms, and infected asymptomatically. The exact state is often not observed. In addition, the unobserved transmission times of asymptomatic infections further complicate analysis. Under the assumption of missing at random, data‐augmentation techniques can be used to integrate out such uncertainties. We adapt an importance‐sampling‐based Monte Carlo Expectation‐Maximization (MCEM) algorithm to the setting of an infectious disease transmitted in close contact groups. Assuming the independence between close contact groups, we propose a hybrid EM‐MCEM algorithm that applies the MCEM or the traditional EM algorithms to each close contact group depending on the dimension of missing data in that group, and discuss the variance estimation for this practice. In addition, we propose a bootstrap approach to assess the total Monte Carlo error and factor that error into the variance estimation. The proposed methods are evaluated using simulation studies. We use the hybrid EM‐MCEM algorithm to analyze two influenza epidemics in the late 1970s to assess the effects of age and preseason antibody levels on the transmissibility and pathogenicity of the viruses.