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ANTIGONE Sintesi della relazione

Project ID: 278976
Finanziato nell'ambito di: FP7-HEALTH
Paese: Netherlands

Periodic Report Summary 4 - ANTIGONE (ANTIcipating the Global Onset of Novel Epidemics)

Project Context and Objectives:
In recent years, an increased number of zoonotic viruses and bacteria have crossed the species barrier to humans and caused or threatened to cause human pandemics with high morbidity and mortality. Examples in recent years are the pandemic Influenza A/H1N1 virus and the outbreak of enterohaemorrhagic Escherichia coli (EHEC) O104:H4. Because of our inability to predict the emergence of these pathogens, it is difficult to take preventive measures. For any zoonotic virus or bacterium to emerge from its original animal reservoir(s) and develop into a pathogen with human pandemic potential, it must successfully cross various consecutive and interdependent barriers. These barriers may be divided into three categories: (1) the interspecies barriers, which encompass those that determine the level and nature of exposure to pathogens; (2) the intrahuman barriers, which determine the ability of a zoonotic pathogen to gain access to the appropriate tissue, replicate in the appropriate cell type, deal appropriately with the host immune response, and be excreted from the infected human host; and (3) the interhuman barriers, which a zoonotic pathogen must overcome in order to acquire the ability and opportunity to transmit efficiently among humans and cause human epidemics or pandemics. We term this interlinked sequence of events from animal reservoir to human pandemic the “Chain of Emergence”.

It is poorly understood which pathogen, host, vector, and environmental factors allow zoonotic pathogens to successfully cross these barriers. A better understanding of these factors will not be realized if addressed from the narrow perspective of a specific category of pathogens, a single discipline (e.g., virology or bacteriology), or a specific reservoir host (e.g., bats), which will inevitably omit a substantial part of the factors contributing to emergence of viruses and bacteria with human pandemic potential. For this reason, ANTIGONE will address this topic from the perspective the Chain of Emergence. In this way, focus is achieved on the determining factors and justice is done to the variety of zoonotic viruses and bacteria, reservoir host species, and routes of transmission involved over all stages in the chain of emergence.

In order to identify the key factors that render zoonotic pathogens prone to cross the species barrier and gain efficient transmissibility among humans, we have the following main objectives:
• To identify and understand the key factors that render zoonotic viruses and bacteria with human pandemic potential prone to cross the species barriers, adapt to the human host and further to gain human-to-human transmissibility.
• To translate our increased understanding of key factors in the chain of emergence to risk assessment, and options for prevention and intervention of human pandemics emerging from zoonotic pathogens.
• To develop and implement a One Health training programme, combining human and veterinary medical expertise with those from other relevant disciplines, in order to equip the future generation of scientists with the necessary knowledge to deal with emerging zoonotic infectious diseases.

In order to reach these objectives, we have a two-pronged approach. First, we perform primary research studies to fill important gaps in our understanding of how zoonotic pathogens can gain pandemic potential. These studies focus on selected viruses and bacteria, including SARS coronavirus, Nipah virus, Ebola virus, E. coli, M. bovis, and S. suis. Integral to these activities is a cross-disciplinary training programme for young scientists (Young ANTIGONE) and the development of risk assessment models. Second, we organize expert workshops where experts from the human and veterinary fields, from within and outside ANTIGONE, discuss key issues in infectivity, pathogenicity, and transmissibility of zoonotic pathogens and determine general criteria to assess the risk of these pathogens to gain human pandemic potential.

Project Results:
Research on key factors that allowed pathogens to cross from different animal reservoirs to humans led to the discovery of pigeon paramyxovirus type 1 (an NDV isolate) that was associated with a human case of fatal pneumonia, implicating pigeons as a source of human exposure to this virus. Regarding livestock reservoirs, red deer and wild boar were shown to be a source of infection for humans through shedding of C. burnetii, the cause of Q-fever. Changes resulting from viral and bacterial infections in a variety of mosquito and tick vectors were studied to understand the factors affecting the competence of these vectors for zoonotic pathogens. ANTIGONE partners played an important role in our understanding of the newly emerged MERS-CoV, showing that this coronavirus uses a receptor that is conserved between bats, pigs, and humans, suggesting that there is a low barrier against host switching. Furthermore, it established the central role of dromedaries in human exposure to MERS-CoV. Research indicated that only minimal human-to-human transmission of MERS-CoV had occurred. In addition, it was shown that the slaughterhouse setting is particular favourable for transmission to humans.

Regarding the intrahuman barrier, full genome sequencing of several model pathogens not only allowed to follow the process of evolution in the human host, but also provided clues to factors for host-switching. Furthermore, a new method—antibody landscape—was developed to study the role of antibody-mediated herd immunity on antigenic variation among pathogen strains, and indicated that pre-emptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals. In addition, investigation of Nipah virus and SARS-CoV and related coronaviruses for the ability to antagonize the innate immunity in the new (human) host, a critical characteristic of host-switching viruses, led to the discovery of potential targets for antiviral therapy.

The research on the interhuman barrier has been in acceleration in part as a result of research on HPAIV H5N1, which showed that several recently circulating isolates of HPAIV H5N1 are only a few mutations away from becoming efficiently transmissible among mammals, and highlighted critical areas of research to mitigate this risk. The level of knowledge gained for efficient human-to-human transmissibility of influenza viruses, is valuable for similar studies in other respiratory pathogens, such as SARS-CoV, pneumoviruses, and Y. pestis.

Important research was performed on the relationship between climate change and emergence of tick-borne diseases, indicating that the combination of climate, host abundance and social factors may explain the upsurge of epidemics transmitted by ticks to humans. For risk assessment of introduction of bat-borne zoonotic pathogens in Europe, a generic model framework and structure was developed. Results based on Nipah virus suggested that the main risk of an introduction event to the EU is from legal trade of fruit products. In the light of recent events, the model has been parameterized for MERS-CoV and Ebola virus.

A special focus in ANTIGONE is on the E. coli O104:H4 outbreak. Research revealed that travel was associated with a high rate of acquisition of virulence factors of E. coli O104:H4, and that EHEC virulence may increase during human infection. Furthermore, research on O104:H4 indicated that the pESBL plasmid from the outbreak strain may play a crucial role in its resistance to antimicrobials and other compounds. Research on the role of outer membrane vesicles (OMVs) demonstrates the potential role of OMVs in the virulence and pathogenicity of EHEC O104:H4. Research on rapid, sensitive, and specific detection of O104:H4 and the other major EHEC serotypes that cause haemolytic uremic syndrome, resulted in a system of real-time multiplex PCR-based detection assays that could be used as surveillance tool for the detection of pathogenic strains.

Potential Impact:
ANTIGONE will contribute to a better understanding of the emergence and transmission of pathogens with pandemic potential by a combination of expert workshops and primary research studies. In the expert workshops, we will identify the key factors that render zoonotic pathogens prone to cross the species barrier by making a concerted and intensive effort to synthesize the expertise of ANTIGONE with existing available knowledge on the emergence of infectious diseases of zoonotic origin. In the primary research studies, we will fill in critical gaps in our knowledge of the process of pathogen emergence. This combination of studies provides the necessary breadth (expert workshops) and depth (primary research studies) for an optimal improvement of our understanding of zoonotic pathogen emergence. This will help to predict the zoonotic and pandemic potential of pathogens, and improve our abilities of early detection and effective response against outbreaks of emerging zoonotic pathogens. In addition, ANTIGONE will provide a relevant combination of training in human medicine, veterinary medicine, and other critical disciplines—“One Health”—to prepare a new generation of scientists to deal with tomorrow’s global health problems. ANTIGONE will reduce the separation between human and veterinary medicine in the surveillance, research, prevention and mitigation of emerging infectious diseases by training a new generation of scientists according to the concept of One Health.

ANTIGONE will contribute to improved preparedness planning, in particular modelling and prediction, but also development of appropriate intervention measures by filling in critical gaps in our knowledge of zoonotic pathogen emergence, by identifying the key factors allowing zoonotic pathogens to cross the species barrier at each of three levels (interspecies, intrahuman, interhuman), by performing primary research studies on risk assessment and modelling of emerging zoonotic diseases, by bringing together scientists from ANTIGONE and from the rest of the world together with policy makers together to integrate, synthesize, and translate the state-of-the art, and by equipping a new generation of scientists with the knowledge to deal with these diseases.

The primary research studies indicated above will provide new data on critical gaps in our knowledge of the emergence of significant zoonotic pathogens, including Nipah virus, Crimean Congo Haemorrhagic Fever virus, SARS-coronavirus, Influenzavirus, Ebola virus, hanta virus, E. coli, M. bovis, C. burnetii, B. burgdorferi, A. phagocytophilum, Y. pestis and S. suis. This new knowledge in itself will contribute to the expected impact by generating new opportunities for prevention and control of emerging zoonotic pathogens.

A core component of this project is to synthesize the expertise of ANTIGONE with existing available knowledge across the spectrum of emerging infectious diseases, in order to identify the key factors that render zoonotic pathogens prone to cross the species barrier for each of the three categories: interspecies, intrahuman, and interhuman. This synthesis will form an important contribution to the expected impact of ANTIGONE by showing the way to target and improve efforts in preparedness planning, prevention, and intervention of emerging zoonotic pathogens. We thus expect ANTIGONE to not only create a step-change in scientific basis for, but critically also in the implementation of, broadly effective preparedness plans, prevention strategies, and intervention strategies.

List of Websites:


Thijs Kuiken, (Professor in Comparative Pathology)
Tel.: +31 704 4066


Life Sciences
Numero di registrazione: 182377 / Ultimo aggiornamento: 2016-05-20
Fonte d'informazione: SESAM