With global trade and the worldwide ecological crisis, the danger of animal diseases spreading to human beings – known as zoonoses – is set to increase in the decades to come. The recent global SARS epidemic has provided a foretaste of the new challenges facing public health systems that are mobilising doctors, veterinarians and biologists.
Forensic scienceCertain diseases – such as influenza, so named because Italian Renaissance physicians believed it to be influenced by the stars – return at regular intervals. Others strike like bolts out of the blue. Marburg fever, rocketed a peaceful German university town of the same name to unwanted fame almost 40 years ago when seven people died, within a few hours of each other, from violent haemorrhagic fever. Other diseases never disappear. These include brucellosis or leishmaniosis, a disease with which many Mediterranean populations have had to learn to live.
All the preceding examples are diseases known as zoonoses. Whilst this term is little known to the general public, many specialists believe that zoonoses will represent a major threat to public health in the coming century.
Breaking down barriers Scientists are overdramatising the situation, some would say. Have humans not always lived in contact with animals? Has our immune system not learned, over millions of years, to combat these pathogens? Does the species barrier provide protection against these animal infections? The answer is, unfortunately, no. ‘Most emerging human diseases come from zoonoses, that is the natural spread of animal pathogens from animals to human beings,’ a trio of specialists (Daszak, Cunningham and Hyatt) wrote in the prestigious Science Review (21 January 2000) (1).
The AIDS-causing VIH-1 virus (surface burgeoning of a lymphocyte). Isolated in 1983 by Professor Montagnier at the Institute Pasteur (FR).
These species-hopping diseases include influenza, all the more dangerous because the virus can be transmitted from farm animals to human beings, AIDS, where proof is accumulating that the HIV virus passed from monkeys to people through the hunting and consumption of bushmeat. The terrible Marburg virus, which is closely related Ebola, was discovered in 1967 when green monkeys captured in Uganda were brought to a laboratory in the German city of the same name. In short, viruses, but also bacteria and parasites, often penetrate the species barrier.
Worse still, the opportunities for pathogens to jump across this “frontier” have multiplied in recent decades. ‘Rapid urbanisation, population movements, the clearing of new agricultural land, the growing trade in meat, milk and other animal products, the increasing speed and numbers of vehicles and even tourism have contributed to making zoonoses a problem that is no longer limited to certain rural areas, but is in some cases becoming global,’ is how Aristarchos Seimenis, of the World Health Organisation’s (WHO) Mediterranean Zoonoses Control Centre (GR) analyses the situation.
Hidden dangers of the global village Zoonoses represent a little known aspect of globalisation. Global warming is allowing certain species, in particular insects, to colonise new regions where they propagate new pathogens. Tropical deforestation is bringing humans into contact with animals they have not encountered before. The Hendra and Nipah viruses, discovered in 1994 and 1999, and deadly in some 50% of cases, appear to originate in fruit-eating bats from south-east Asian forests.
With the acceleration of international travel and trade, all inhabitants of the “global village” are concerned – a fact that is reinforcing the importance of North-South co-operation. Two centuries ago, a giraffe caused a sensation in Europe. Today, importers of reptiles, birds and other small tropical pets are flourishing. These newcomers too represent new potential diseases … Over 200 zoonoses have been counted today and there are certainly many more.
Our ignorance does not stop at their number. What do we know about the biochemical mechanisms of the species barrier? ‘Very little,’ says Alistair MacMillan of the New Haw Central Veterinary Laboratory (UK). ‘Pathogen-host interactions are right now the subject of intense research. A better understanding of the pathogenesis mechanisms, facilitated by growing knowledge of genomes, should help us see more clearly.’
The EU-USA Biotechnology Research Task Force concluded at its meeting on 25-26 June in Washington that there was an urgent need to organise a discussion meeting on this topic. ‘This workshop, scheduled for 2004, will focus more particularly on experimental hypotheses and models that can potentially verify the molecular and ambient mechanism governing the transmission of infectious agents from one species to another. Human beings are, of course, always the backdrop, but the questions are posed in terms of mechanisms, as our knowledge is rudimentary and exclusively empirical,’ explains Etienne Magnien, director for biotechnologies, food and agriculture at the European Commission’s Research DG.
Plasmodium falciparum.. Malaria haematozoan transmitted by anopheles (enlargement x 75,000).
If we do not yet understand how the species barrier works, do we at least know why certain pathogens, in particular viruses, are able to suddenly cross it? ‘The most traditional vision says that emerging viruses appear suddenly because they evolve de novo. But this emphasis on the variety of emerging viruses leads us to forget what many of them have in common. The vast majority of “new viruses” are, in fact, not new at all. They are derivates of what I would call viral circulation: the transference to human beings of diseases already existing in animal populations,’ states Stephen Morse, an American virologist at the University of Columbia.
This “viral circulation” phenomenon is particularly clear in the case of type A influenza viruses. Different strains exist, each adapted to infecting one particular species: horses, poultry, pigs, sea mammals and, of course, human beings. In ducks, both domestic and migrant, the virus is, on the other hand, not very dangerous. This turns these birds into a natural reservoir in which the virus can multiply and mutate.
Its genome is made up of eight independent segments of ribonucleic acid (RNA). This has two major consequences. On the one hand, since the RNA-reproducing enzyme (RNA polymerase) is a lot less faithful than its counterpart for DNA, multiplication errors are more frequent, producing mutations that confer new properties to the virus.
Antigenic breaking On the other hand, its structure of independent segments permits the rare phenomenon of antigenic breaking, leading to the replacement of one segment by another. When it is the genes that code for surface proteins – those recognised by our immune system – that are affected, the virus acquires totally new properties. This mutation is particularly fearsome when it occurs in pigs, which can be infected both by duck and human viruses. All that is needed, during co-infection, is for one of the segments coding for a surface protein of the human virus to be replaced by its duck counterpart for the new strain to be no longer recognised by our human immune system.
The terrible Spanish flu pandemic which, immediately after World War I, resulted in the death of between 20 and 40 million people across the world, was very likely caused by such an antigenic break. Two other pandemics (in 1957 and 1968) followed, both originating in China. ‘The reason is to be found in farming practices which combine pigs, ducks and chickens on the same farm, making China a veritable incubator of new viruses,’ explains Christop Scholtissek of the Veterinary Virology Institute in Gleissen (DE). For this specialist, the appearance of Severe Acute Respiratory Syndrome (SARS) cannot be explained by a comparable mechanism. The fact is that – unlike influenza – the coronavirus behind the disease does not possess a segmented genome.
A watchful eye What can be done to counter these long misunderstood or neglected zoonoses? One key activity is the monitoring of both animal and human health. Since we cannot foresee when and where they will appear, we need to be able to detect these diseases as soon as they emerge, and before they take on epidemic proportions. Vigilance is organised around three principles. First of all, training practitioners to identify speedily atypical symptoms which could presage a new disease. This was recently demonstrated by Carlo Urbani, a WHO worker in Vietnam. Although he paid for it with his life, Dr Urbani was the first to identify the SARS virus. Secondly, doctors should develop on-site epidemiological work, in which they become detectives cracking the mystery of where an infection comes from and how it is transmitted. Thirdly, laboratory diagnosis methods for analysing the nature of the pathogen need to be developed.
Since 1991, this surveillance – carried out by an EU-wide network – has encompassed all communicable diseases. However, the new threats from zoonoses are requiring an intensification of these synergies (see box ‘Learning from SARS’)
Hantaviruses Alongside this public health policy, major research efforts are being undertaken to gain a better knowledge of the state of health of both wild and domestic animal populations. A research consortium of German, Finnish, Lithuanian and Swedish laboratories has just described the various forms of hantaviruses – which cause respiratory diseases – infecting small rodents in eastern Europe.
‘Hantaviruses can pass to human beings, in particular forestry workers and farmers whose professions bring them into contact with these rodents. A particularly virulent form, found in the Balkans, is deadly in 12% of cases,’ explains virologist Detlev Krüger of Berlin’s Humboldt University (DE). The European project he coordinates has helped develop a diagnostic which can recognise all the forms of hantavirus and may become the basis for a vaccine(2). A new programme coordinated by Antti Vaheri of the University of Helsinki (FI) will follow up this work, combining the skills of virologists, veterinarians, molecular biologists and zoologists. Their task: to gain a better understanding of the dynamics of hantaviruses in rodent populations(3).
The veterinary challenge
Clethrionomys glareolus, a common rodent that can pass hantaviruses to humans.
As well as posing public health and ecological problems, zoonoses present serious challenges to European farming. ‘The most recent avian influenza epidemics, caused by the flu virus, beat all records. Several tens of millions of head of poultry were lost in Italy, the Netherlands, Germany, Belgium and other European countries, either from the sickness itself or by preventive slaughter measures,” Isabel Minguez-Tudela, in charge of this dossier at DG Research, recalls. The Eurosurveillance epidemiological watch network indicates that dozens of types of human conjunctivitis and several cases of influenza, one of them deadly, are attributable to this sudden flare-up of zoonoses. This underlines the importance of the European AVIFLU project, coordinated by Jill Banks of the Veterinary Laboratories Agency (UK), which has set itself the objective of developing ‘rapid diagnostic tests permitting the containment of the propagation of the virus by contact between infected animals at the sub-clinical stage(4)’.
Swine influenza poses different problems owing to the widespread use of a certain vaccine in European farms. “In recent years, we have observed a growing genetic and immunological variability of this virus. These changes appear to coincide with a growing virulence, and the lower effectiveness of vaccines,’ Guus Koch of the Lelystad Veterinary Sciences and Health Institute (NL) points out. This researcher coordinates a group of 14 laboratories from 10 EU countries which have set out to construct a database to monitor the evolution of this virus(5) closely. Bearing in mind the role of in spreading viruses highlights the importance of this work for managing the risk of zoonoses.
(1) P. Daszak, A. A. Cunningham et A. Hyatt, ‘Emerging infectious diseases of wildlife – Threats to biodiversity and human health’, Science (2000) 287: 443 -449
(2) ‘Bivalent hantavirus vaccine for Europe: different approaches and evaluation in animal models’ – Project ended on 01/08/2003 – EU funding: €1.25 million – Contact: Detlev Krüger – firstname.lastname@example.org
(3) ‘Diagnostics and control of rodent-borne viral zoonoses in Europe’ – 36-month project began on 01/09/2002– EU funding: €1.5 million – Contact: Antti Vaheri – email@example.com
(4) ‘Pathogenesis and improved diagnosis and control of avian influenza infections’ – 36-month project began on 01/10/2002– EU funding: €1.84 million – Contact: Jill Banks – firstname.lastname@example.org
(5) ‘European surveillance network for influenza in pigs’ – 36-month project began on 01/01/2001 – EU financing: €104,365 – Contact: Guus Koch – G.Koch@id.dlo.nl
Since 1994, the Ebola virus has been responsible for a series of epidemics, some with a mortality rate in excess of 80%, in tropical Africa. One of these, recorded at the end of 2001 in the Mekambo region of Gabon, combined a human catastrophe ...
Learning from SARS
‘SARS awakened Europe to the need for better preparation and to considerably boost co-operation at Union level. The EU and Member States already had a system for monitoring the propagation of the SARS virus, but they lacked a system for recommending ...
The scourge of ticks
Several species responsible for zoonoses live in the forests covering almost one-third of the Union’s territory. Ticks can communicate a number of diseases. With no requirement among Member States to declare cases, we know very little about the ...
Halting avian and swine influenzas
The extent and insidious form of the SARS epidemic, which took scientists by surprise, has demonstrated the ever-growing need for anticipatory research into viral transmission from animals to humans. One such example is the FLUPAN project which, since ...
Since 1994, the Ebola virus has been responsible for a series of epidemics, some with a mortality rate in excess of 80%, in tropical Africa. One of these, recorded at the end of 2001 in the Mekambo region of Gabon, combined a human catastrophe with an epizooty striking gorillas and chimpanzees. Knowledge gained from this tragedy allowed a simple diagnostic test to be developed for the first time. This success was the fruit of co-operation between researchers from the Mérieux-Pasteur Research Centre (France) and the International Medical Research Centre in Franceville, Gabon. This effort was supported by the European Commission’s International Co-operation (INCO) programme.
This new test uses magnetic colloids to pick up the virus in blood serum, and then detects certain of its genetic sequences. This test has the sensitivity of laboratory tests, but with the advantage that it can be used in the rough conditions of the field. It permits the identification of people incubating the virus, enabling health workers to quarantine them. European Research Commissioner Philippe Busquin praised this remarkable advance, saying: ‘this success highlights the importance of international and multidisciplinary co-operation between African and European teams.’
Learning from SARS
The Coronavirus was held responsible for the recent SARS epidemic.
‘SARS awakened Europe to the need for better preparation and to considerably boost co-operation at Union level. The EU and Member States already had a system for monitoring the propagation of the SARS virus, but they lacked a system for recommending – and even more for decreeing – measures to be taken at EU level to gain control of it,’ European Health Commissioner David Byrne said recently. The Commissioner proposed that a European Disease Prevention and Control Centre be set up to meet this need. Its primary missions will be epidemiological surveillance, including a network of pathologists, who can be called upon 24 hours a day to formulate scientific opinions on policies for implementation and to provide technical assistance. This independent agency, based on national institutes, should come into being in 2005.
The Research Directorate-General has launched a specific call for proposals dedicated to the understanding and prevention of SARS. With a budget of €9 million, the call closed on 30 September 2003.
Several species responsible for zoonoses live in the forests covering almost one-third of the Union’s territory. Ticks can communicate a number of diseases. With no requirement among Member States to declare cases, we know very little about the health impact of these parasites. It is to remedy this shortage of information that a European project is developing a database containing epidemiological information and information on clinics treating these pathologies.
In certain regions, foxes carry around a fearful parasite, the echinococcosis. In human beings, this worm that attacks the liver can be deadly. Identifying risk factors, developing preventive strategies, and communicating these to the general public are the main objectives of the European Echinorisk project.
‘Tick-borne diseases’ – 01/09/2002 to 31/08/2006 – European contribution: €171 708 – Contact: Philippe Brouqui -
‘Risk assessment and prevention of alveolar echinococcosis’ – 01/09/2001 to 30/11/2004 – European contribution: €499 959 – Contact: Peter Kern
Halting avian and swine influenzas
The extent and insidious form of the SARS epidemic, which took scientists by surprise, has demonstrated the ever-growing need for anticipatory research into viral transmission from animals to humans. One such example is the FLUPAN project which, since the end of 2001, has been developing diagnostic tools and vaccines against the potential threats posed by the reservoir of influenza-type viral infections originating in birds and pigs. One of the main objectives of this research is the production of vaccines based on mammal cell structures.
‘Preparing for an influenza pandemic: new vaccinations strategies (FLUPAN)’ – Project runs until 30/11/2004 – EU funding: €2.1 million – Contact: J.M. Wood