MicrobiologyBytes

Malaria counts among the worst scourges of humankind, accounting for some 500 million clinical cases per year and more than one million deaths, mostly children. It amounts to an immeasurable health burden and inhibits economic prosperity in numerous tropical countries, most extensively in Africa. Plasmodium falciparum is the most virulent among the four Plasmodium species parasitic to humans, accounting for 85% of all malaria cases, and nearly all of the mortality. The extreme pathogenicity of P. falciparum has suggested that it is a recent human parasite, acquired by transfer from a nonhuman host. Some early molecular phylogenies seemed to be consistent with this hypothesis, because they showed P. falciparum to be more closely related to Plasmodium gallinaceum, a chicken parasite, than to any of the other human parasite species. A considered possibility was that P. falciparum evolved from an avian parasite following a horizontal host transfer, perhaps in association with the Neolithic domestication of the chicken. It was recently shown that the closest relative of P. falciparum is P. reichenowi, a malaria parasite isolated from a captive chimpanzee that had not been included in earlier studies. The close phylogenetic relationship between P. falciparum and P. reichenowi, their distinctness from the other human malaria parasites, and their remoteness from bird or lizard parasites was soon confirmed by other studies.

The zoonotic origin of P. falciparum elevates interest in the possible ongoing transmission of other malaria parasites of primate origin into the human population. The repeated emergence of human malaria parasites from zoonotic reservoirs raises the question of whether ongoing transmission of P. reichenowi from chimpanzees to humans may be possible (or vice versa). The fact that this transmission has not happened repeatedly may reflect the difficulty in changing the sialic acid binding specificity of the parasite-binding proteins. In this regard, it is interesting that a major barrier limiting cross-transmission of avian influenza into humans (and vice versa) is due to differences in sialic acid linkage binding specificity.

The origin of malignant malaria. 2009 PNAS USA August 3, 2009
Plasmodium falciparum, the causative agent of malignant malaria, is among the most severe human infectious diseases. The closest known relative of P. falciparum is a chimpanzee parasite, Plasmodium reichenowi, of which one single isolate was previously known. The co-speciation hypothesis suggests that both parasites evolved separately from a common ancestor over the last 5–7 million years, in parallel with the divergence of their hosts, the hominin and chimpanzee lineages. Genetic analysis of eight new isolates of P. reichenowi, from wild and wild-born captive chimpanzees in Cameroon and Cote d’Ivoire, shows that P. reichenowi is a geographically widespread and genetically diverse chimpanzee parasite. The genetic lineage comprising the totality of global P. falciparum is fully included within the much broader genetic diversity of P. reichenowi. This finding is inconsistent with the co-speciation hypothesis. Phylogenetic analysis indicates that all extant P. falciparum populations originated from P. reichenowi, likely by a single host transfer, which may have occurred as early as 2–3 million years ago, or as recently as 10,000 years ago. The evolutionary history of this relationship may be explained by two critical genetic mutations. First, inactivation of the CMAH gene in the human lineage rendered human ancestors unable to generate the sialic acid Neu5Gc from its precursor Neu5Ac, and likely made humans resistant to P. reichenowi. More recently, mutations in the dominant invasion receptor EBA 175 in the P. falciparum lineage provided the parasite with preference for the overabundant Neu5Ac precursor, accounting for its extreme human pathogenicity.

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Rabies causes an estimated 55,000 human deaths globally each year, 23,750 of which occur in Africa. Moreover, 11 million people undergo rabies postexposure prophylaxis (PEP) worldwide each year. Rabies is a zoonotic disease with dogs remaining the principal host in Asia, parts of America, and large parts of Africa, and rabid dogs are the cause of most human rabies cases. Between 30% to 60% of the victims of dog bites are children under the age of 15. Inappropriate dog vaccination programs, limited access to vaccination, and postexposure treatment of individuals that have been exposed to rabid dogs are major problems in developing countries.

Rabies virus (RV), a negative-stranded RNA virus of the rhabdoviridae family, has a relatively simple, modular genome that encodes 5 structural proteins: a RNA-dependent RNA polymerase (L), a nucleoprotein (N), a phosphorylated protein (P), a matrix protein (M), and an external surface glycoprotein (G). The N, P, and L together with the genomic RNA form the ribonucleoprotein complex (RNP). The main feature of rabies virus is neuroinvasiveness, which refers to its unique ability to invade the CNS from peripheral sites. Virus uptake, axonal transport, trans-synaptic spread, and the rate of virus replication are key factors that determine the neuroinvasiveness of RV.

The regulation of virus replication also appears to be one of the important mechanisms contributing to RV pathogenesis. Pathogenic RV strains replicate at a lower rate than attenuated strains, which helps preserve the structure of neurons that is used by the viruses to reach the CNS. In addition, the lower expression levels of virus antigens, in particular the RV G, which is the major viral antigen responsible for the induction of protective immunity, hinders early detection by the host immune system. In contrast to wildlife RVs, most attenuated RV strains replicate very quickly and express large amounts of G, thereby inducing strong adaptive immune responses that result in virus clearance. These properties provide the basis for the use of attenuated RV strains for the pre- and PEP of rabies. A live-attenuated RV vaccine is likely to provide effective immunization with a single dose, which has practical, cost, and logistical advantages over conventional multi-dose vaccines with respect to the worldwide eradication of dog rabies. In addition, because live-attenuated RV vaccines are capable of inducing immune responses that can clear virulent RVs from the CNS, there is the possibility that such vaccines could serve as the foundation for the treatment of early stage human rabies.

Effective preexposure and postexposure prophylaxis of rabies with a highly attenuated recombinant rabies virus. PNAS USA 2009 106(27): 11300-5
Rabies remains an important public health problem with more than 95% of all human rabies cases caused by exposure to rabid dogs in areas where effective, inexpensive vaccines are unavailable. Because of their ability to induce strong innate and adaptive immune responses capable of clearing the infection from the CNS after a single immunization, live-attenuated rabies virus (RV) vaccines could be particularly useful not only for the global eradication of canine rabies but also for late-stage rabies postexposure prophylaxis of humans. To overcome concerns regarding the safety of live-attenuated RV vaccines, we developed the highly attenuated triple RV G variant, SPBAANGAS-GAS-GAS. In contrast to most attenuated recombinant RVs generated thus far, SPBAANGAS-GAS-GAS is completely nonpathogenic after intracranial infection of mice that are either developmentally immunocompromised (e.g., 5-day-old mice) or have inherited deficits in immune function (e.g., antibody production or type I IFN signaling), as well as normal adult animals. In addition, SPBAANGAS-GAS-GAS induces immune mechanisms capable of containing a CNS infection with pathogenic RV, thereby preventing lethal rabies encephalopathy. The lack of pathogenicity together with excellent immunogenicity and the capacity to deliver immune effectors to CNS tissues makes SPBAANGAS-GAS-GAS a promising vaccine candidate for both the preexposure and postexposure prophylaxis of rabies.

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Rabies has been one of the most feared diseases throughout human history and has the highest human case-fatality proportion of any infectious disease. Every year over 7 million people receive post-exposure prophylaxis, and an estimated 55,000 people die from rabies. Over 99% of these deaths occur in developing countries where rabies is endemic in domestic dog populations. However, the impacts of canine rabies are often overlooked, largely because human rabies deaths are now extremely rare in Western Europe and North America, where mass vaccination successfully eliminated the disease from domestic dog populations.

Although canine rabies has been successfully eliminated from Western Europe and North America, in the developing world someone dies every ten minutes from this horrific disease, which is primarily spread by domestic dogs. A quantitative understanding of rabies transmission dynamics in domestic dog populations is crucial to determining whether global elimination can be achieved. The unique pathology of rabies allowed researchers to trace case-to-case transmission directly during a rabies outbreak in northern Tanzania. From these unusual data, they generated a detailed analysis of rabies transmission biology and found evidence for surprisingly low levels of transmission. They also analysed outbreak data from around the world and found that the transmission of canine rabies has been inherently low throughout its global historic range, explaining the success of control efforts in developed countries. However, they show that when birth and death rates in domestic dog populations are high, such as in the study populations in Tanzania, it is more difficult to maintain population-level immunity in between vaccination campaigns. Nonetheless, although the level of vaccination coverage required is higher than would be predicted from naïve transmission models, global elimination of canine rabies can be achieved through appropriately designed, sustained domestic dog vaccination campaigns.

Transmission dynamics and prospects for the elimination of canine rabies. PLoS Biol. 2009 Mar 10;7(3):e53
Rabies has been eliminated from domestic dog populations in Western Europe and North America, but continues to kill many thousands of people throughout Africa and Asia every year. A quantitative understanding of transmission dynamics in domestic dog populations provides critical information to assess whether global elimination of canine rabies is possible. We report extensive observations of individual rabid animals in Tanzania and generate a uniquely detailed analysis of transmission biology, which explains important epidemiological features, including the level of variation in epidemic trajectories. We found that the basic reproductive number for rabies, R0, is very low in our study area in rural Africa (approximately 1.2) and throughout its historic global range (<2). This finding provides strong support for the feasibility of controlling endemic canine rabies by vaccination, even near wildlife areas with large wild carnivore populations. However, we show that rapid turnover of domestic dog populations has been a major obstacle to successful control in developing countries, thus regular pulse vaccinations will be required to maintain population-level immunity between campaigns. Nonetheless our analyses suggest that with sustained, international commitment, global elimination of rabies from domestic dog populations, the most dangerous vector to humans, is a realistic goal.

Related:

• Simplified rabies vaccination
• Negative sense RNA viruses

In 2002, the publication of the genome of Plasmodium falciparum, the most malignant agent of malaria, generated hope in the fight against this deadly disease by the opportunities it offered to discover new drug targets. Since then results have not lived up to the expectations. The development of comparative genomics to further understanding of P. falciparum has indeed been hindered by a lack of knowledge of closely related species’ genomes. Only one species, P. reichenowi, infecting chimpanzees, was previously known as a sister lineage of P. falciparum.

Researchers based in Gabon and France have now reported the discovery of a new malaria agent infecting chimpanzees in Central Africa. To investigate the diversity of Plasmodium parasites circulating in chimpanzees in Africa, the team collected blood from 19 wild-borne animals kept as pets by villagers in Gabon. Two were found infected by a Plasmodium parasite. This new species, named Plasmodium gaboni, is a close relative of the most virulent human malaria agent, P. falciparum. Based on its whole mitochondrial genome, they demonstrate that this new species is a close relative of P. falciparum and P. reichenowi. The analysis of its genome should thus offer the opportunity to explore P. falciparum specific adaptations to humans. These results suggest that malaria may have been present in early hominoids and may have experienced a radiation along with that of its hosts. This discovery highlights the paucity of our knowledge on the richness of Plasmodium species infecting primates and suggests more research in this area is urgently needed.

A New Malaria Agent in African Hominids. 2009 PLoS Pathog 5(5): e1000446
Plasmodium falciparum is the major human malaria agent responsible for 200 to 300 million infections and one to three million deaths annually, mainly among African infants. The origin and evolution of this pathogen within the human lineage is still unresolved. A single species, P. reichenowi, which infects chimpanzees, is known to be a close sister lineage of P. falciparum. Here we report the discovery of a new Plasmodium species infecting Hominids. This new species has been isolated in two chimpanzees (Pan troglodytes) kept as pets by villagers in Gabon (Africa). Analysis of its complete mitochondrial genome (5529 nucleotides including Cyt b, Cox I and Cox III genes) reveals an older divergence of this lineage from the clade that includes P. falciparum and P. reichenowi (21+/-9 Myrs ago using Bayesian methods and considering that the divergence between P. falciparum and P. reichenowi occurred 4 to 7 million years ago as generally considered in the literature). This time frame would be congruent with the radiation of hominoids, suggesting that this Plasmodium lineage might have been present in early hominoids and that they may both have experienced a simultaneous diversification. Investigation of the nuclear genome of this new species will further the understanding of the genetic adaptations of P. falciparum to humans. The risk of transfer and emergence of this new species in humans must be now seriously considered given that it was found in two chimpanzees living in contact with humans and its close relatedness to the most virulent agent of malaria.

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Hans Rosling unveils new data visuals that untangle the complex risk factors of one of the world’s deadliest (and most misunderstood) diseases: HIV. He argues that preventing transmissions – not drug treatment – is the key to ending the epidemic.

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Geostatistical maps are increasingly being used to plan neglected tropical disease control programmes. A decade after the conclusion of a schistosomiasis control program in Mali, prevalence of the disease has regressed to pre-intervention levels. New research finds that clusters of schistosomiasis infections occur generally in the same areas ten years after the end of a donor-funded control program, conducted between 1982 and 1992.

Schistosomiasis is a parasitic disease caused by several species of fluke of the genus Schistosoma. Although it has a low mortality rate, schistosomiasis often is a chronic illness that can damage internal organs and, in children, impair growth and cognitive development. Mali is one of the first countries in sub-Saharan Africa to have initiated a national schistosomiasis control program. Lack of government funding curtailed the program’s activities after 1998, until a new program, backed by the Schistosomiasis Control Initiative, began in 2004.

The authors undertook a comparative study of the spatial distribution of schistosomiasis in Mali between 1984-1989 and 2004-2006. They show that the spatial distribution of schistosomiasis was similar in both time periods, even in the face of large-scale control program based on mass distribution of anti-parasitic drugs. Long-term stability in the spatial distribution of schistosomiasis means that reviewing historic data can provide a useful, initial source of evidence for planning targeted contemporary control program. However, if these control program are to have a sustainable impact on the burden of schistosomiasis they must be delivered over a very long time period, or supplementary methods need to be implemented, such as improvement in water sanitation and hygiene.

This work has two main implications: that historic data can be used, in the first instance, to plan contemporary control programmes due to the stability of the spatial distribution of schistosomiasis; and that a decade of donor-funded mass distribution of praziquantel has had no discernable impact on the burden of schistosomiasis in subsequent generations of Malians, probably due to rapid reinfection.

A Comparative Study of the Spatial Distribution of Schistosomiasis in Mali in 1984–1989 and 2004–2006. 2009 PLoS Negl Trop Dis 3(5): e431
We investigated changes in the spatial distribution of schistosomiasis in Mali following a decade of donorfunded control and a further 12 years without control. National pre-intervention cross-sectional schistosomiasis surveys were conducted in Mali in 1984–1989 (in communities) and again in 2004–2006 (in schools). Bayesian geostatistical models were built separately for each time period and on the datasets combined across time periods. In the former, data from one period were used to predict prevalence of schistosome infections for the other period, and in the latter, the models were used to determine whether spatial autocorrelation and covariate effects were consistent across periods. Schistosoma haematobium prevalence was 25.7% in 1984–1989 and 38.3% in 2004–2006; S. mansoni prevalence was 7.4% in 1984–1989 and 6.7% in 2004–2006 (note the models showed no significant difference in mean prevalence of either infection between time periods). Prevalence of both infections showed a focal spatial pattern and negative associations with distance from perennial waterbodies, which was consistent across time periods. Spatial models developed using 1984–1989 data were able to predict the distributions of both schistosome species in 2004–2006 (area under the receiver operating characteristic curve was typically >0.7) and vice versa. A decade after the apparently successful conclusion of a donor-funded schistosomiasis control programme from 1982–1992, national prevalence of schistosomiasis had rebounded to pre-intervention levels. Clusters of schistosome infections occurred in generally the same areas accross time periods, although the precise locations varied. To achieve long-term control, it is essential to plan for sustainability of ongoing interventions, including stengthening endemic country health systems.

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Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981 and more than 30 million people (22 million in sub-Saharan Africa alone) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-positive people died within ten years of infection. Then, in 1996, highly active antiretroviral therapy (ART) – combinations of powerful antiretroviral drugs – was developed and the life expectancy of HIV-infected people living in affluent countries improved dramatically. Now, in industrialized countries, all-cause mortality (death from any cause) among HIV-infected patients treated successfully with ART is similar to that of the general population and the mortality rate (the number of deaths in a population per year) among patients with HIV/ AIDS is comparable to that among patients with diabetes and other chronic conditions.

Unfortunately, combination ART is costly, so although HIV/AIDS quickly became a chronic disease in industrialized countries, AIDS deaths continued unabated among the millions of HIV-infected people living in low- and middle-income countries. Then, in 2003, governments, international agencies and funding bodies began to implement plans to increase ART coverage in developing countries. By the end of 2007, nearly three million people living with HIV/AIDS in these countries were receiving ART – nearly a third of the people who urgently need ART. In sub-Saharan Africa more than 2 million people now receive ART and mortality in HIV-infected patients who have access to ART is declining. However, no-one knows how mortality among HIV-infected people starting ART compares with non-HIV related mortality in sub-Saharan Africa. This information is needed to ensure that appropriate health services (including access to ART) are provided in this region. In a new study, researchers compared mortality rates among HIV-infected patients starting ART with non-HIV related mortality in the general population of four sub-Saharan countries.

The researchers obtained estimates of the number of HIV-unrelated deaths and information about patients during their first two years on ART at five antiretroviral treatment programs in the Cote d’Ivoire, Malawi, South Africa, and Zimbabwe from the World Health Organization Global Burden of Disease project and the International epidemiological Databases to Evaluate AIDS initiative. They then calculated the excess mortality rates among the HIV-infected patients (the death rates in HIV-infected patients minus the national HIV-unrelated death rates) and the standardized mortality rate (SMR; the number of deaths among HIV-infected patients divided by the number of HIV-unrelated deaths in the general population). The excess mortality rate among HIV-infected people who started ART when they had a low CD4 cell count and clinically advanced disease was 17.5 per 100 person-years of follow-up. For HIV-infected people who started ART with a high CD4 cell count and early disease, the excess mortality rate was 1.0 per 100 person-years. The SMRs over two years of ART for these two groups of HIV-infected patients were 47.1 and 3.4, respectively. Finally, patients who started ART with a high CD4 cell count and early disease who survived the first year of ART had an excess mortality of only 0.27 per 100 person-years and an SMR over two years followup of only 1.14.

These findings indicate that mortality among HIV-infected people during the first two years of ART is higher than in the general population in these four sub-Saharan countries. However, for patients who start ART when they have a high CD4 count and clinically early disease, the excess mortality is moderate and similar to that associated with diabetes. Because the researchers compared the death rates among HIV-infected patients with estimates of national death rates rather than with estimates of death rates for the areas where the ART programs were located, these findings may not be completely accurate. Nevertheless, these findings support further expansion of strategies that increase access to ART in sub-Saharan Africa and suggest the excess mortality among HIV-infected patients in this region might be largely prevented by starting ART before an individual’s HIV infection has progressed to advanced stages.

Mortality of HIV-Infected Patients Starting Antiretroviral Therapy in Sub-Saharan Africa: Comparison with HIV-Unrelated Mortality. 2009 PLoS Med 6(4): e1000066

Mortality in HIV-infected patients who have access to highly active antiretroviral therapy (ART) has declined in sub-Saharan Africa, but it is unclear how mortality compares to the non-HIV–infected population. We compared mortality rates observed in HIV-1–infected patients starting ART with non-HIV–related background mortality in four countries in sub- Saharan Africa. Patients enrolled in antiretroviral treatment programmes in Cote d’Ivoire, Malawi, South Africa, and Zimbabwe were included. We calculated excess mortality rates and standardised mortality ratios (SMRs) with 95% confidence intervals (CIs). Expected numbers of deaths were obtained using estimates of age-, sex-, and country-specific, HIV-unrelated, mortality rates from the Global Burden of Disease project. Among 13,249 eligible patients 1,177 deaths were recorded during 14,695 person-years of follow-up. The median age was 34 y, 8,831 (67%) patients were female, and 10,811 of 12,720 patients (85%) with information on clinical stage had advanced disease when starting ART. The excess mortality rate was 17.5 (95% CI 14.5–21.1) per 100 person-years SMR in patients who started ART with a CD4 cell count of less than 25 cells/ml and World Health Organization (WHO) stage III/IV, compared to 1.00 (0.55–1.81) per 100 person-years in patients who started with 200 cells/ml or above with WHO stage I/II. The corresponding SMRs were 47.1 (39.1–56.6) and 3.44 (1.91– 6.17). Among patients who started ART with 200 cells/ml or above in WHO stage I/II and survived the first year of ART, the excess mortality rate was 0.27 (0.08–0.94) per 100 person-years and the SMR was 1.14 (0.47–2.77). Mortality of HIV-infected patients treated with combination ART in sub-Saharan Africa continues to be higher than in the general population, but for some patients excess mortality is moderate and reaches that of the general population in the second year of ART. Much of the excess mortality might be prevented by timely initiation of ART.

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Ebola and Marburg virus are filoviruses that cause outbreaks of highly lethal haemorrhagic fever. Mortality rates in these diseases average more than 50%, with the highest recorded rates seen for Ebola Zaire virus (88%) and Marburg Angola virus (90%). Infection with these filoviruses produces a very high fever followed by interference with blood coagulation and vascular permeability, causing internal bleeding, bruising and skin rashes. After an asymptomatic incubation period, which can last days to weeks, symptoms of a typical filovirus infection emerge; headache, nausea, fever and malaise followed by more serious haemorrhagic symptoms and, in fatal cases, death results from multi-organ failure owing to shock.

Present treatments for filovirus infection are palliative, and consist primarily of supportive care, including hydration and pain management. There is no effective treatment or cure for these diseases. Therefore, vaccine development is crucially important as a strategy for fighting filovirus outbreaks. However, vaccine efficacy testing for Ebola virus is very difficult. There is no readily identifiable high-risk human population that can be targeted for a placebo-controlled clinical trials because disease outbreaks are unpredictable and sporadic, both geographically and temporally. Normally, clinical trials of medicines and vaccines intended for human use follow a lengthy but predictable sequence of safety and efficacy testing.

Because of its sporadic nature, the incidence of Ebola virus infection in human populations is not predictable and does not allow for adequate testing. Moreover, the immune correlates of protection from filovirus disease in humans remain unknown and therefore cannot be used to assess candidate vaccine efficacy. To facilitate the licensing of medicines when efficacy cannot be evaluated in the setting of natural infection, the U.S. Food and Drug Administration (FDA) introduced a new regulation in 2002 as an alternative licensing pathway for pharmaceutical products that target highly lethal pathogens. The FDA’s “animal rule” allows approval based on animal efficacy data. The animal rule is intended to be used as a pathway for regulatory approval only when there is no other way to licence a vaccine (Correlates of protective immunity for Ebola vaccines: implications for regulatory approval by the animal rule. 2009 Nature Reviews Microbiology 7: 393-400).

In the case of Ebola virus, the relevant animal models are non-human primates and mice. The immune correlates of Ebola virus infection consist of immunoglobulin G responses, although other factors, such as T cells, are also likely to be important in a successful immune response. Current vaccine candidates against Ebola virus include the virus glycoprotein and nucleocapsid proteins. Initial animal testing of Ebola vaccines has shown a protective effect in non-human primates and positive antibody titres in humans.

To date, no vaccines have received regulatory approval and been licensed using the FDA animal rule. This pathway does not diminish the level of regulatory contol required for vaccine approval; extensive human testing is still required to demonstrate safety and immunogenicity. The predictive relationship between animals and humans for protective efficacy is unknown, and therefore an immune correlate is used to bridge the gap between animal efficacy studies and human immunogenicity trials. It has not yet been determined what level of efficacy in animals will be required for vaccine approval, but other vaccines currently administered to the U.S. population have shown efficacies in human trials that are as low as 18%. Even this level of efficacy will provide a benefit against pathogens such as filoviruses with high mortality rates, and therefore may be acceptable against emerging natural infections or bioterrorism threats.

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Bluetongue is a disease of ruminants caused by Bluetongue virus (BTV) and it is transmitted by biting midges. In sheep, clinical signs of BTV infection can include fever, vasodilation, swelling and, in severe cases, death, although the severity of symptoms varies with the breed of sheep, the individual animal and the strain of virus involved. Cattle are a major reservoir host for BTV infection, primarily because of the less obvious clinical signs in these animals. After an exhaustive search for a natural agent of transmission, Culicoides midges were shown to be the vectors for Bluetongue virus (Culicoides and the emergence of bluetongue virus in northern Europe. Trends Microbiol 2009 17(4): 172-178).

Although BTV infection was initially centred in Africa, the virus was first detected in Greece in 1989, from where it has spread steadily north. Since the disease is spread exclusively by insects, and because the virus is quite specific about which midge species can be used as vectors, predictions about the spread of the disease were based on known ranges of different midge species, which in turn depends on climate. However, midges can sometimes be carried over very long distances by weather systems, or by ships or aircraft.

Despite widespread speculation regarding the exact origin of BTV-8 as the strain of the virus found in northern Europe, no single convincing hypothesis has been proposed. Although future full-genome sequencing might assist this task (as was the case in the incursion of West Nile virus into North America), the small number of reference strains of BTV-8 from areas of potential origin collected before the incursion into northern Europe makes it unlikely that this approach will provide unambiguous evidence. As long as our understanding of the potential routes of virus introduction remains poor, we will be unable to accurately estimate the potential for future introductions of BTV, as has been illustrated by the more recent detection of BTV-6 in Europe, or of other midge-borne arboviruses, such as African horse sickness virus (AHSV).

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Although the technology to produce safe, effective, inactivated vaccines existed, no coordinated action was taken by any Member State of the European Union (EU) to begin production of a BTV-8 vaccine until late 2007, when the full damage began to become evident. This was in part due to the assumption that the virus would not overwinter under northern European conditions (despite the fact that BTV had been documented overwintering successfully in other areas with far cooler winter temperatures). In the absence of an available vaccine, knowledge concerning the entomology of the insects involved in BTV transmission became paramount.

The spread of BTV has provided a severe test of the way in which the movement of vector-borne pathogens is predicted, identified and controlled in Europe. There are many arobovirus diseases (spread by arthropod vectors such as midges, mosquitos and ticks), affecting human as well as animal health. Whether BTV represents a herald for future incursions by other arboviruses into Europe remains difficult to know. It is clear that there exists a similar potential for emergence of other insect-borne pathogens on grounds of climate alone, but where different vectors are used – for example, in the case of AHSV – the dynamics of the current BTV outbreak cannot easily be used to estimate risk. What has been shown by this outbreak is that arbovirus–vector relationships are highly dynamic and extremely difficult to combat. Unless regions that are potentially at risk of transmission are prepared to invest the resources required to provide adequate information regarding vectors and suitable control methods, this will remain the case.

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