MicrobiologyBytes

A myriad of factors favor the emergence and re-emergence of arthropod-borne viruses (arboviruses), including migration, climate change, intensified livestock production, an increasing volume of international trade and transportation, and changes to ecosystems (e.g., deforestation and loss of biodiversity). Consequently, arboviruses are distributed worldwide and represent over 30% of all emerging infectious diseases identified in the past decade. Although some arboviral infections go undetected or are associated with mild, flu-like symptoms, many are important human and veterinary pathogens causing serious illnesses such as arthritis, gastroenteritis, encephalitis and hemorrhagic fever and devastating economic loss as a consequence of lost productivity and high mortality rates among livestock. One of the most consistent molecular features of emerging arboviruses, in addition to their near exclusive use of RNA genomes, is the inclusion of viral, non-structural proteins that act as interferon antagonists. In this review, we describe these interferon antagonists and common strategies that arboviruses use to counter the host innate immune response. In addition, we discuss the complex interplay between host factors and viral determinants that are associated with virus emergence and re-emergence, and identify potential targets for vaccine and anti-viral therapies.

The Role of Interferon Antagonist, Non-Structural Proteins in the Pathogenesis and Emergence of Arboviruses. (2011) Viruses 3(6): 629-658; doi:10.3390/v3060629

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Arthropod-borne viruses (arboviruses) are transmitted biologically among vertebrate hosts by hematophagous (blood feeding) arthropod vectors such as mosquitoes and other biting flies, and ticks. Being, by definition, biologically transmitted, arboviruses must replicate in the arthropod vector prior to transmission, as opposed to being mechanically transmitted, without replication in the vector, through contaminated mouthparts. Biological transmission can be vertical, involving the passage of the virus from an infected female vector to both male and female offspring. Horizontal transmission can be venereal, from a vertically infected male directly to a female vector, as well as oral from a female vector to a vertebrate host via the saliva during blood feeding. The latter horizontal mode of transmission is most common for the majority of arboviruses and involves infection of the vector alimentary tract following a viremic bloodmeal, dissemination of the virus in the vector, and eventual virus replication in the salivary glands, followed by the injection of infectious saliva during blood feeding.

The arboviruses include a wide variety of RNA virus taxa including the alphaviruses (genus Alphavirus, one of two genera in the family Togaviridae); the flaviviruses (genus Flavivirus, one of three genera in the family Flaviviridae); the bunyaviruses (Bunyaviridae: Bunyavirus), nairoviruses (Bunyaviridae: Nairovirus) and phleboviruses (Bunyaviridae: Phlebovirus); the orbiviruses (one of nine genera in the family Reoviridae); the vesiculoviruses (one of six genera in the family Rhabdoviridae) and the thogotoviruses (one of four genera in the family Orthomyxoviridae). These groups of RNA viruses have a variety of types of RNA genomes and replication strategies, suggesting that the arthropod-borne transmission strategy has arisen many times during the evolution of RNA viruses. The only known DNA arbovirus is African swine fever virus (Asfarviridae: Asfarvirus), and the paucity of DNA arboviruses suggests that the greater genetic plasticity and higher mutation rates exhibited by RNA viruses allow them to accommodate a cycle of alternating replication in disparate vertebrate and invertebrate hosts.

Arboviruses circulate among wild animals, and cause disease after spillover transmission to humans and/or domestic animals that are incidental or dead-end hosts. Viruses such as dengue (DENV) and chikungunya (CHIKV) that have lost the requirement for enzootic amplification now produce extensive epidemics. Many arboviruses that have evolved and diversified in the tropics have produced virulent and invasive strains that have caused major outbreaks at temperate latitudes. The ability of these viruses to cause human disease depends on factors ranging from epidemiology to viral genetics. Herein, we review how some of these factors have led to arboviral emergences and resulted in human disease, by using several examples of viruses with a known epidemic history as well as some that have a poorly recognized epidemic potential.

Present and future arboviral threats. Antiviral Res. 2010 85(2): 328-345
Arthropod-borne viruses (arboviruses) are important causes of human disease nearly worldwide. All arboviruses circulate among wild animals, and many cause disease after spillover transmission to humans and agriculturally important domestic animals that are incidental or dead-end hosts. Viruses such as dengue (DENV) and chikungunya (CHIKV) that have lost the requirement for enzootic amplification now produce extensive epidemics in tropical urban centers. Many arboviruses recently have increased in importance as human and veterinary pathogens using a variety of mechanisms. Beginning in 1999, West Nile virus (WNV) underwent a dramatic geographic expansion into the Americas. High amplification associated with avian virulence coupled with adaptation for replication at higher temperatures in mosquito vectors, has caused the largest epidemic of arboviral encephalitis ever reported in the Americas. Japanese encephalitis virus (JEV), the most frequent arboviral cause of encephalitis worldwide, has spread throughout most of Asia and as far south as Australia from its putative origin in Indonesia and Malaysia. JEV has caused major epidemics as it invaded new areas, often enabled by rice culture and amplification in domesticated swine. Rift Valley fever virus (RVFV), another arbovirus that infects humans after amplification in domesticated animals, undergoes epizootic transmission during wet years following droughts. Warming of the Indian Ocean, linked to the El Niño-Southern Oscillation in the Pacific, leads to heavy rainfall in east Africa inundating surface pools and vertically infected mosquito eggs laid during previous seasons. Like WNV, JEV and RVFV could become epizootic and epidemic in the Americas if introduced unintentionally via commerce or intentionally for nefarious purposes. Climate warming also could facilitate the expansion of the distributions of many arboviruses, as documented for bluetongue viruses (BTV), major pathogens of ruminants. BTV, especially BTV-8, invaded Europe after climate warming and enabled the major midge vector to expand is distribution northward into southern Europe, extending the transmission season and vectorial capacity of local midge species. Perhaps the greatest health risk of arboviral emergence comes from extensive tropical urbanization and the colonization of this expanding habitat by the highly anthropophilic (attracted to humans) mosquito, Aedes aegypti. These factors led to the emergence of permanent endemic cycles of urban DENV and CHIKV, as well as seasonal interhuman transmission of yellow fever virus. The recent invasion into the Americas, Europe and Africa by Aedes albopictus, an important CHIKV and secondary DENV vector, could enhance urban transmission of these viruses in tropical as well as temperate regions. The minimal requirements for sustained endemic arbovirus transmission, adequate human viremia and vector competence of Ae. aegypti and/or Ae. albopictus, may be met by two other viruses with the potential to become major human pathogens: Venezuelan equine encephalitis virus, already an important cause of neurological disease in humans and equids throughout the Americas, and Mayaro virus, a close relative of CHIKV that produces a comparably debilitating arthralgic disease in South America. Further research is needed to understand the potential of these and other arboviruses to emerge in the future, invade new geographic areas, and become important public and veterinary health problems.

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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