Mosquito-borne flaviviruses provide some of the most important examples of emerging and resurging diseases of global significance. Here, we describe three of them: the resurgence of dengue in tropical and subtropical areas of the world, and the spread and establishment of Japanese encephalitis and West Nile viruses in new habitats and environments. These three examples also illustrate the complexity of the various factors that contribute to their emergence, resurgence and spread. Whereas some of these factors are natural, such as bird migration, most are due to human activities, such as changes in land use, water impoundments and transportation, which result in changed epidemiological patterns. The three examples also show the ease with which mosquito-borne viruses can spread to and colonize new areas, and the need for continued international surveillance and improved public health infrastructure to meet future emerging disease threats.

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Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses

Flaviviruses are vector-borne RNA viruses that can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, congenital abnormalities and fetal death. This epidemiological pattern has occurred numerous times during the last 70 years, including epidemics of dengue virus and West Nile virus, and the most recent explosive epidemic of Zika virus in the Americas. Flaviviruses are now globally distributed and infect up to 400 million people annually. Of significant concern, outbreaks of other less well-characterized flaviviruses have been reported in humans and animals in different regions of the world. The potential for these viruses to sustain epidemic transmission among humans is poorly understood. In this Review, we discuss the basic biology of flaviviruses, their infectious cycles, the diseases they cause and underlying host immune responses to infection. We describe flaviviruses that represent an established ongoing threat to global health and those that have recently emerged in new populations to cause significant disease. We also provide examples of lesser-known flaviviruses that circulate in restricted areas of the world but have the potential to emerge more broadly in human populations. Finally, we discuss how an understanding of the epidemiology, biology, structure and immunity of flaviviruses can inform the rapid development of countermeasures to treat or prevent human infections as they emerge. Flaviviruses, a group of vector-borne RNA viruses that includes dengue virus, West Nile virus, Zika virus and several lesser-known species, often emerge in human populations and cause epidemics. Here, Pierson and Diamond review the basic biology of these viruses, their life cycles, the diseases they cause and available therapeutic options. They also discuss the global distribution of flaviviruses, with a focus on lesser-known species that have the potential to emerge more broadly in human populations.

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The continued threat of emerging flaviviruses

West Nile virus: epidemiology and ecology in North America.

Two different West Nile virus (WNV) strains caused lethal encephalitis in a flock of geese and a goshawk in southeastern Hungary in 2003 and 2004, respectively. During the outbreak in geese, 14 confirmed human cases of WNV encephalitis and meningitis were reported in the same area. Sequencing of complete genomes of both WNV strains and phylogenetic analyses showed that the goose-derived strain exhibits closest genetic relationship to strains isolated in 1998 in Israel and to the strain that emerged in 1999 in the United States. WNV derived from the goshawk showed the highest identity to WNV strains of lineage 2 isolated in central Africa. The same strain reemerged in 2005 in the same location, which suggests that the virus may have overwintered in Europe. The emergence of an exotic WNV strain in Hungary emphasizes the role of migrating birds in introducing new viruses to Europe.

https://stacks.cdc.gov/view/cdc/16130/cdc_16130_DS1.pdf

Lineage 1 and 2 strains of encephalitic West Nile virus, central Europe.

West Nile (WN) virus is a mosquito-transmitted flavivirus. It is widely distributed in Africa, the Middle East, Asia, and southern Europe and was recently introduced to North America. Birds are involved in the cycle of transmission as amplifying hosts. Humans and horses are considered accidental dead-end hosts. WN fever was initially considered a minor arbovirosis, usually inducing a nonsymptomatic or a mild flu-like illness in humans, but some cases of encephalitis associated with fatalities were reported in Israel in the 1950s. After two silent decades, several human and equine outbreaks of fatal encephalitis occurred from 1996 to 2000 in Romania, Morocco, Tunisia, Italy, Russia, Israel, and France. In Romania, a few cases of WN encephalitis in humans are noticed every year, and in France, recent WN infections have been detected in monitored sentinel birds in 2001 and 2002. Phylogenetic studies have shown two main lineages of WN strains. Strains from lineage I are present in Africa, India, and Australia and are responsible for the outbreaks in Europe and in the Mediterranean basin, and strains from lineage II have been reported only in sub-Saharan Africa. In 1998, a virulent WN strain from lineage I was identified in dying migrating storks and domestic geese showing clinical symptoms of encephalitis and paralysis in Israel. A nearly identical WN strain suddenly emerged in New York in 1999, killing thousands of native birds and causing fatal cases in humans. The virus is now well established in the New World, and it disseminates rapidly. New modes of transmission through blood donations, organ transplants, and the intrauterine route have been reported. In Europe, an enhanced surveillance of WN infection in humans, horses, birds, and vectors may reveal the presence of the virus in different locations. Nevertheless, outbreaks of WN virus remain unpredictable. Further coordinated studies are needed for a better understanding of the ecology and the pathogenicity of the WN virus.

West Nile Virus: An Overview of Its Spread in Europe and the Mediterranean Basin in Contrast to Its Spread in the Americas

During late summer 2001 in Austria, a series of deaths in several species of birds occurred, similar to the beginning of the West Nile virus (WNV) epidemic in the United States. We necropsied the dead birds and examined them by various methods; pathologic and immunohistologic investigations suggested a WNV infection. Subsequently, the virus was isolated, identified, partially sequenced, and subjected to phylogenetic analysis. The isolates exhibited 97% identity to Usutu virus (USUV), a mosquito-borne Flavivirus of the Japanese encephalitis virus group; USUV has never previously been observed outside Africa nor associated with fatal disease in animals or humans. If established in central Europe, this virus may have considerable effects on avian populations; whether USUV has the potential to cause severe human disease is unknown.

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Emergence of Usutu virus, an African mosquito-borne flavivirus of the Japanese encephalitis virus group, central Europe.

In 2013, several Austrian piglet-producing farms recorded outbreaks of action-related repetitive myoclonia in newborn piglets ("shaking piglets"). Malnutrition was seen in numerous piglets as a complication of this tremor syndrome. Overall piglet mortality was increased and the number of weaned piglets per sow decreased by more than 10% due to this outbreak. Histological examination of the CNS of affected piglets revealed moderate hypomyelination of the white substance in cerebellum and spinal cord. We detected a recently discovered pestivirus, termed atypical porcine pestivirus (APPV) in all these cases by RT-PCR. A genomic sequence and seven partial sequences were determined and revealed a 90% identity to the US APPV sequences and 92% identity to German sequences. In confirmation with previous reports, APPV genomes were identified in different body fluids and tissues including the CNS of diseased piglets. APPV could be isolated from a "shaking piglet", which was incapable of consuming colostrum, and passaged on different porcine cells at very low titers. To assess the antibody response a blocking ELISA was developed targeting NS3. APPV specific antibodies were identified in sows and in PCR positive piglets affected by congenital tremor (CT). APPV genomes were detected continuously in piglets that gradually recovered from CT, while the antibody titers decreased over a 12-week interval, pointing towards maternally transmitted antibodies. High viral loads were detectable by qRT-PCR in saliva and semen of infected young adults indicating a persistent infection.

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Congenital infection with atypical porcine pestivirus (APPV) is associated with disease and viral persistence.

A novel pestivirus species was discovered in a piglet-producing farm in Austria during virologic examinations of congenital tremor cases The emergence of this novel pestivirus species, provisionally termed Linda virus, in domestic pigs may have implications for classical swine fever virus surveillance and porcine health management

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Novel Pestivirus Species in Pigs, Austria, 2015

The correlation between parvovirus infections and lesions in the central nervous system other than cerebellar hypoplasia was studied in 100 cats. The animals were necropsied with a history of various diseases, one third showing typical clinical and pathomorphological signs of panleukopenia. In 18 cats polyclonal antiserum against canine parvovirus consistently labeled neurons mainly in diencephalic regions, whereas the cerebellar cortex remained negative in all cases. In situ hybridization with digoxigenin-labeled minus-sense RNA probes, hybridizing with monomer-replicative form DNA or mRNA, revealed positive signals in nuclei of several neurons of the brain, again excluding the cerebellum. PCR applied to formalin-fixed and paraffin-embedded brain tissue and intestinal tissues of the diseased cats and subsequent DNA sequence analysis yielded canine parvovirus type 2 (CPV-2)-like sequences in the central nervous system. Two aspects of these findings are intriguing: (i) parvoviruses appear to be capable of replicating in neurons, cells that are considered to be terminally differentiated and (ii) CPV-like viruses of the old antigenic type CPV-2 appear to be able to infect cats.

Evidence of Parvovirus Replication in Cerebral Neurons of Cats

During late summer 2001 in Austria, a series of deaths in several species of birds occurred, similar to the beginning of the West Nile virus (WNV) epidemic in the United States. We necropsied the dead birds and examined them by various methods; pathologic and immunohistologic investigations suggested a WNV infection. Subsequently, the virus was isolated, identified, partially sequenced, and subjected to phylogenetic analysis. The isolates exhibited 97% identity to Usutu virus (USUV), a mosquito-borne Flavivirus of the Japanese encephalitis virus group; USUV has never previously been observed outside Africa nor associated with fatal disease in animals or humans. If established in central Europe, this virus may have considerable effects on avian populations; whether USUV has the potential to cause severe human disease is unknown. sutu virus (USUV) is a relatively unknown member of the mosquito-borne cluster within the Flavivirus genus, closely related to important human pathogens such as Japanese encephalitis virus (JEV), Murray Valley encephalitis virus (MVEV), Dengue virus (DENV), Yellow fever virus (YFV), Saint Louis encephalitis virus (SLEV), and West Nile virus (WNV) (1–3). Isolated for the first time from mosquitoes in South Africa in 1959 and named after a river in Swaziland (4), USUV was sporadically isolated from several mosquito and bird species over the next decades (5–7). Only two isolations have been reported from mammals, one from Praomys sp. (African soft-furred rats) and one from a man with fever and rash (5). The virus has never been associated with severe or fatal diseases in animals or humans, and it has never before been observed outside tropical and subtropical Africa. From the beginning of August through mid-September

http://stacks.cdc.gov/view/cdc/13945/cdc_13945_DS1.pdf

Barbara Rebel-Bauder

Papers

Emergence of Usutu virus, an African mosquito-borne flavivirus of the Japanese encephalitis virus group, central Europe.

Congenital infection with atypical porcine pestivirus (APPV) is associated with disease and viral persistence.

Novel Pestivirus Species in Pigs, Austria, 2015

Evidence of Parvovirus Replication in Cerebral Neurons of Cats

Emergence of Usutu virus, an African Mosquito-Borne Flavivirus of the Japanese Encephalitis Virus Group,