Precision Medicine 2015; 2: e604. doi: 10.14800/pm.604; © 2015 by Lwande Wesula Olivia, et al. http://www.smartscitech.com/index.php/pm
REVIEW
West nile virus, a reemerging virus Lwande Wesula Olivia1, Gladys Mosomtai2, Samwel Symekher3 1
Department of Clinical Microbiology, Virology, Umeå University, Umea, Sweden Earth Observation Unit, International Centre of Insect Physiology and Ecology, Nairobi, Kenya 3 Centre for Virus Research, Kenya Medical Research Institute, Nairobi, Kenya 2
Correspondence: Lwande Wesula Olivia E-mail:
[email protected] Received: February 04, 2015 Published online: March 11, 2015
West Nile virus (WNV) is a re-emerging pathogen with a wide spread distribution in most parts of the world. WNV was first identified from the blood of a febrile female patient in West Nile district in Uganda in 1937 and since then, subsequent isolations of the virus have been reported mainly in humans, horses and birds. Evidence of the virus being present in mosquitoes and ticks has also been documented. However, the recent expansion of WNV in terms of its distribution and ability to cause devastating epidemics is not well understood. Moreover, the factors involved in its maintenance and dissemination are yet to be unraveled. There is scarcity of data on the genetic diversity and evolution of WNV. Little is known about the actual burden posed by the virus in terms of public and animal health. This review envisages bringing in to light up to date information on WNV epidemiology, vector competence, molecular biology, phylogeny, diagnosis and management. This will provide an in-depth understanding of the resurgence of the virus which will aid in the establishment of the appropriate strategies such as regular surveillance that will support early detection, accurate diagnosis, prevention and control of WNV. Keywords: West Nile virus; Evolution, Ticks; Mosquitoes; Human; Horses; Birds; Lineages To cite this article: Lwande Wesula Olivia, et al. West nile virus, a reemerging virus. Precision Med 2015; 2: e604. doi: 10.14800/pm.604.
pool of Rhipicephallus pulchellus ticks sampled from livestock in Kenya has been documented [6].
Introduction West Nile virus (WNV) is a flavivirus in the family Flaviviridae belonging to the Japanese encephalitis serocomplex that comprises of viruses such as St. Louis encephalitis, Kunjin and Murray Valley encephalitis [1]. WNV transmission cycle involves passeriform birds and mosquitoes with human and equids serving as dead-end hosts [2] . The virus is mainly transmitted by mosquitoes of the Culex species although other secondary mosquito vectors such as; Aedes, Anopheles and Ochlerotatus may also play a role in transmission [3]. Experimental studies carried out on soft and hard ticks have demonstrated the potential role of ticks in the transmission and dissemination of the virus [4, 5]. In addition, evidence of a natural infection of WNV from a
West Nile virus has been documented to cause devastating outbreaks that pose a significant threat to the health of humans and animals [7]. Evidence of the virus causing severe encephalitis in humans and horses has been reported especially in South Africa where lineage 2 of the virus is bound to circulate [8]. WNV causes infection in both domestic and wild animals such as: horse, striped skunk, eastern chipmunk, eastern gray squirrel and domestic rabbit [9] . The virus can cause mild symptoms such as: fever, headache, body aches, eye pain, rash, vomiting and swollen lymph nodes and in severe cases the virus causes encephalitis, myelitis, meningitis and death [10].
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Precision Medicine 2015; 2: e604. doi: 10.14800/pm.604; © 2015 by Lwande Wesula Olivia, et al. http://www.smartscitech.com/index.php/pm
Figure 1. A map of West Nile virus distribution across the globe. This map shows reported epidemics of WNV in Africa, Asia, Australia, Europe, and the Americas (North and South America).
Over the recent years, WNV has undergone geographic expansion in all continents except the Antarctica [11]. However, the driving factors behind its rapid expansion are not clear. Certain ecological factors have been linked to the spread of the virus for instance: high temperatures have been shown to influence the duration of the viral incubation time from infection to infectiousness of mosquitoes hence increase in viral transmission efficiency to birds; and increased rainfall which results in abundance of vectors hence increase in transmission. Other factors that may contribute to the spread include; change in land use patterns, irrigation, population growth, urbanization, transportation, containerized shipping and lack of effective vector control and probable climate change [12]. The introduction of WNV in USA remains a mystery that needs to be resolved since the mechanisms by which the virus found its way in North America remains unknown [13]. It is hypothesized that due to the genetic relatedness of WNV isolates from Israel and New York, the virus could have been imported from Middle East into North America by either an infected bird, mosquito, human or vertebrate host [14]. Currently there is scarcity of data on the genetic diversity and evolution of WNV. The actual burden caused by the virus with respect to public and animal health is not known. The sporadic nature of outbreaks caused WNV pose a challenge
when it comes to development of diagnostics, vaccines and appropriate control strategies. This review aims at providing current valuable information on WNV epidemiology, vector competence, molecular biology, genetic diversity, diagnosis and management. The review will provide an in-depth understanding of the evolution and genetic diversity of the diverse WNV strains at global level. Epidemiology of West Nile Virus West Nile virus has a wide spread distribution across the globe. It is indigenous to Africa and has since extended to the Middle East, Asia, Europe, USA and Australia [13, 15, 16] (Figure 1). West Nile virus was first isolated from the blood of a febrile female patient in the West Nile District of Uganda in 1937 and since then, subsequent outbreaks of the virus in humans have been documented to occur in different countries including; Algeria (1994), Romania (1996–2010), Tunisia (1997, 2012), the Czech Republic (1997), Israel (1999–2000, 2005–2010, 2012), USA (1999) Russia (1999–2001, 2004– 2007, 2010–2013), Morocco (1996), France (2003), Hungary (2003–2013), Portugal (2004), Spain (2004, 2010), Italy (2008–2013) and South Africa (2009), Greece (2010), Australia (2011) among other countries [17-19]. In the face of these numerous outbreaks, the epidemiology of the virus is not clearly understood due to the sporadic nature of the
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Precision Medicine 2015; 2: e604. doi: 10.14800/pm.604; © 2015 by Lwande Wesula Olivia, et al. http://www.smartscitech.com/index.php/pm
Figure 2. The West Nile virus genome. This figure encompasses both the structural [including C (97-465), pr (466-741), M (742-966), E (967-2469)] and nonstructural proteins [including NS1 (2470-3525), NS2A (3526-4218), NS2B (4219-4611), NS3 (4612-6468), NS4A (6469-6915), NS4B (6916-7680) and NS5 (7681-10395)] found on the virus.
outbreaks. There is likelihood that there may be other mosquito vectors apart from the Culex, Aedes, Anopheles, Ochlerotatus species mentioned in the review that may play a major role in the transmission, maintenance and dissemination of the virus across large geographical distances [20, 21]. The significance of diverse mosquito species in WNV needs to be ascertained [21]. In addition, ticks for example Ornithodoros moubata species have also demonstrated to serve as reservoirs and vectors of WNV [22]. The ability of ticks to maintain the virus for a long period of time may be attributed to the longevity in terms of their life cycle [22]. However, information as to whether are likely to be major vectors of WNV has not been adequately explored [4]. Migratory birds’ particularly passerine birds (crows, jays, magpies, ravens, grackles among others) have been the means by which WNV was introduced to Europe and Middle East however, the establishment of WNV in the USA is not clear [23, 24]. The enzootic transmission of WNV principally involves avian hosts and ornithophilic mosquito vectors with humans and horses serving as incidental hosts through spillover transmission. The primary vector involved in WNV transmission cycle is Culex species most commonly; Cx. pipiens, Cx. restuans, Cx. tarsalis, Cx. nigripalpus, Cx. annulirostris, Cx. vishnui, Cx. tritaeniorhynchus and C. salinariu whereas the secondary mosquito vectors species include Aedes, Anopheles, Ochlerotatus japonicus and Ochlerotatus triseriatus [3]. Vector competence studies conducted on both soft (Argas persicus, A. hermanni and Ornithodoros moubata) and hard ticks (Hyalomma marginatum) have indicated the potential role of ticks in WNV transmission [17, 25]. The detection of WNV from Rh. pulchellus may suggest possible role of ticks in natural transmission of WNV [6].
serious neurological illness of meningitis and/or encephalitis characterized by headache, neck stiffness, disorientation, muscle weakness, seizures, flaccid paralysis or coma [27]. The case fatality rate of WNV increases with age ranging from 4-14% but 15-29% in older individuals [28, 29]. Vector Competence of West Nile Virus Vector competence studies performed in the laboratories have shown that the different vectors (mosquitoes and ticks) have the potential of transmitting the virus [17, 25]. Nevertheless, the ability of each vector to acquire and disseminate the virus varies according to species. Currently over 65 mosquito species are capable of acquiring WNV infection [30]. Culex mosquitoes species namely; Cx. tarsalis, Cx. quinquefasciatus, Cx. stigmatosoma, Cx. thriambus, Cx. pipiens, and Cx. nigripalpus have the capability to acquire and transmit the virus to their respective hosts [31]. Ticks have also been demonstrated to have competence for both infection and transmission of WNV [4]. Studies performed mainly on both soft and hard ticks such as Argas persicus, A. hermanni, Ornithodoros moubata and Hyalomma marginatum species indicate the possible role of ticks in WNV transmission [4, 17, 25, 32]. Different vectors have preference for a variety of hosts and for example C. pipiens in the eastern United States may feed on mammals and humans instead of birds [33-35]. The ability of WNV to replicate in mosquitoes, ticks, mammals and birds provides an opportunity for this virus to amplify across a wider geographical coverage enabling the circulation of different strains across continents. For vector competence to be achieved, a number of factors need to be considered for example; host fitness, vector species, favorable environmental conditions and the geographical area [36]. Molecular Biology of West Nile Virus
The incubation period for WNV ranges from 2 to 14 days and about 80% of WNV cases are asymptomatic but a few progress from mild to severe disease [13]. In mild cases of the disease the patient presents with fever, headache, myalgia, lymphodenopathy and a maculopapular rash [26]. In severe cases of the disease the patients may progress to a more
West Nile virus like any flavivirus consists of a positive-sense (+), single-stranded (ss) RNA molecule of approximately 11kb [37]. The virus contains a single open reading frame that codes for three structural and seven non-structural proteins namely; the envelope protein (E), the
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Precision Medicine 2015; 2: e604. doi: 10.14800/pm.604; © 2015 by Lwande Wesula Olivia, et al. http://www.smartscitech.com/index.php/pm
precursor membrane (prM), and the capsid (C), NS1, 2A, 2B, 3, 4A, 4B, and 5 respectively [38] as shown in figure 2. The structural proteins are involved in virus entry, fusion and encapsidation of the viral genome during assembly. The envelope glycoprotein is the major structural protein that plays an important role in membrane binding and inducing a protective immune response following virus infection. It carries epitopes detected by neutralization and haemagglutination inhibition tests that have been used to identify different subgroups and species of Flaviviruses. The prM protein is also known to embed in the lipid bilayer and is thought to protect E from undergoing premature fusion upon virus exocytosis to the cell surface. The capsid protein interacts with the RNA genome to form the nucleocapsid, which is surrounded by a lipid bilayer [16]. A high proportion of capsid protein localizes to the nucleus, while viral assembly takes place in the cytoplasm, with budding in the endoplasmic reticulum (ER) although the nuclear functions of capsid are not fully understood, recent evidence suggests a role in gene regulation through binding with histone proteins [30, 39] . The nonstructural proteins have diverse roles for instance; NS1 is plays a vital role in the replication of the virus, NS2A and NS2 B inhibit the innate immune response against viral infection, NS3 cleaves other non-structural proteins from the viral polyprotein, NS4A and NS4B have similar functions as NS2A and NS2B and NS5 serves as the viral polymerase and encodes a methyltransferase [37]. Phylogeny of West Nile Virus West Nile virus is classified into eight lineages around the globe [19]. Lineage 1 which is mainly associated with human disease is divided into three clades a, b and c. Clade 1a is distributed in Africa, the Middle East, Europe and Americas; 1b, which is also known as Kunjin virus (KUNV), is found in Australia and 1c in India [40]. WNV lineage 1 has been implicated as a major cause of neurological disease in humans and horses in the USA and Europe [13, 41]. Lineage 2 comprises of WNV strains isolated in sub-Saharan Africa, Hungary and eastern Austria [42]. Over the past few years’ neuroinvasive strains of WNV were considered to belong to lineage 1 whereas lineage 2 strains were less virulent. However, lineage 2 strains isolated in South Africa have been shown to be virulent and have been associated with neurological disease in horses and humans [43]. Increased virulence in WNV strains is linked to the presence of envelope protein glycosylation sites (a N-Y-S tripeptide located at positions 154–156 in the envelope protein) [44]. Lineage 3 is comprised of Rabensberg virus that is found in southern Moravia and Czech Republic. Rabensberg virus was isolated form Culex pipiens mosquitoes. Lineage 4 consists
of the LEIVKrnd88-190 strain isolated from Dermacentor marginatus ticks in Russia [42]. Lineage 5 is consists of isolates obtained from humans and Culex and Anopheles spp mosquitoes and humans in India. Lineage 6 is comprised of a virus known as Koutango which is found in Senegal [6]. Lineage 7 consists of Sarawak viruses found in Malaysia and lineage 8 is composed of a new virus found in Spain for which partial sequences have been obtained from Culex pipiens [19]. Diagnosis of West Nile Virus The most appropriate specimen for the detection of WNV is serum and cerebrospinal fluid [45, 46]. WNV diagnosis is based on clinical case definition and serology [47, 48]. However, this can be a challenge especially due to similar clinical manifestations and cross-reactivity with related Flaviruses such as Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Yellow fever, Usutu and Dengue [49]. This can be ruled out by plaque reduction neutralization assay (PRNT) which serves as the gold standard for serological diagnosis [50]. For accuracy, PRNT should be performed during acute and convalescent phase of illness [50]. In most clinical settings, the most common assay used for detection of WNV is the antibody-capture Enzyme Linked-Immunosorbent assay (MAC-ELISA) [51]. The detection of IgM antibodies in cerebrospinal fluid indicates presence of the infection in the central nervous system as these antibodies do not cross the blood-brain barrier [52]. Other serological tests though rare such as haemagglutination and complement fixation can also be used to screen for WNV although antibody-capture enzyme immunoassays and immunoflourescent antibody tests are the most common [53, 54]. Nucleic acid testing, a transcription based amplification technique has been employed in the development of rapid kits that are essentially used for screening of WNV among blood donors [55]. This test is useful in the detection of WNV in immuno-compromised patients especially when antibody development is delayed [56]. WNV can also be screened in acute-phase cerebrospinal fluid and whole blood using Reverse Tracriptase Polymerase Chain Reaction (RT-PCR) , Reverse Transcriptase Loop-Mediated Isothermal Amplification (RT-LAMP) and viral isolation procedures [45, 57, 58] . Virus isolation using cell culture is an expensive and involving exercise that is rarely performed in most clinical settings due to specialized biocontainment facilities equipped for work with the live virus. Recent advances in next generation sequencing technologies have made it possible to obtain whole genomes of the diverse WNV strains circulating around the globe [59, 60].
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Precision Medicine 2015; 2: e604. doi: 10.14800/pm.604; © 2015 by Lwande Wesula Olivia, et al. http://www.smartscitech.com/index.php/pm pests and vector-borne diseases in Europe 2007; 1:123-151. Wageningen Academic Publishers, Wageningen
Prevention and Control of West Nile Virus West Nile virus is an arthropod-borne virus that is transmitted primarily by mosquito vectors. The main focus of prevention and control of the virus is by establishment of appropriate vector control strategies [61]. These measures include the elimination of any potential mosquito breeding sites, such as containers or old tires that collect standing water. Use of mosquito nets and repellents containing permethrin, pyrethrins, orbutoxypolypropylene glycol as a means of creating a barrier hence preventing mosquito bites is applied in most settings. Modified live recombinant virus vaccines have been formulated for prevention of WNV in horses [62]. These vaccines are initially administered followed by a booster in 3 to 6 weeks. However, it is recommended that subsequent boosters be given twice annually in WNV endemic areas. Currently, there is no licensed vaccine for human use/consumption. There is therefore need for an efficacious vaccine that can help prevent humans from being infected by the virus. Conclusions and Future Directions WNV is a global threat to both animals and humans due to its rapid expansion and ability to cause neurological disease characterized by meningo-encephalitis in humans and horses. There is a possibility that WNV circulates amidst epidemics without being noticed due to lack of well established surveillance systems that assist in detecting and quantifying the magnitude of the virus in different regions of the world. The factors leading to the emergence and resurgence of the virus need to be further investigated so as to have clear facts in place. Although WNV outbreaks are sporadic in nature, there is dire need for a human vaccine since the virus has been shown to cause significant morbidity and mortality in most parts of the world. The identification of the definite means of introduction of WNV in USA will guide in the establishment of proper prevention and control strategies against the virus. Currently there is lack of proper diagnostics that are sensitive and specific for WNV detection. More studies inclined to development of accurate and timely methods of viruses’ diagnosis should be performed so as to aid in management and treatment of infected humans and animals. Moreover, genetic diversity studies should be done to ascertain the significance of certain amino acid changes and whether these changes play a role in virulence. References 1.
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