Ross River Virus (RRV) Infection in Horses and Humans: A Review
A fascinating and important arbovirus is Ross River Virus
(RRV) which is endemic and epizootic in nature in certain parts of the world.
RRV is a member of the genus Alphavirus within the Semliki Forest complex
of the family Togaviridae, which also includes the Getah virus. The virus is
responsible for causing disease both in humans as well as horses. Mosquito species
(Aedes camptorhynchus and Aedes vigilax; Culex annulirostris)
are the most important vector for this virus. In places of low temperature as
well as low rainfall or where there is lack of habitat of mosquito there is
also limitation in the transmission of the virus. Such probability is higher
especially in temperate regions bordering endemic regions having sub-tropical
climate. There is involvement of articular as well as non-articular cells in
the replication of RRV. Levels of pro-inflammatory factors viz., tumor necrosis
factor-alpha (TNF-α); interferon-gamma (IFN-γ); and macrophage chemo-attractant
protein-1 (MAC-1) during disease pathogenesis have been found to be reduced.
Reverse transcription-polymerase chain reaction (RT-PCR) is the most advanced
molecular diagnostic tool along with epitope-blocking enzyme-linked immunosorbent
assay (ELISA) for detecting RRV infection. Treatment for RRV infection is only
supportive. Vaccination is not a fruitful approach. Precise data collection
will help the researchers to understand the RRV disease dynamics and thereby
designing effective prevention and control strategy. Advances in diagnosis,
vaccine development and emerging/novel therapeutic regimens need to be explored
to their full potential to tackle RRV infection and the disease it causes.
Received: September 10, 2013;
Accepted: October 21, 2013;
Published: January 29, 2014
A self-limiting human rheumatic disease characterized by acute and chronic
symmetrical peripheral polyarthralgia-polyarthritis, debilitating arthropathy,
fever, myalgia and/or rash, transmitted by mosquitoes can be caused by a variety
of alphaviruses such as chikungunya virus, Ross River virus, Barmah Forest virus,
Sindbis virus, O'nyong-nyong virus and Mayaro virus (Suhrbier
et al., 2012). A fascinating as well as important arbovirus is Ross
River Virus (RRV) which is endemic as well as epizootic in nature in certain
parts of the world like Australia as well as Papua New Guinea. The virus has
been found to be epidemic in the South Pacific during the 1980s. In humans,
infection with RRV may cause disease that typically presents polyarthralgia
(or arthritis) along with fever as well as rashes. More outbreaks due to disease
caused by this virus were recorded during the World War II thereby giving rise
to the name epidemic polyarthritis. There is considerable burden of morbidity
due to this virus and there can be spread of the virus to other countries as
well. For justification as well as designing of prevention programs accurate
data are required on costs of economy and to understand in a better way the
transmission as well as behavioral and environmental risks (Anstey
et al., 1991; Amin et al., 1998;
Aaskov et al., 1997; Harley
et al., 2001). The Ross River virus (RRV) is a member of the genus
Alphavirus within the Semliki Forest complex of the family Togaviridae,
which also includes the Getah virus. It is an arthropod-borne virus (arbovirus)
that is transmitted by several mosquito species and is endemic and enzootic
in Australia (Azuolas, 1998; Russell,
1994, 2002). RRV has similar cladistic classification,
ecology and clinical signs in horses as that reported for Getah virus (Hinchcliff,
2007). Substantial sequence homology exists between Getah and RRV genomes
(Strauss and Strauss, 1994). Getah virus causes disease
in horses and pigs, whereas RRV causes disease in horses and humans (El-Hage
et al., 2008). The horse is assumed to be an amplifying host of the
virus since experimentally infected horses can infect mosquitoes (Kay
et al., 1987). RRV infection has been suspected of causing musculoskeletal
disease in performance horses in many riverland and northern regions of Australia
for more than 25 years although documented cases are scarce. RRV has been isolated
from horses exhibiting clinical signs such as reluctance to move, joint swellings
and ataxia, in conjunction with positive RRV IgM serology (Pascoe
et al., 1978; Azuolas et al., 2003;
El-Hage et al., 2008). In humans, RRV is the
most common Australian arbovirus disease and is often associated with a characteristic
syndrome of debilitating polyarthritis (Fraser, 1986;
Russell, 1994, 2002; Jeandel
et al., 2004). In many cases, joint pain and disability may persist
for several months or longer (Boughton, 1996; Suhrbier
and La Linn, 2004; Colin de Verdiere and Molina, 2007).
MATERIALS AND METHODS
Etiology: RRV is a small, enveloped virus with the genome being single-stranded
positive-sense RNA (Johnston and Peters, 1996). The RRV
T48 strain genome is as long as 11,853 nucleotides coding for nonstructural
proteins (nsP1 to nsP4) (four in number), a capsid protein and envelope glycoproteins
(E1 to E3) (Faragher et al., 1988). The E1 and
E2 viral glycoproteins are embedded in the lipid bilayer to form the envelope
(Strauss and Strauss, 1994). Single E1 and E2 molecules
associate to form heterodimers. The E1-E2 heterodimers form contact side-by-side
between E2 and nucleocapsid monomers. The E3 glycoprotein is not incorporated
in the virion (Cheng et al., 1995). The capsid
protein and the genome form the nucleocapsid of about 400 Å in diameter
containing several copies of capsid protein (240 in number) having icosahedral
symmetry (Strauss and Strauss, 1994; Cheng
et al., 1995). T is the triangulation number that gives copies equivalent
to a multiple of 60 giving the number of subunits in the structure of the virus.
Geographic genetic variability has been reported among RRV isolates (Lindsay
et al., 1993). Given the range of virulence within RRV genotypes
(Fraser, 1986; Russell, 1994),
it is likely that most strains produce only subclinical or no disease.
Epidemiology and disease transmission: The RRV is endemic and enzootic
in Australia and Papua New Guinea (Russell, 1994; Hii
et al., 1997; Frances et al., 2004).
The virus is found in most areas of continental Australia, Tasmania, West Papua
and Papua New Guinea, New Caledona, Fiji, Samoa and the Cook Islands (Russell,
2002; Frances et al., 2004; Klapsing
et al., 2005; Ryan et al., 2006).
The virus caused a large epidemic in 1979 and 1980 involving Fiji (Aaskov
et al., 1981), New Caledonia, Samoa (Fauran
et al., 1984) and the Cook Islands (Rosen et
al., 1981). In Australian humans, RRV causes the most common arboviral
disease that has characteristically having constitutional effects, rash and
rheumatic manifestations (Fraser, 1986). Mild pyrexia
and constitutional signs initially occur, with rash on the skin and oral lesions
later. Arthritis or arthralgia affects primarily the wrists, knees, ankles and
small joints of the extremities. The signs and symptoms like joint pain and
disability may persist for months and the disease can relapse (Harley,
2000; Harley et al., 2001; Jeandel
et al., 2004; Suhrbier and La Linn, 2004;
Colin de Verdiere and Molina, 2007). The syndrome caused
by RRV was initially referred to as epidemic polyarthritis (Dowling,
1946). In Australia, RRV associated disease is common in humans with nearly
5000 cases per year and much larger numbers during disease epidemics (Russell,
2002; Hinchcliff, 2007). The vertebrate hosts include
a large number of eutherian, marsupial and monotreme mammals and birds (Russell,
2002). Kangaroos and wallabies (Macropod species) are thought to be the
most imperative amplifying hosts, although this is debated (Old
and Deane, 2005).
The RRV is an arthropod borne virus, maintained in the mosquito-vertebrate-mosquito-host
and transmitted via the bite of an infected mosquito. The virus is annually
active in most regions of Australia but exists as strains of varied virulence.
Native macropods are thought to be the natural vertebrate hosts but there may
be involvement of horses and humans during epidemic activity and mosquitoes
are vertically infected. Different mosquito species are involved as vectors
in various regions and in different seasonal and conditions of environment.
The saltmarsh mosquitoes in coastal areas viz., Aedes camptorhynchus
and Aedes vigilax are the most important vectors in southern and northern
regions, respectively, whereas Culex annulirostris in inland areas is
the most important vector (Russell, 1998, 2002).
Recently, four other Australian mosquito species viz., Verrallina carmenti,
Verraullina lineata, Mansonia septempunctata (Diptera: Culicidae)
and Verrallina funerea (Diptera: Culicidae) have been shown to possess
the potential to contribute to RRV transmission cycles (Jeffery
et al., 2006, 2007; Webb
et al., 2008). A study on mosquito feeding patterns and natural infection
of vertebrates with RRV found that under natural conditions, mosquito feeding
(including that of Culex annulirostris, Aedes vigilax and Aedes
notoscriptus) was primarily on dogs (37.4%) but also on birds (18.4%), horses
(16.8%), brushtail possums (13.3%), humans (11.6%) and cats, flying foxes
and macropods, depending on site and that brushtail possums and horses played
a role in the urban transmission of RRV (Kay et al.,
2007). Rainfall, high tide and maximum temperature appears to play important
roles in RRV transmission (Tong et al., 2004).
The life cycle of mosquito as well as the host is dominated by the sets of climate.
There is impact of temperature and rainfall; humidity as well as tides on replication
of the virus substantially. They also affect the breeding as well as survival
of mosquitoes and help in the RRV proliferation (Hu et
al., 2004; Russell and Kay, 2004; Gatton
et al., 2005). A systematic study on climatic, social and environmental
factors and RRV disease revealed disease transmission cycles sensitivity
to climate and tidal variability, with rainfall, temperature and high tides
being among the major determinants of the transmission of RRV disease at the
macro level. The nature as well as magnitude of the interrelationship between
variability of climate; density of mosquito and the RRV disease transmission
varied with geographic area and socio-environmental condition. The analysis
indicated the existence of a complex relationship between climate variability,
social and environmental factors and RRV transmission, suggesting that different
strategies may be needed for the control and prevention of RRV disease at different
levels (Hu et al., 2007; Tong
et al., 2008).
Climate and mosquito surveillance data have been used for epidemiological predictions
for human RRV infections (Woodruff, 2003; Gatton
et al., 2005; Williams et al., 2009;
McIver et al., 2010), with climate data on their
own being moderately sensitive (64%) for predicting epidemics during the early
period of warning. Mosquito surveillance data when added increased the sensitivity
of the early warning model to 90% and of later warning model 85% (Woodruff
et al., 2006). Based on correlations revealing strong associations
between monthly RRV infections in humans and climatic variables and also four
implicated mosquito species populations. Jacups et
al. (2008) have created three models to identify the best predictors
of RRV infections for the Darwin area of Australia. The climate-only model which
included total rainfall, minimum daily average temperature as well as maximum
tide explained deviance of 44.3%. The vector-only variables, using average monthly
trap numbers of Culex annulirostris; Aedes phaecasiatus; Aedes
notoscriptus and Aedes vigilax explained 59.5% deviance. The third
global model including rainfall, minimum temperature and three mosquito species
was found to be best which explained 63.5% deviance and predicted RRV disease
in humans accurately. A plausible association between mouse (Mus musculus)
abundance and RRV incidence in northwest Victoria, Australia has also been suggested
to be coinciding with the seasonal abundance and relative absence of the mosquito
vector Culex annulirostris, suggesting that short-lived highly fecund amplification
hosts may profoundly influence disease transmission.
In places of low temperature as well as low rainfall or where there is lack
of habitat of mosquito there is also limitation in the transmission of the virus.
In certain parts of the country where there is epidemic of the infection due
to RRV because of annual pattern of the disease the chance of future epidemic
may change. Such probability is higher especially in temperate regions bordering
endemic regions having sub-tropical climate. During a year the temperate regions
which are cooler in nature may experience RRV activity for a longer time of
the year (McMichael et al., 2003; ABC
Online, 2006; Carver et al., 2008; http://emedicine.medscape.com/article/233913).
Molecular studies on the nsP3 and E2 genes of RRV indicated that intra-host
multiple viral lineages were responsible for the long-term persistence of RRV
at different geographical locations (Liu et al.,
2011). The RRV shows a continuous low relative genetic diversity through
time and the chances of rapid antigenic variation/ evolution in future as a
result of vaccination is negligible (Jones et al.,
2010; Aaskov et al., 2012).
Pathogenesis: There is involvement of articular as well as non-articular
cells in the replication of RRV as well as its dissemination. Experimental models
to study the pathogenesis have shown that the disease occurs when cellular as
well as tissue damage by replication of the virus as well as immune response
indirectly activate in target tissues in coordinated effort. There has been
description of various types of cells as targets for replication of arthritogenic
alphavirus that include cells from joints; bones and muscles; as well as cells
of the immune system that gets infiltrated in the synovium as well as tissues
that are infected. This highlights the association between the virus affected
tissues where replication of the virus takes place and the local process of
inflammation that contributes to the pathogenesis (Atkins
et al., 1982; Lundstrom, 1999; Morrison
et al., 2006; Al Kindi et al., 2012;
Atkins, 2012). For investigation of the role of cellular
immune response during RRV infection there has been development of several animal
models. Inflammation of severe nature has been observed in bones as well as
joints and muscle tissues in models of mice. The mice that is deficient in recombinase
activating gene (RAG-/-) are having the lacunae of functional T as
well as B lymphocytes. Cluster of differentiation positive (CD4+)
T cells are involved in the swelling of joints. Such symptoms altogether suggest
that immune response that is adaptive in nature has got a restricted role in
the pathology of the disease caused by RRV. Interferon-gamma (IFN-γ) is
expressed at a lower rate along with lower expression of tumor necrosis factor
alpha (TNF-α); and interleukin-beta (IL-β) in tissues of muscles as
well as joints. The clinical course of the disease in mice induced by RRV is
reduced by IFN-γ and TNF-α neutralization. Reinforcement of such information
has been done by observing that patients who use to develop chronic symptoms
(like in case of Chikungunya virus) use to show activation of various
cells of the immune system intensely in the phase of acute nature of the disease
that include: dendritic cell (DC) as well as Natural killer (NK) cells; CD4+and
CD8+cells (Griffin et al., 1992;
Linn et al., 1996; Mateo
et al., 2000; Suhrbier and La Linn, 2004;
Assuncao-Miranda et al., 2010, 2013).
A small plaque variant Ross River virus (PERS) that grows persistently in macrophages
produced comparatively marked increase in disease severity and mortality in
mice (Lidbury et al., 2011). The seminal role
of macrophage Migration Inhibitory Factor (MIF) and MIF receptor CD74 in determining
the clinical severity of alphavirus-induced arthritis and myositis has been
reported (Herrero et al., 2011a, 2013).
Mannose binding lectin (MBL) may have a role in promoting RRV-induced musculoskeletal
disease in both mice and humans and therefore, humans suffering from RRV-induced
arthritis and myositis can be relieved by targeting the MBL pathway of complement
activation (Gunn et al., 2012). The inflamed musculoskeletal
tissues resulting from RRV activate a unique set of myeloid cells which prevent
virus clearance and delay disease resolution in an arginase 1-dependent manner
(Stoermer et al., 2012). The pathogenesis of
RRV-induced disease and development of antiviral drugs against RRV has greatly
been helped by the mouse model (Herrero et al.,
2011b). Vital and distinct roles of determinants in both nsP1 and PE2 in
the pathogenesis of RRV-induced musculoskeletal inflammatory disease in mice
have been reported (Jupille et al., 2011).
It has recently been shown that RRV fitness in vertebrate and invertebrate
cells is regulated by a tyrosine-to-histidine switch at E2 glycoprotein position
18 (E2 Y18H). This mutation led to the attenuation of wild type RRV and caused
significantly less severe musculoskeletal disease in mice, with reduced viral
loads in musculoskeletal tissues, less viremia and inefficient virus spread.
Its replication in mammalian cells was also significantly reduced. However,
the efficiency of replication of RRV E2 Y18H in C6/36 mosquito cells was better
than the wild type RRV (Jupille et al., 2013).
Disease: In horses, several clinical features in RRV infection appears
to be similar to Getah virus infection and characterized by pyrexia, lameness,
stiffness, swollen joints, inappetence, reluctance to move and mild colic (Sentsui
and Kono, 1980; Azuolas, 1998; Bennett
et al., 1998; Brown and Timoney, 1998; Azuolas
et al., 2003; Hinchcliff, 2007). El-Hage
et al. (2008) observed clinical findings of submandibular lymphadenopathy,
pyrexia, oral petechiae, synovial effusion, muscle pain/stiffness, limb oedema,
high serum fibrinogen and globulin levels and IgM titres in four horses which
were diagnosed as RRV infected. The duration of disease is uncertain and disease
can persist for weeks to months or recur in horses. Postmortem examination reports
of horses with confirmed disease caused by RRV are not available. As the disease
syndrome is not well characterized, the RRV pathogenicity in horses is not well
understood. Disease descriptions are based on a small number of horses that
established viremia parallel with the clinical signs or on larger number of
seropositive horses. Horses experimentally infected with RRV also show minimal
clinical symptoms (Studdert et al., 2003). Due
to fewer disease reports, characteristic or diagnostic alterations in serum
biochemistry or hematology are not exactly known to occur in affected horses.
An area with year-round mosquito activity has high prevalence rate of seropositive
horses (approximately 80% in Queensland) whereas with seasonal mosquito activity
has lower (50% around Gippsland lakes in southern Australia) (Azuolas,
1998). RRV is minimally pathogenic in horses as reflected by the high rates
of infection but the absence of similarly high rates of clinical disease. There
is probability that seroconversion or virus isolation from horses with clinical
abnormalities is not causally related and may only be a chance affair (Hinchcliff,
2007). High rate of subclinical RRV infection of horses occur in endemic
regions, which increases the risk of incorrect provenance of clinical abnormalities
to infection by the virus. Thus, clinical abnormalities in a horse with Ross
River viremia or serum antibodies may not be attributable to infection by RRV.
Arthralgia is a common feature of the patients suffering from infection due
to RRV with or without arthritis. Fatigue as well as fever, myalgia and maculopapular
rashes are the constitutional symptoms in approximately 50% of the patients.
The 20-60 years age group of patients is the worst sufferers but any age group
may be affected by the disease (Harley et al., 2002;
In humans, it has been observed that RRV disease, although severe at onset,
progressively resolve over 3-6 months and other causes primarily unrelated rheumatic
conditions or depression have been attributed in patients experiencing long-term
disease lasting for more than 12 months found responsible (Jeandel
et al., 2004; Suhrbier and La Linn, 2004;
Colin de Verdiere and Molina, 2007). RRV polyarthritis
probably arises from inflammation associated with productive viral infections
in macrophages of the synovia persisting despite neutralizing antibodies and
antiviral cytokine responses. Downregulation of cytokine responses may facilitate
persistence by virus-antibody complexes binding to Fc receptors and induction
of interleukin-10. Escaping neutralizing antibodies by the virus remains unclear
but may involve phagocytosis of apoptotic virus-infected cells and infection
of the phagocyte via the phagosome (Suhrbier and La Linn,
2004; Rulli et al., 2007). Utilizing a mouse
model of RRV disease, Morrison et al. (2006) observed
that the primary targets of infection by RRV are bone and joint; muscle tissues
(skeletal) of the hind limbs in both outbred CD-1 mice as well as adult C57BL/6J
mice. Histological examinations showed severe inflammation of these tissues
caused by RRV infection. The inflammatory infiltrate within the skeletal muscle
tissue comprised of the macrophages, NK cells and CD4+ and CD8+T
lymphocytes. The researchers also found that adaptive immune response does not
play a critical role in the development of disease. But in their further studies
authors Morrison et al. (2007) demonstrated that
the complement system enhances the severity of disease induced by RRV in mice.
In the inflamed tissues and in the serum of RRV-infected wild-type mice products
of activation of complement have been detected whereas mice deficient in C3
(C3-/-), the central component of the complement system, developed
disease signs of much less severity than did wild-type mice. Complement activation
was also detected in synovial fluid from RRV-infected patients. They suggested
that complement plays an essential role in the effector phase but not the phase
of induction of arthritis and myositis induced by RRV. In yet another study
using macrophage-depleted mice model, macrophage-derived pro-inflammatory factors
were shown to be critical to the development of arthritis and myositis after
infection with RRV. Histological analyses of muscle and ankle joint tissues
revealed a substantial decrease in inflammatory infiltrates in infected "macrophage-depleted
mice", where levels of the pro-inflammatory factors, tumor necrosis factor-alpha;
interferon-gamma and macrophage chemo-attractant protein-1 were also dramatically
reduced, compared with samples obtained from infected mice without depletion
of macrophage. Detection of these factors has also been done in the synovial
fluid of patients with polyarthritis induced by RRV. There is reduction in the
severity of disease in mice as these factors get neutralized whereas nuclear
factor kappaB has been blocked by treating with sulfasalazine ameliorated RRV
inflammatory disease and tissue damage (Lidbury et al.,
2008). There is resolution of majority of the symptoms within 3-6 months
in most of the patients. There may be chronic course of the symptoms in certain
patients with persistence of symptoms that are non-rheumatic in nature that
includes fatigue as well as poor concentration. In certain instances a co-morbid
condition may be responsible for prolonged illness and there is importance of
investigation for certain other conditions that may either cause or contribute
to the symptoms. Patients may experience a RRV disease course that is relapsing
in nature (Mylonas et al., 2002).
Diagnosis: The diagnosis of RRV differentially from other diseases is
done with a broad sense including a spectrum of infectious as well as non-infectious
causes of polyarthopathy. The disease must be differentiated from Burma forest
virus as well as B19 strain of Parvovirus otherwise known as erythema infectiosium.
Among the diseases that are non-infectious in nature but must be differentiated
from RRV are: Rheumatoid arthritis; Stills disease in adults; Reiters
syndrome and Henoch Schonlein purpura. The diagnosis of RRV should be taken
into consideration if the patient has a high erythrocyte sedimentation rate
(ESR); anaemia; persistence of reduction in movement of joints; and radiological
changes (Harley et al., 2001; Smith,
Diagnosis of RRV infection is based on virus isolation from samples (blood
or serum) collected during the acute phase of the disease or by detecting specific
viral antibodies in serum. RRV can be isolated from infected horses during the
short time period when there is an overlap of clinical signs, positive IgM serology
and viremia (Azuolas et al., 2003). Virus can
be isolated in mice or tissue cultures. The detection of a RRV serum IgM titre,
either alone or in combination with an IgG titre, is indicative of a recent
infection, whereas presence of IgG antibodies is indicative of more distant
infection. Generally, IgM response occurs within 7 to 10 days post infection
and peaks within 2 to 3 weeks, before rapidly declining, as later IgG becomes
the dominant antibody (Azuolas et al., 2003;
El-Hage et al., 2008). Both virus exposure and
presumably infection can be confirmed by seroconversion. The virus isolation
has been made from horses with IgM antibodies to RRV but not from horses with
IgG antibodies because of the chronological pattern of antibody appearance in
the blood. Polymerase chain reaction (PCR) techniques have been demonstrated
to identify RRV (Studdert et al., 2003). The
molecular tool of reverse transcription-polymerase chain reaction (RT-PCR) has
also been developed for RRV which can be detected in blood and synovial fluid.
Specific, sensitive and rapid diagnostic tests using RT-PCR have been developed
and validated for the detection of RRV, Kunjin virus (KV) and Murray Valley
encephalitis virus (MVEV) infections in horses. The primer sets used for the
RT-PCR assay were based on nucleotide sequence encoding the envelope glycoprotein
E2 of RRV and on the nonstructural protein 5 (NS5) of KV and MVEV, which detected
RRV in sera from 8 horses showing clinical signs consistent with RRV infection.
The RRV RT-PCR was analytically found to be sensitive enough to detect as little
as 50 TCID50 of RRV per mL of serum. Not only sera samples, the RRV
primers were also able to detect virus in three independent mosquito pools known
to contain RRV by virus isolation in cell culture (Studdert
et al., 2003). Recently, an epitope-blocking enzyme-linked immunosorbent
assay (ELISA) has been developed and described to be a very sensitive and rapid
detection method for antibodies to RRV in human sera and other known vertebrate
host species (Stocks et al., 1997; Oliveira
et al., 2006).
Treatment: Treatment for RRV infection is only supportive as that for
Getah virus infection. It is prudent to minimize the exposure of horses to infected
mosquitoes. There is no vaccine to prevent infection or disease of horses by
RRV. However, in humans, nonsteroidal anti-inflammatory drugs (NSAIDs) have
been reported to give immediate symptomatic relief with no evidence of long-term
sequelae or relapse (Fraser and Marshall, 1989; Suhrbier
and La Linn, 2004). Condon and Rouse (1995) found
that of 255 patients, 36.4% felt that the best and most effective relief,
is provided by NSAIDS while 16.4% felt that aspirin or paracetamol was the most
effective. Physical interventions (swimming, hydrotherapy, physiotherapy, or
massage) were the most beneficial for 10.3% of patients but for 24.1% rest was
the only source of symptom relief.
Prevention and control: Attempts to prepare formaldehyde inactivated
RRV vaccine failed at preclinical trial levels (Kistner
et al., 2007). Recent insights into the RRV-host relationship in
association with pathology and molecular biology of infection have generated
a number of potential avenues for improvement in treatment. Although proposal
has been given for development of vaccine, the small size of market and potential
for antibody-dependent enhancement (ADE) of disease has decreased the attraction
of this approach. In RRV-ADE insights into the basis of molecular mechanism
recently and the ability of the virus to manipulate host inflammatory and immune
responses create potential new opportunities for invention therapeutically.
Dysregulation induced by these viruses must be overcome by such interventions
of protective host responses to promote clearance of virus and/or ameliorate
inflammatory immunopathology (Rulli et al., 2005,
2007; Lidbury et al., 2008).
A Vero cell culture-derived, whole-virus inactivated RRV vaccine was found to
be highly protective in animal models of viremia and disease (Holzer
et al., 2011). This vaccine was further tested in humans and was
found to be safe and induced protective antibodies in them. This vaccine did
not cause any antibody-dependent enhancement (ADE) of disease (Aichinger
et al., 2011). The development of protective antibody responses against
RRV is influenced by Toll-like receptor 7 (TLR7)-dependent signalling (Neighbours
et al., 2012).
The best way to prevent against the disease is to take precautionary measures
against mosquito bites. During the time of heavy infestations of mosquitoes
it is better to avoid remaining outside. Such are the early evenings during
the months of warm weather which must be avoided. Insect repellants must be
used along with wearing of protective clothings which are light coloured. The
living as well as sleeping areas must be screened. Regular checking of the home
is necessary to prevent the spread of mosquito breeding areas potentially. Any
type of water containers which remain uncovered must be emptied on regular basis
(Heymann, 2004). For studying the virus spread it is significant
to collect suspected region of acquisition for all types of cases. The national
dataset has got one of the limitation that there is no any routine collection
of suspected region of acquisition for all kinds of cases and thus there is
requirement of using the residential place as a proxy for the particular region
of acquisition. It is now mandatory to collect suspected region of acquisition
in all states as well as territories and to record the information at the national
level. Precise data collection will help the researchers to understand the RRV
disease geographical distribution in a more better way (Selden
and Cameron, 1996; Mackenzie, 1999; Kelly-Hope
et al., 2004; Ratnayake, 2005).
In the era of One Health, One Medicine, One World notion, issue of climate
changes and global warming and ever increasing mosquitoes/vector populations,
quick, confirmatory and advanced diagnostics supported with early warning and
surveillance/monitoring systems need to be fully applied for detecting RRV infections
in animals and humans (Studdert et al., 2003;
Schmitt and Henderson, 2005; Oliveira
et al., 2006; Woodruff et al., 2006;
Belak, 2007; Tong et al.,
2008; McIver et al., 2010; Deb
and Chakraborty, 2012; Deb et al., 2013;
Dhama et al., 2012, 2013a,
b, c, 2014;
Suhrbier et al., 2012). Continuous efforts need
to be made for developing effective, safer and novel vaccines (Meeusen
et al., 2007; Dhama et al., 2008,
2013d; Jones et al., 2010;
Aichinger et al., 2011; Holzer
et al., 2011; Aaskov et al., 2012)
and exploring alternative treatment modalities against this virus (Dhama
et al., 2013e, f, g;
Mahima et al., 2012; Tiwari
et al., 2014). Due attention need to be given to follow appropriate
and timely prevention and control measures including of strict biosecurity plans
for tackling RRV infection and the disease it causes, which would help safeguard
health of animals and humans.
CONCLUSION AND FUTURE PERSPECTIVES
RRV is an important member of the family Alphavirus causing polyarthralgia
in human and several different symptoms in horses starting from pyrexia till
arthritis. As the disease is mosquito-borne special study is required regarding
the ecology as well as climate and environment governing the breeding of mosquitoes.
Epidemiologists as well as environmentalists have given special attention to
the pattern of the distribution of the disease caused by RRV with special reference
to the mosquito breeding. In recent times much attention has been paid towards
the antiviral immunity especially regarding the cells of the immune system involved
in the disease process. Special experiments have been carried out in mice from
time to time to understand the immune response to the viral antigen. With the
advent of special diagnostic assays like RRV RT-PCR as well as special type
of ELISA viz., epitope-blocking ELISA it has become easier for the diagnosticians
to better diagnose the disease with rapidity as well as accuracy. Treatment
for RRV infection is only supportive as that for Getah virus infection. Physical
interventions may benefit certain patients. There have been a number of potential
avenues for improving treatment due to recent insights into the RRV-host relationship
and this is because of elaborate study regarding the pathology as well as molecular
biology of infection. The small market size has decreased the vaccinal approach
for preventing the disease. Precise data collection will help the researchers
to understand the RRV disease and its geographical distribution in an efficient
manner as well as comprehend the disease dynamics procedures in an interesting
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