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An introduction to arboviruses of medical
importance to Europe
Chantal Reusken
Arboviruses (arthropod-borne) grouped based on common mode of
transmission between vertebrates by bite of infected arthropod.
(biological vs mechanical transmisison).
Arthropods like midges, mosquitoes, sandflies and ticks.
Arboviruses
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http://www.microbiologybook.org/mhunt/rnavir.gif
Taxonomic classification:
3 virus families relevant for Public Health
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dengue virus (DENV)
West Nile virus (WNV)
yellow fever virus (YFV)
Zika virus (ZIKV)
Japanese encephalitis virus (JEV)
St. Louis encephalitis virus (SLEV)
tick-borne encephalitis virus (TBEV)
Omsk haemorraghic fever virus
(OHFV)
Kyasanur forest virus
Alkhumra virus
Flaviviridae, flavivirus
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Ashraf et al., Viruses 2015
Schematic diagram of flavivirus polyprotein organization and processing.
René Assenberg et al. J. Virol. 2009;83:12895-12906
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Taxonomic classification:
3 virus families relevant for Public Health
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Togaviridae, alphavirus
chikungunya virus (CHIKV)
Eastern equine encephalitis virus (EEEV)
Western equine encephalitis virus (WEEV)
Venezuelan equine encephalitis virus (VEEV)
Ross river virus (RRV)
Barmah Forest virus
Sindbis virus (SINV)
Mayaro virus (MAYV)
O’Nyong-nyong virus (ONNV)
Phylogenetic tree of all Alphavirus species, and selected subtypes and variants, generated from partial E1 envelope glycoprotein gene sequences by using the neighbor-joining program
with the F84 distance formula (61).
Ann M. Powers et al. J. Virol. 2001;75:10118-10131
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Schematic diagram of alphavirus genome organization and processing
http://viralzone.expasy.org/all_by_species/625.html
Taxonomic classification:
3 virus families relevant for Public Health
Bunyaviridae, nairo-, phlebo-, orthobunyavirus
Rift Valley fever virus (RVFV)
Crimean-Congo haemorrhagic fever virus (CCHFV)
Toscana virus (TOSV)
Tahyna virus (TAHV)
sandfly fever virus (SFV)
California encephalitis virus (CEV)
Oropouche virus
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Lopes, 2011
Bunyaviridae
Genome Bunyaviridae
Eifan et al., 2013
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Lifecycle
(Weaver and Barret, 2004)
(Weaver and Barret, 2004)
I. man is accidental host
Man dead-end host; does not contribute to virus maintenance and amplification.
Because:
Man has low viremia -> no infection of vectors
and/or
Primary vectors are not anthropophilic
Need: Presence of bridge vectors
West Nile virus,
Usutu virus
Tahyna virus
Tick-borne encephalitis virus
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(Weaver and Barret, 2004)
II. man is accidental host; two parallel cycles
Man dead-end host; does not contribute to virus maintenance and amplification.
Parallel transmission cycle involving
amplification in domestic animals
Japanese encephalitis virus
Equine encephalitis viruses
Rift Valley fever virus
(Weaver and Barret, 2004)
III. Man amplification host; two parallel cycles
Man develops high viremia, virus transmission can be sustained man-mosquito
cycle
Parallel transmission cycles
Jungle/urban yellow fever (South America)
Sylvatic/urban chikungunya (Africa)
Sylvatic/urban O’Nyong-nyong
Zika virus (Africa)
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IV. man is only amplification host
Man develops high viremia: virus transmission is sustained in man-mosquito cycle.
Primary vectors are anthropophilic
High vector/man densities to sustain transmisison
(Urban) dengue virus
(Urban) chikungunya (Indian Ocean/Caribbean
Zika virus (Caribbean/Pacific)
Courtesey M.Niedrig, RKI
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Transmission cycle tick-borne CCHFV
Bente et al., 2013
Alternative transmission routes: ZIKV
Blood-transfusion mediated transmission
Trans-placental and perinatal transmission
Sexual transmission :
Evidence in approx 20 cases
Isolation of ZIKV semen day 14 post onset illness
ZIKV detection semen day 28, 62 post onset illness
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Other ways to look at arboviruses……
a laboratory perspective -> serologic relationships
f.i. flaviviruses: serogroups
crossreactivity incl vaccinated
a control perspective -> specific virus-vector relationships
f.i. Aedes aegypti YFV, DENV, CHIKV, ZIKV.
Culex spp. WNV, JEV, SLEV, RRV, VEEV
Specific virus – vector –host associations
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Transmission cycle:
human-mosquito-human
(3-12 days)
Not all mosquito species will transmit virus “X”
Vector competence:
susceptibility + transmissibility
infected -> infective
(Beerntsen et al., 2000)
innate characteristics of vector:
efficiency of mosquito barrier crossing by specific virus
Lab vs field !
Virus genetics
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Vector capacity
V = vector competence
m = vector density vs competent host density
a = vector daily blood feeding rate (host preferences)
P = vector daily survival rate
n = extrinsic incubation period (days)
ma2VPn
-logePC=
efficiency of virus X transmission by mosquito species Y in defined context
ZIKV transmitted by Aedes spp.
In Africa in field: Ae. africanus, Ae. aegypti, Ae. albopictus, Ae. apicoargenteus,
Ae. luteocephalus, Ae. vitattus, Ae. taylori, Ae. dalzieli, Ae. hirsutus, Ae. metallicus,
Ae. unilinaetus, Ae. opok and Ae. furcifer (isolation and/or PCR detection).
(Mansonia uniformis, Culex perfuscus and Anopheles coustani
mosquitoes in Senegal)
Ae. aegypti is the only species for which transmission outside
Africa has been confirmed
Ae. albopictus has shown competence for ZIKV-Africa
dissemination in lab but has never been implied in ZIKV
epidemiology in the field outside Africa
Mosquitoes and ZIKV transmission
Reviewed in Charrel, Reusken et al., 2016
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Predicted global distribution Ae. aegypti
(Kraemer et al., 2015)
Presence of mosquito alone is not only requirement for ZIKV circulation
Other ways to look at arboviruses……
a laboratory perspective -> serologic relationships
f.i. flaviviruses: serogroups
a control perspective -> vector relationships
f.i. Aedes aegypti YFV, DENV, CHIKV.
Culex spp. WNV, JEV, SLEV, RRV, VEEV
a physician’s perspective -> pathogenic relationships + geographic relationships
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Main arbovirus syndromes
Often overlap
Fever syndrome
Fever with general malaise/myalgia/headache/retro-orbital pain
Arthritiis/Arthralia and rash syndrome
Poly-Arthritis/arthralgia and exanthema or maculopapular rash
Haemorrhagic syndrome
Petechiae/low platelet counts/ enlarged liver/bleeding/shock
Neurological syndrome
Meningitis, encephalitis, meningo-encephalitis, myelitis
Microcephaly/GBS ?
Convulsions, paralysis
Europe
South America
North America
Caribbean and Central America
Sub-Saharan Africa
West and Central Asia
South and Southeast Asia
Oceania
East Asia
North Africa
AR NS HS
WNV* WNV* DENV^
CHIKV CEV/LCV*
DENV^ EEEV
WEEV
CTFV
SLEV
POWV
AR NS HS
DENV^* OROV* DENV^*
CHIKV* WEEV
OROV* EEEV
GROV VEEV
WNV ILHV
ZIKV WNV
SLEV
AR NS HS
DENV^* TOSV* RVFV*
WNV* RVFV* CCHFV*
CHIKV* TAHV YFV*
TAHV DENV^*
SINV §SFV*
BUNV
AR NS HS
DENV^* WNV* RVFV*
WNV* RVFV* DENV^*
YFV* BUNV NRIV
CHIKV* TAHV ILEV
ZIKV BWA CCHFV
SINV BUNV
ONNV ILEV
BWA
TAHV
ILEV
TATV
NRIV
AR NS HS
WNV* TBEV* DENV^
SINV* WNV* CCHFV
DENV^ TOSV*
TAHV INKV §SFV*
INKV LIV
CHIKV TAHV
BATV
AR NS HS
DENV^* CHIKV* RVFV*
WNV* WNV* DENV^*
TAHV RVFV* CCHFV
SINV BANV OHFV
TAHV AHFV
§SFV* TBEV
AR NS HS
DENV^* JEV* DENV^*
CHIKV* TBEV SFTSV
WNV WNV OHFV
TAHV BANV CCHFV
TAHV
§SFV
AR NS HS
DENV^* JEV* DENV^*
WNV* WNV* KFDV
ZIKV* TBEV SFTSV
CHIKV* BANV CCHFV
TBEV TAHV
TAHV §SFV
AR NS HS
RRV* MEV* DENV^
BFV* JEV
ZIKV* WNV
DENV^
WNV
CHIKV
SINV
AR NS HS
DENV^* OROV* DENV^*
OROV* WEEV YFV
CHIKV EEEV
MAYV VEEV
WNV SLEV
GROV WNV
ZIKV ILHV
ROCV
Cleton et al 2012 Journal of Clinical virology & Cleton et al 2015 PNTD
Spread & syndromes of vector-borne viral
diseases: overlapping!
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Common signs and symptoms of ZIKV in humans
Incubation period: typically 3-7 days (range 3-12 days).
Only 20% symptomatic
• Fever (62-65%)
• Headache/general malaise (45-58%)
• Macular/papular rash (90-96%)
• Non-purulent conjunctivitis (38-55%)
• Retro-orbital pain (40%)
• Myalgia and arthralgia (48-65%)
Symptoms last for 2-7 days
ZIKV and Guillian-Barré syndrome
-> possible causal relation
Suggested association ZIKV infection with GBS (n= 42) during outbreak
in French Polynesia in 2013-2014
2015/2016, 8 ZIKV affected countries with increased incidence of GBS
and/or laboratory confirmation of a ZIKV infection among GBS cases.
Source: WHO situation report 19 February 2016
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Guillain-Barré syndrome (GBS)
Post-infectious immune-mediated polyradiculoneuropathy
(demyelination of peripheral nerves)
Incidence 1-2/100.000/year (life-time risk of 1:1000)
Usually 2-4 weeks after viral illness, immunization or allergic reaction
Clinical features:
rapidly progressive weakness in legs and arms
proportion with involvement cranial and/or sensory nerves
respiratory failure requiring ventilation at ICU (25%)
Pathology:
Demyelination and macrophage infiltration:
(axonal degeneration)
Clinical course:
acute onset and monophasic
frequent residual disability (15% wheelchair bound) Courtesy Bart Jacobs, EMC
Hypothesis on pathogenesis of GBS:
Molecular mimicry
cross-reactive immune response
immune defense
nerve destruction
Courtesy Bart Jacobs
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ZIKV and microcephaly
-> possible causal relation
Research in 1950’s-70’s showed ZIKV tropism for neurones, glial cells
(astrocytes) in mouse brains
Outbreak French Polynesia: 03/14-05/15 18 cases with CNS malformations
incl 9 microcephaly cases (normally 0-2 cases yr)
Brazil 10/15-02/16: 5640 cases suspected microcephaly
583 confirmed, 950 discarded (normally < 200 yearly but no uniform
definition)
Microcephaly signs and symptoms
Isolated condition
or associated with
- Mental retardation
-Delayed motor functions and speech
-Facial distortion
-Dwarfism or short stature
-Hyperactivity
-seizures
-Difficulties with coordination and balance
-Some walk slower than normal.
-Brain abnormalities
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Key facts – global
• Vector-borne diseases account for 17% of the estimated global burden of all
infectious diseases.
• 50% global population is at risk from vector-borne disease.
• Malaria caused an estimated 627 000 deaths in 2012: more than any other vector-
borne disease. 219 million infections.
• The fastest growing vector-borne disease is dengue fever,
30-fold increase incidence over the last 50 years.
40% global population is at risk from dengue virus
+/- 390 million infections each year in over 100 countries.
• 77.000 Europeans on average fall sick from vector-borne diseases every year.
World Health Day 2014
Vector-borne diseases38
Source: WHO
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Examples of vector-borne diseases
in the WHO European Region
World Health Day 2014
Vector-borne diseases
Mosquito-borne
• Dengue fever
• Chikungunya
• Malaria
• West Nile fever
• Ockelbo
• Usutu
• Batai
• Tahyna
Sandfly-borne
• Leishmaniasis
• Toscana virus
• Sandfly fevers
Tick-borne
• Lyme disease
• Tick-borne encephalitis
• Crimean–Congo
haemorrhagic fever
• Omsk-Haemorrhagic fever
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Jones et al., Nature 2008
wildlife livestock
resistent Vector-borne
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Increasing and decreasing trends
Source: WHO centralized information system for infectious diseases (CISID)
(http://data.euro.who.int/cisid).
World Health Day 2014
Vector-borne diseases41
0
10000
20000
30000
40000
50000
60000
Lyme disease Malaria WNF TBE Crimean Leishmania
Number of cases: 1990, 2000, 2010
1990 2000 2010
Complex
Braks et al Parasites and Vectors, 2011
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Growing public health concern
A combination of factors increases the threat of vector-borne
diseases in Europe:
• changing social and economic conditions;
• globalized travel and trade;
• increased urbanization;
• climate change;
• environmental and ecosystem changes.
•Pathogen adaptation to vector/hostWorld Health Day 2014
Vector-borne diseases43
Source: who
Globalization; trade
Trade in used tires and lucky bambooCharrel et al., 2007
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Sources of Scrap Tires Imported into U.S., 1989-1994
Courtesy of Dr. L. Petersen, CDC Fort Collins
Destination of U.S. Scrap Tires Exports, 1989-1994
Courtesy of Dr. L. Petersen, CDC Fort Collins
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Charrell et al., 2007
Efficient lab vector for 22 arboviruses
Efficient field vector for DENV + CHIKV
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Future Ae. albopictus in Europe
Minimal climate impact
2010
Minimal climate impact
2030
ECDC, technical report 2009
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Risks Public Health exotic vectors
(increased) transmission native pathogens
Introduction of novel pathogens (transovarial transmission)
e.g. DENV in Ae. Albopictus in NL ?
Scholte et al., 2008
Hofhuis et al., 2009.
Transmission novel pathogens introduced independently
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Globalization; travel
Cliff and Haggett, 2004
Increase travel 4 generations = increased exposure
58,288 flight routes… 1 Earth….within 24-30 hours
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Tilston et al., 2009;ECDC 2011, www.cbs.nl
zomervakanties 2009
Spanje 900
Portugal 180
Italie 730
Griekenland 520
Hongarije 70
Tsjechie 180
Turkije 440
Egypte 70
Totaal 3090
X 1000CHIKV
Travel within Europe to areas with increased risk for CHIKV circulation
(climate based)
Estimated yearly number CHIKV viremic travellers arriving in Europe (pre current caribbean outbreak).
-> 185.000 CHIKV viremic returning travelers per year
( extracted from Tilston et al., 2009)
0
2000
4000
6000
8000
10000
12000
14000
16000
Seychelles La Reunion Maldives Maurit ius India Gabon Sri Lanka Congo Malaysia
France
Germany
Italy
UK
Switzerland
Belgium
the Netherlands
Spain
X 10
1221
81
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Risk factor:
returning viremic travellers =
introduction of virus in naive areas
where vector is present…….
…………autochthonous transmisison
FACT !
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Global spread chikungunya virus
Geographic distribution ZIKV until outbreak New World
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Current outbreak
*first autochthonous transmission Brazil May 2015
* since: estimated 0.5 – 1.5 million cases in Brazil only
Situation as of 26 February 2016 (source PAHO)
DENV-1
DENV-2
Messina et al., 2014
DENV-2
DENV-3 DENV-4
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Climate (change)
Arthropods are cold-blooded (ectothermic) -> sensitive to climatic
factors.
Climate affects:
survival and reproduction rates vectors (vector abundance)
habitat suitability; vector distribution
Intensity and temporal activity vector (biting rates)
Rate of amplification/survival pathogens in vector
Public health action
• Vector surveillance
• Disease surveillance
• Monitoring drivers
prompt implementation control measures
Laboratory preparedness and response
World Health Day 2014
Vector-borne diseases64 Source : WHO
Early warning
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World Health Day
2014
Vector-borne
diseases
#Just1Bit
e
“There is a clear warning
signal to the European
Region that diseases
carried by vectors may
spread and intensify in the
years ahead. This is not
the time to lower our
guard.”
World Health Day 2014
Vector-borne diseases66
– Zsuzsanna Jakab
WHO Regional Director for Europe
Message from the Regional
Director