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An introduction to arboviruses of medical
importance to Europe
Chantal Reusken
c.reusken@erasmusmc.nl
Arboviruses
 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.
1
http://www.microbiologybook.org/mhunt/rnavir.gif
Taxonomic classification:
3 virus families relevant for Public Health
Flaviviridae, flavivirus
 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
4
2
Ashraf et al., Viruses 2015
Schematic diagram of flavivirus polyprotein organization and processing.
René Assenberg et al. J. Virol. 2009;83:12895-12906
3
Taxonomic classification:
3 virus families relevant for Public Health
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)
7
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
4
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
5
Bunyaviridae
Lopes, 2011
Genome Bunyaviridae
Eifan et al., 2013
6
Lifecycle
(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
(Weaver and Barret, 2004)
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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)
(Weaver and Barret, 2004)
8
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
9
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
10
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
11
Transmission cycle:
human-mosquito-human
(3-12 days)
Not all mosquito species will transmit virus “X”
Vector competence:
susceptibility + transmissibility
infected -> infective
innate characteristics of vector:
efficiency of mosquito barrier crossing by specific virus
Virus genetics
Lab vs field !
(Beerntsen et al., 2000)
12
Vector capacity
ma2VPn
C=
-logeP
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)
 efficiency of virus X transmission by mosquito species Y in defined context
Mosquitoes and ZIKV transmission
 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
Reviewed in Charrel, Reusken et al., 2016
13
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
14
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
Spread & syndromes of vector-borne viral
diseases: overlapping!
AR
WNV*
SINV*
DENV^
TAHV
INKV
CHIKV
North America
AR
WNV*
CHIKV
DENV^
NS
WNV*
CEV/LCV*
EEEV
WEEV
CTFV
SLEV
POWV
HS
DENV^
North Africa
AR
NS
DENV^*
TOSV*
WNV*
RVFV*
CHIKV*
TAHV
TAHV
SINV
§SFV*
BUNV
Caribbean and Central America
AR
DENV^*
CHIKV*
OROV*
GROV
WNV
ZIKV
NS
HS
OROV* DENV^*
WEEV
EEEV
VEEV
ILHV
WNV
SLEV
NS
OROV*
WEEV
EEEV
VEEV
SLEV
WNV
ILHV
ROCV
HS
RVFV*
CCHFV*
YFV*
DENV^*
AR
DENV^*
CHIKV*
WNV
TAHV
West and Central Asia
AR
DENV^*
WNV*
TAHV
SINV
§SFV*
Sub-Saharan Africa
South America
AR
DENV^*
OROV*
CHIKV
MAYV
WNV
GROV
ZIKV
Europe
NS
HS
TBEV*
DENV^
WNV*
CCHFV
TOSV*
INKV
§SFV*
LIV
TAHV
BATV
HS
DENV^*
YFV
AR
DENV^*
WNV*
YFV*
CHIKV*
ZIKV
SINV
ONNV
BWA
TAHV
ILEV
TATV
NRIV
NS
WNV*
RVFV*
BUNV
TAHV
BWA
BUNV
ILEV
HS
RVFV*
DENV^*
NRIV
ILEV
CCHFV
NS
CHIKV*
WNV*
RVFV*
BANV
TAHV
TBEV
HS
RVFV*
DENV^*
CCHFV
OHFV
AHFV
East Asia
NS
JEV*
TBEV
WNV
BANV
TAHV
HS
DENV^*
SFTSV
OHFV
CCHFV
§SFV
South and Southeast Asia
AR
DENV^*
WNV*
ZIKV*
CHIKV*
TBEV
TAHV
NS
JEV*
WNV*
TBEV
BANV
TAHV
HS
DENV^*
KFDV
SFTSV
CCHFV
§SFV
Oceania
AR
RRV*
BFV*
ZIKV*
DENV^
WNV
CHIKV
SINV
NS
MEV*
JEV
WNV
HS
DENV^
Cleton et al 2012 Journal of Clinical virology & Cleton et al 2015 PNTD
15
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 vectorborne 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.
Source: WHO
38
World Health Day 2014
Vector-borne diseases
19
Examples of vector-borne diseases
in the WHO European Region
Mosquito-borne
Sandfly-borne
• Dengue fever
• Chikungunya
• Malaria
• West Nile fever
• Ockelbo
• Usutu
• Batai
• Tahyna
• Leishmaniasis • Lyme disease
• Toscana virus • Tick-borne encephalitis
• Sandfly fevers • Crimean–Congo
haemorrhagic fever
Tick-borne
• Omsk-Haemorrhagic fever
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wildlife
resistent
World Health Day 2014
Vector-borne diseases
livestock
Vector-borne
Jones et al., Nature 2008
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Increasing and decreasing trends
Number of cases: 1990, 2000, 2010
60000
50000
40000
30000
20000
10000
0
Lyme disease
Malaria
WNF
1990
TBE
2000
Crimean
Leishmania
2010
Source: WHO centralized information system for infectious diseases (CISID)
(http://data.euro.who.int/cisid).
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World Health Day 2014
Vector-borne diseases
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;
Source: who
• environmental and ecosystem changes.
•Pathogen adaptation to vector/host
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World Health Day 2014
Vector-borne diseases
Globalization; trade
Trade in used tires and lucky bamboo
Charrel 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
23
Charrell et al., 2007
Efficient lab vector for 22 arboviruses
Efficient field vector for DENV + CHIKV
24
Future Ae. albopictus in Europe
Minimal
Minimal climate
climate impact
impact
2030
2010
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
Increase travel 4 generations = increased exposure
Cliff and Haggett, 2004
58,288 flight routes… 1 Earth….within 24-30 hours
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Travel within Europe to areas with increased risk for CHIKV circulation
(climate based)
CHIKV
zomervakanties 2009 X 1000
Spanje
900
Portugal
180
Italie
730
Griekenland
520
Hongarije
70
Tsjechie
180
Turkije
440
Egypte
70
Totaal
3090
Tilston et al., 2009;ECDC 2011, www.cbs.nl
Estimated yearly number CHIKV viremic travellers arriving
in Europe (pre current caribbean outbreak).
-> 185.000 CHIKV viremic returning travelers per year
X 10
16000
14000
12000
France
Germany
10000
Italy
UK
8000
Switzerland
Belgium
6000
the Netherlands
Spain
4000
2000
1221
81
0
Seychelles
La Reunion
Maldives
Mauritius
India
Gabon
Sri Lanka
Congo
Malaysia
( extracted from Tilston et al., 2009)
28
Risk factor:
returning viremic travellers =
introduction of virus in naive areas
where vector is present…….
…………autochthonous transmisison
FACT !
29
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-2
DENV-1
DENV-2
Messina et al., 2014
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
Early warning
• Disease surveillance
• Monitoring drivers
prompt implementation control measures
Laboratory preparedness and response
World Health Day 2014
64
SourceVector-borne
: WHO
diseases
32
World Health Day
2014
Vector-borne
diseases
#Just1Bit
e
Message from the Regional
Director
“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.”
– Zsuzsanna Jakab
WHO Regional Director for Europe
66
World Health Day 2014
Vector-borne diseases
33