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An introduction to arboviruses of medical
importance to Europe
Chantal Reusken
[email protected]
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.
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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
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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)
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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
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)
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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
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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
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
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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 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
25
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
26
Globalization; travel
Increase travel 4 generations = increased exposure
Cliff and Haggett, 2004
58,288 flight routes… 1 Earth….within 24-30 hours
27
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 !
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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-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