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An introduction to arboviruses of medical

importance to Europe

Chantal Reusken

c.reusken@erasmusmc.nl

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