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Home , Nairoviridae, Ross River virus

Setting the course scene: An introduction to 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. 2017, new classification: Order . Families: Hantaviridae, Feraviridae, Fimoviridae, Jonviridae, Nairoviridae, Peribunyaviridae, , Phenuiviridae, and Tospoviridae http://www.microbiologybook.org/mhunt/rnavir.gif Families relevant for Public Health

Flaviviridae,

. Dengue (DENV) . (WNV) . virus (YFV) . (ZIKV) . virus (JEV) . St. Louis encephalitis virus (SLEV) . Tick-borne encephalitis virus (TBEV) . Omsk haemorraghic fever virus (OHFV) . Kyasanur forest virus (KFDV) . Alkhumra virus (ALKV)

4 Ashraf et al., 2015 Schematic diagram of flavivirus polyprotein organization and processing.

René Assenberg et al. J. Virol. 2009;83:12895-12906 ZIKV ZIKV

Worldwide distribution of . Distributions of YFV, JEV, TBEV, DENV, ZIKV and WNV are indicated.

Adapted from : Tomohiro Ishikawa, Atsushi Yamanaka, Eiji Konishi A review of successful flavivirus vaccines and the problems with those flaviviruses for which vaccines are not yet available ☆ Vaccine, Volume 32, Issue 12, 2014, 1326–1337 http://dx.doi.org/10.1016/j.vaccine.2014.01.040 Families relevant for Public Health

Togaviridae,

. virus (CHIKV) . Eastern equine encephalitis virus (EEEV) . Western equine encephalitis virus (WEEV) . Venezuelan equine encephalitis virus (VEEV) . virus (RRV) . . (SINV) . Mayaro virus (MAYV) . O’Nyong-nyong virus (ONNV)

8 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 Schematic diagram of alphavirus genome organization and processing

http://viralzone.expasy.org/all_by_species/625.html Families relevant for Public Health

Nairoviridae, Peribunyavirae,Phenuiviridae

. virus (RVFV) . Crimean-Congo haemorrhagic fever virus (CCHFV) . Toscana virus (TOSV) . Tahyna virus (TAHV) . Sandfly fever virus (SFV) . California encephalitis virus (CEV) . Oropouche virus Lopes, 2011 Eifan et al., 2013 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   Japanese encephalitis virus  Equine encephalitis viruses  Tick-borne encephalitis virus (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

(Weaver and Barret, 2004) III. two parallel cycles

. Man develops high viremia, virus transmission can be sustained man- cycle . Parallel transmission cycles  Jungle/urban Yellow fever  Sylvatic/urban Chikungunya (Africa)  Sylvatic/urban O’Nyong-nyong  Zika (Africa)

(Weaver and Barret, 2004) IV. man is only amplification host

. Man develops high viremia: virus transmission is sustained in man-mosquito cycle. . Primary vectors are anthropophilic . High /man densities to sustain transmisison

 (Urban)  (Urban) Chikungunya (Indian Ocean/Caribbean  Zika virus (Caribbean/Pacific) YFV

Monath et al, 2001 Transmisison cycle tick-borne CCHFV

Bente et al., 2013 TBEV

(Dobler et al., 2010) Alternative transmission routes

. Blood-transfusion mediated transmission . Transplant transmission . Trans-placental and perinatal transmission . Sexual transmission . No-socomial transmisison 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 Transmission cycle: human-mosquito-human

(3-12 days) Not all mosquito species will transmit virus “X”

Vector competence:

susceptibility + transmissibility = infected -> infective

A. blood meal B. midgut D. entry midgut epithelial cells E. entry hemolymph-filled hemocoel H. entry salivary glands

innate characteristics of vector efficiency of mosquito barrier crossing by specific virus (Beerntsen et al., 2000) 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 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 Main syndromes

. Often overlap

. Fever with general malaise/myalgia . Arthritis/arthralgia and rash . Haemorrhagic fever . Neurological syndrome Arthritis and rash

Cleton et al., 2012 Meningo-encephalitis

2931 31maartCleton 2018 et al., Journal of Clinical Virology 2012 29 maart 2018 Hemorrhagic fever

Cleton et al., 2012 Diagnostic challenges arboviruses Many diseases display overlapping symptoms and geographical distribution Within cross-reactivity!

Europe AR NS HS WNV* TBEV* DENV^ East Asia North America DENV^ WNV* CCHFV AR NS HS AR NS HS TAHV LIV DENV^* JEV* DENV^* WNV* CEV/LCV* DENV^ SINV* TOSV* §SFV* WNV TBEV OHFV DENV^ WNV* CHIKV BATV CHIKV* WNV SFTSV CHIKV POWV TAHV SLEV TAHV BANV CCHFV EEEV West and Central Asia TAHV WEEV AR NS HS CTFV DENV^* CHIKV* RVFV* North Africa WNV* WNV* CCHFV AR NS HS TAHV TBEV DENV^* Caribbean and Central America DENV^* TOSV* RVFV* SINV BANV OHFV South and Southeast Asia AR NS HS WNV* RVFV* CCHFV* TAHV AHFV AR NS HS DENV^* OROV* DENV^* CHIKV* TAHV YFV* §SFV* RVFV* DENV^* JEV* DENV^* WNV WEEV SINV DENV^* WNV* WNV* KFDV ZIKV* EEEV TAHV §SFV* ZIKV* TBEV SFTSV OROV* VEEV BUNV TBEV BANV CCHFV CHIKV* ILHV Sub-Saharan Africa CHIKV* TAHV WNV AR NS HS TAHV SLEV DENV^* WNV* DENV^* Flaviridea WNV* RVFV* RVFV* YFV* BUNV NRIV Togaviridae South America ZIKV TAHV ILEV CHIKV* BWA CCHFV AR NS HS SINV BUNV Bunyaviridae DENV^* OROV* DENV^* ONNV ILEV ZIKV* WEEV YFV BWA / Seadornaviridae WNV EEEV Oceania TAHV CHIKV* VEEV AR NS HS ILEV MAYV* SLEV RRV* MEV* DENV^ TATV §WSBV OROV* WNV BFV* JEV NRIV ILHV CHIKV WNV ROCV SINV WNV DENV^ ZIKV

§Fever with general malaise/myalgia +

AR=Arthritis/arthralgia and rash Fig 1. Geographical distribution of medically important arboviruses that cause febrile disease in HS=Haemorrhagic symptoms humans. Cleton et al 2012 Journal of Clinical virology & Cleton et al 2015 PNTD NS=neurological symptoms Recent emerging viral diseases.

Entero 68

Usutu virus

MERS Polio

Zika

Zika

Yellow fever

Updated from Hilary• D. MarstonVector et-borne al., Sci diseases Transl Med account for 17% of the estimated global burden of 2014;6:253ps10 all infectious diseases.

Arbovirus • 50% global population is at risk from vector-borne disease.

• The fastest growing vector-borne disease is , 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.

Source: WHO, pre-outbreak CHIKV and ZIKV in the New World Kreuder Johnson et al., 2015 Determinants and Drivers of Infectious Disease Threat Events in Europe

Semenza et al., 2016 Determinants and Drivers of Infectious Disease Threat Events in Europe

A combination of factors increases the threat of vector-borne diseases:

• changing social and economic conditions; • globalized travel and trade => pathogen and vector • increased urbanization; population growth •environmental and ecosystem changes. •climate change;

•Pathogen adaptationFood to- bornevector/host Vector/rodent-borne

Semenza et al., 2016 Globalization; trade

Trade in used tires and lucky bamboo Charrel et al., 2007 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 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 Globalization, travel

Increase travel 4 generations Increase in flight routes from/to Paris 30 yrs

Cliff and Haggett, 2004

Globally 58,288 flight routes… 1 Earth….within 24-30 hours Bogoch et al., 2016; http://qz.com/605711/zika-is-just-one-flight-away-from-these- 57-countries/ Risk factor: returning viremic travellers = introduction of virus in naive areas where vector is present……. …………autochthonous transmisison 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 Gabon Sri Lanka Congo Malaysia

( extracted from Tilston et al., 2009) FACT ! DENV-2 DENV-1

DENV-2

Messina et al., 2014 DENV-3 DENV-4 Global spread chikungunya virus Geographic distribution ZIKV until outbreak New World Climate (change)

. Arthropods are cold-blooded (ectothermic) -> sensitive to climatic factors.

. Climate affects: . survival and reproduction rates vectors (vector abundance) . habitat suitability; vector distribution (higher altitudes, latitudes) . Intensity and temporal activity vector (biting rates) . Rate of amplification/survival pathogens in vector Future Ae. albopictus in Europe habitat suitability moving north-wards

MinimalMinimal climateclimate impactimpact 20302010

ECDC, technical report 2009 WNV and USUV introduction in Europe: bird migration

2016

Dimitri Engel et al. mBio 2016; doi:10.1128/mBio.01938-15 Temperature as driver of USUV outbreak in W-Europe, 2016

FIGURE 1. Number (panel A) and cumulative percentage (panel B) of outbreak-related USUV- positive live and dead birds, western Europea, 2016

FIGURE 3. Monthly temperature anomalies and distribution of outbreak- related USUV-positive birds, western Europea, 2016 Cadar et al., Eurosurveillance 2016 Examples of vector-borne diseases in the WHO European Region

Mosquito-borne Sandfly-borne Tick-borne

• Dengue fever • Leishmaniasis • Lyme disease • Chikungunya • Toscana virus • Tick-borne encephalitis • Malaria • Sandfly fevers • Crimean–Congo • haemorrhagic fever • Ockelbo • Usutu • Omsk-Haemorrhagic fever • Batai World Health Day 2014 • Tahyna 54 Vector-borne diseases Public health action

• Vector surveillance Early warning • Disease surveillance • Monitoring drivers prompt implementation control measures

Laboratory preparedness and response

World Health Day 2014 55 SourceVector : WHO-borne diseases 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

World Health Day 2014 56 Vector-borne diseases