Hantavirusesas emerging pathogensin Europe and Africa

Boris KlempaDepartment of Virus EcologyInstitute of VirologySlovak Academy of SciencesBratislava, Slovakia

Yosemite Hantavirus OutbreakAugust, 2012

source: Robert-Koch-Institute, Berlin

1.200

1.500

2001 2002 2003 2004 2005

300

600

900

2006 2007

185 228144

242

448

72

1.6881.800

241

2008

2.100

20102009

181

2.017

2011

305

2.568

1.-9.2012

Reported hantavirus diseasesin Germany 2001-2012

Hantaviruses cause two human zoonoses

Puumala

Dobrava-BelgradeSin Nombre

Andes

Hantaan

Seoul

H F R S

H C P S

hemorrhagic fever with renal syndrome (HFRS) case fatality rate of up to 15%

hantavirus cardiopulmonary syndrome (HCPS) case fatality rate of up to 50%

SangassouTanganyaAzagny

MagboiMouyassue

Klempa et al., Emerg Inf Dis 2006; 2007Klempa et al., J Inf Dis 2010Klempa et al., J Virol 2012Weiss et al., 2012

H C P S

HFRS 200,000 - 300,000 cases annually

, hemorrhagesfever

renal dysfunction

Ferluga D , Vizjak A JASN 2008;19:1653-1658©2008 by American Society of Nephrology

Difficulties to study hantaviruses

biosafety level 3 or 4 conditions

slow growth on cell cultures

no detectable CPE on cell cultures

no reverse genetics

no animal model

virus detectable in patients only very shortly after clinical onset

1. Step 2. Step

Genus specific PCRSequencingPhylogenetic analyses

Recombinant antigen expression for serodiagnosticsPrimer design for specific PCR

Neutralisation assay for serotypingComparative pathogenesis studies

Strategical approach to identify new hantaviruses and human

disease

Virus isolation in cell culture

DOBV is present in Central Europe in Apodemus agrarius and forms a separate DOBV-Aa lineage

Klempa et al., J Virol 2003

DOBV-Aa causes HFRS

Klempa et al., J Clin Microbiol 2004

DOBV-Aa cell culture isolates allow fine-serotyping and comparative pathogenesis studies Klempa et al., J Clin Microbiol 2005Klempa et al., Emerg Infect Dis 2008Kirsanovs et al., Virus Genes 2010Popugaeva et al., Plos ONE 2012

Apodemus flavicollis A. agrarius

Dobrava-Belgrade hantavirus emerging in Central Europe

% of patients(n = 36)

average duration: 6.8 days

Abdominal pain 81 Vomiting 62

Diarrhea 42

Facial flushing 73

Haemorrhagic sclerae 54

Oliguria <500 µl 85

Increased blood urea, creatinine 85

Acute onset, fever 100

Case fatality rate 16.7 !

Observation

New DOBV lineage discoveredin Apodemus ponticus

Dzagurova et al., Clin Infect Dis, 2012Isolation from a fatal HFRS case

Apodemus ponticus

Klempa et al., Emerg Infect Dis, 2008

Sochi virus, novel genetic variant of DOBV, causes severe HFRS in

Russia

First African hantaviruses

0.1

Cao Bang

Jemez Springs

SeewisAsh River

Seoul

Hantaan

DobravaSangassou

Puumala

Tula

Andes

Sin Nombre

Thottapalayam

Arvicolinae-associated

Sigmodontinae-associated

Murinae-associated

Hylomyscus simus

Sangassou, GuineaKlempa et al., Emerg Infect Dis 2006

Soricidae-associated

Tanganya

Tanganya, Guinea

Crocidura theresae

Klempa et al.,Emerg Infect Dis, 2007

Klempa et al., J Inf Dis 2010

Seroepidemiological study in Guinea• recombinant N protein expression

• ELISA • immunization

• immunofluorescence test• neutralisation assay (FRNT)

Klempa et al., J Virol 2012

Comparative pathogenesis study

• uses ß1 integrin as entry receptor

• is a strong inducer of IFN- λ in type I IFN-deficient Vero E6

• complete genome sequencing• unique properties within Murinae-

associated hantaviruses

Isolation of Sangassou virus, the first hantavirus from Africa

89

0,2

SEOV

DOBV

SERV

HTNV

ANDV

MAPV RIOMV

CHOVSNV

LNV

TULV

PUUV

VLAVTPMV

NVAV

ALTV

MJNV

MGBV

ARRVJMSVCBNV

RPLV

SWSV

ARTV

KKMV

OXBV

ASAV

Muridae-associated

Cricetidae-associated

Soricidae-associatedTalpidae-associated

Soricidae-associatedTalpidae-associatedNycteridae-associated

90

74

91

96

83

82

86

99

99 70

99

99

72

TANGV

SANGV Magboi virusNycteris hispidaSierra Leone

Weiss, Witkowski et al., Emerg Inf Dis 2012

Hantavirus in African bats

Hantaviruses

still have a potential to emerge:

• new virus species• in new natural hosts• in new geographical regions• during new outbreaks

Michal StankoMarta SiebenstichováZuzana GulášováMartina LičkováLukáš RadosaInstitutes of Virology and Zoology,Slovak Academy of SciencesBratislava, Slovakia

Detlev H. KrügerBrita AustePeter WitkowskiAndreas RangInstitute of Virology, CharitéBerlin, Germany

Jan ter Meulen Emilie LecomptePhilipps UniversityMarburg, Germany

Lamine KoivoguiViral Hemorrhagic Fever ProjectConakry, Guinea

Elisabeth Fichet-CalvetChristiane DenysMuseum National d'Histoire NaturelleParis, France

Fabian LeendertzSabrina WeissRobert Koch Institute Berlin, Germany

Christian DrostenJan Felix DrexlerBonn University, Germany

Acknowledgements

VEGAEvgeniy A. Tkachenko Tamara Dzagurova Chumakov Institute Russian Academy of Medical Sciences, Moscow, Russia