infezioni virali emergenti e riemergenti degli …...1997: avian influenza 2002: sars 2012: mers...

INFEZIONI VIRALI EMERGENTI E RIEMERGENTIDEGLI ANIMALI DA COMPAGNIA

Vito Martella,Department of Veterinary Medicine

University of Bari, Italye-mail: [email protected]

GIORNATA DI STUDIOL’AQUILA, 25 marzo 2017

A disease that has appeared in a population for the first time, or that may have existed previously but is rapidly increasing

in terms of incidence or geographic range

EMERGING DISEASE (WHO)

“...NOTHING IN BIOLOGY

MAKES SENSE

EXCEPT IN THE LIGHT OF EVOLUTION…”

Theodosius Dobzhansky

(1900-1975)

Charles Darwin

“...NOTHING IN VIROLOGY

MAKES SENSE

EXCEPT IN THE LIGHT OF EVOLUTION…”

Marian C. Horzinek

(1936-2016)

VIRUS EVOLUTION

http://upload.wikimedia.org/wikipedia/commons/9/9c/Darwin_ape.jpghttp://upload.wikimedia.org/wikipedia/commons/9/9c/Darwin_ape.jpg

VIRUS EVOLUTION

PROLIFERATE FASTER THAN

is the constant changeof a viral population in the face of selection pressures

EVOLUTION

RATES OF MUTATION OF VIRUSES

RNA viruses are the masters of mutation….

VIRUS EVOLUTIONresponsible for the emergence of most emerging and reemerging

infectious diseases faster in RNA viruses than in bacteria and DNA viruses due to the lack

of proof-reading activity of the RdRpthe same mechanisms as in higher organisms: variation (mutation) and

fixation (selection)mutants arise spontaneously and stochastically (deletions, insertions,

recombinations, reassortments)each infection represents a population bottleneck (casual selection of

mutants) and has to face the host immunity (direct selection)

Any disease or infection that is naturally transmissible from vertebrate animals to humans

ZOONOSIS (WHO)

1997: Avian influenza

2002: SARS

2012: MERS

2014: REEMERGENCE OF EBOLA

MAJOR ZOONOSES OF DOGS AND CATS

http://www.upenn.edu/regulatoryaffairs/Documents/iacuc/guidelines/zoonoses_dogs_and_cats.doc

VIRAL ZOONOSES OF DOGS AND CATSRABIES: the most common canine zoonosis

2015, second semester; www.oie.it

The virus is present in 2/3 of the world countries Half of the world population live in an endemic area

VIRAL ZOONOSES OF DOGS AND CATSRABIES: the most deadly canine zoonosis

70,000 human deaths/year>95% human cases caused by dog bites

Cave canem First century Roman mosaicHouse of the Tragic Poet, Pompeii

VIRAL ZOONOSES OF DOGS AND CATS

RABIES: the oldest known canine zoonosis

Mesopotamia, 2300 bc, Eshnunna Code

• First attempt to prevent virustransmission from dogs to humans

• The dog owner was heavily fined incase of death of the bitten person

“If a dog is mad and the authorities have brought the fact to the knowledge of its owners; if he does not keep it in, if it bites a man and causes his death, then the owner shall pay two thirds of a mina (40 shekels) in silver. If it bites a slave and causes his death he shall pay fifteen shekels of silver”

VIRUS DISCOVERY Datta et al., 2015, World J. Virology

NGS IN VIRUS DISCOVERY

Mokili et al., 2011, CurrentOpinion in Virology

EMERGING VIRUSES OF DOGS AND CATS

INFLUENZA VIRUSESROTAVIRUSESCALICIVIRUSESASTROVIRUSESOTHERS

INFLUENZA VIRUSES

ANTIBODIES AGAINST HUMAN INFLUENZA A VIRUSES

DETECTED IN DOGS AND CATS (Nikitin et al., 1972; Fison et al., 1975;

Houser at al., 1980; Buonavoglia et al., 1983)

CATS SUCCESSFULLY INFECTED WITH A/H3N2/Hong Kong/1968

(Paniker and Nair, 1970)

2002: BIRD FLU HPAI H5N1

Host range of HPAI H5N1

Natural infection Experimental infection

BirdsHumansDomestic catWild felidsStone martenSwinePalm civetDog

BirdsMonkeys (C. macaque)Domestic catFerretMiceRabbitsRatsCattle

INFLUENZA VIRUSES

H5N1 in carnivores

Date Species Outcome

Dec 2003

Feb-Mar 2004

Feb 2004

Oct 2004

Jul 2005, Vietnam

Leopard, Tiger

Clouded leopard, Tiger

Domestic cats

Tiger

Owstone palm civet

Rapid death

Rapid death

3/15 dead

147/441 dead/euthanased

3 dead

INFLUENZA VIRUSES

Date and country Species Outcome

2005

Mar 2006, Germany (Rügen)

Mar 2006, Austria

Cats, dogs

Domestic cat

Domestic cat

Seropositives Cats 8/111Dogs 160/609

dead

3 dead

H5N1 in carnivores

INFLUENZA VIRUSES

Cat with H5N1 natural infection, Thailand

Lung: oedema and congestion Liver: multifocal necrosisSongserm et al., 2006, Emerg. Infect. Dis.

Brain (IHC): viral antigens Heart (IHC): viral antigens

H5N1 experimental infection of cats

• Different routes of infection:– Intratracheal– Direct contact– Administration of infected chickens

• Disease (respiratory and systemic signs)– Lung lesions– Multifocal petechiae in the lymphatic

tissue of the respiratory tract– Virus detected in internal organs– Early death

• Virus shedding• Virus transmission to contact cats

Thiry et al., 2007, Vet. Microbiol.

Songserm et al., 2006, Em. Infect. Dis.

HPAI H5N1 in dogs

• Species not highly susceptible to HPAI H5N1

• Serological positivity

• Sporadic clinical cases

• Dogs infected by consumption of contaminated ducks

• Area with high H5N1 prevalence

• After 5 days: fever, lethargy, respiratory distress, rapid death

Lung congestionLung: oedema and heamorrhegs (haemosiderin)

Liver: necrotic areas IHC : viral antigens in hepatocyte nuclei

Songserm et al., 2006, Em. Infect. Dis.

HPAI H5N1 natural infection in dogs

• Infection with different routes:– Oculo-nasopharyngeal – Direct contact with infected cats

• Subclinical infection– Mild fever (39,2-39,7°C)– Conjunctivitis– Mild increase of hepatic enzyme (AST, CPK)– Periportal lymphocytic infiltration

• Viral shedding • Seroconversion (low Ab titres)• No transmission to contact cats

Giese et al., 2008, Emerg. Infect. Dis.

H5N1 experimental infection of dogs

Equine H3N8 in dogs

January 2004 - FLORIDA

OUTBREAK OF RESPIRATORY DISEASE IN GREYHOUNDS

8/22 DEAD DOGS (36%)

CLINICAL SAMPLES TESTED NEGATIVE TO COMMON PATHOGENS

CYNDA CRAWFORD, EL DUBOVI et al., Science, 2005

Equine H3N8 in dogs

HAEMORRAGES IN THE RESPIRATORY TRACT

VIROLOGICAL INVESTIGATIONScanine/Fl/04

Equine H3N8 in dogs

2 GENETIC LINEAGES

EUROPEAN

NORTHERN AMERICAN

Equine H3N8 in dogs

3 SUBLINEAGES

SUB-LINEAGE FLORIDA

CANINE/FL/O4

96-98% NT IDENTITY TO EQUINE H3N8 FLORIDA SUBLINEAGE

ALL GENOMIC SEGMENTSOF EQUINE ORIGIN

Equine H3N8 in dogs

FL

ALTX

AR

WVKS

AR

IA

CO

WI

Equine H3N8 in dogs

• RESPIRATORY DISEASE IN FOXHOUNDS

• SUBSEQUENT IDENTIFICATION OF H3N8

SEROLOGICAL INVESTIGATIONS IN FOXHOUNDS

• SEROPREVALENCE OF 37,5%

• LACK OF Ab IN DOGS BORN AFTER APR 2003

• HIGH SEROPREVALENCE (

• CIRD IN DOGS IN CONTACT WITH INFECTED HORSES

• IDENTIFICATION OF H3N8

Equine H3N8 in dogs

AUSTRALIA, 2007

Kirkland et al., Emerg Infect Dis., 2008

HA

LARGE H3N8 EPIDEMICS IN HORSES

CROSS-SPECIES TRANSMISSION OF EQUINE H3N8 NORTHERN AMERICAN LINEAGE

Equine H3N8 in dogs

UK, 2002 AUSTRALIA, 2007

SUBSEQUENT SEROLOGICAL INVESTIGATIONS HAVE SHOWN:

VIRUS PRESENT IN DOGS SINCE 1998

HIGH SEROPREVALENCE IN DOGS IN CONTACT WITH ILL DOGS

HIGH FREQUENCY OF SUBCLINICAL INFECTIONS

Equine H3N8 in dogs

(Larson et al., Clin Vaccine Immunol. 2011)

MOST SEVERE FORMS IN COINFECTIONS WITH S. equi subsp. zooepidemicus

SOUTH KOREA, 2006

CHINA, 2006-2007

DIRECT TRANSMISSION FROM BIRDS TO DOGS IN LIVE-ANIMAL MARKETS

INDIA, 2011 THAILAND, 2012

Avian-like H3N2 in dogs

Bunpapong et al., Virus Genes 2014

Song et al., Emerg Infect Dis. 2008

Li et al., Infect Genet Evol. 2010

www.avma.org

NA

HA


Li et al., Infect Genet Evol. 2010

USA (CHICAGO), APR 2015

• Fever, inappetance, lethargy

• Cough, nasal discharge

• Limited viral shedding (H3N2 1-2 d, H3N8 7-10 d)

99% IDENTITY TO THE ASIAN VIRUS


http://www.cdc.gov/flu/news/canine-influenza-update.htm

5/23/2016 -7/11/2016 (H3N2)


https://ahdc.vet.cornell.edu/news/civchicago.cfm

Avian-like H3N2 in cats

Zhou et al., Vet Microbiol. 2015CHINA, 2006-2007

AVIAN-LIKE H3N2 Ab IN STRAY CATS IN POULTRY LIVE MARKETS

SOUTH KOREA, 2009-2010 Song et al., J Gen Virol. 2011

LARGE OUTBREAK OF AVIAN-LIKE H3N2 IN DOGS AND CATS OF AN ANIMAL SHELTER IN SEOUL

• Dogs (200): 25% mortality; ? Morbidity• Cats (50): 40% mortality; 100% morbidity

USA, 2009-2010 http://www.uwsheltermedicine.comCATS WITH URD IN AN ANIMAL SHELTER IN NW INDIANAWITH DOGS WITH CIV

http://www.doginfluenza.com/professionals/#

NO EVIDENCE FOR ZOONOTIC ACTIVITY

Equine H3N8 and avian-like H3N2

2009: SWINE FLU

pdm09 H1N1

pdm09 H1N1 in cats

USA (IA), Dec 2009A 13-YEAR-OLD CAT BECAME ILL AFTER ITS OWNERSDISPLAYED SEVERE DYSPNOEA AND PNEUMONIA

Sponseller et al., Emerg Infect Dis. 2010

ITALY, Dec 2009 Dundon et al., Emerg Infect Dis. 2010

FRANCE, Dec 2009 www.avma.org

A 5-YEAR-OLD CAT BECAME ILL AFTER TWO CHILDREN

SEVERE OUTBREAK OF RESPIRATORY AND GI DISEASE

25/90 CATS

50% MORTALITY

COINFECTION WITH FPLV?

THE NETHERLANDS, 2010van den Brand et al., Emerg Infect Dis. 2010

EXPERIMENTAL INFECTION

pdm09 H1N1 in cats

MILD-MODERATE DISEASE

POSITIVE PCR RESULTS

NO VIRUS ISOLATION

8 intratracheallyinfected cats

4 contact catsNO DISEASE

VIRAL SHEDDING

CHINA, Nov 2009NATURAL INFECTION IN TWO DOGS WITH RESPIRATORY DISEASE

Lin et al., J Gen Virol. 2012

USA (NY), Dec 2009A 13-YEAR-OLD DOG BECAME ILL AFTER ITS OWNER

www.avma.org

ITALY, OCT-DEC 2009

SEROLOGICAL EVIDENCE FOR CIRCULATION OF pdmH1N1

Dundon et al., Emerg Infect Dis. 2010

pdm09 H1N1 in dogs

CHINA, Nov 2012 Lin et al., J Gen Virol. 2012


pdm09 H1N1 in dogs

Song et al., J Gen Virol. 2015

LIMITED ROLE IN pdmH1N1 SPREADING

TO HUMANS

pdm09 H1N1 in dogs

VIRUS TRANSMISSIONFROM HUMANS TO PETS

SOUTH KOREA, 2014


Roberts (2004). Science, 305: 1890-1893.ONE DOT=1000 DEATHS

Rotaviruses in humans

SEVERE ACUTE GASTROENTERITIS IN CHILDREN WORLDWIDE OVER A HALF MILLION DEATHS ANNUALLY IN DEVELOPING COUNTRIES

Rotavirusof group/species A

Rotaviruses in animals

ENTERITIS IN FOALS (VACCINES)

ENTERITIS IN DOGS AND CATS

ENTERITIS IN CHICKENS

ENTERO-COLITIS/ENTERITISCOMPLEX OF RABBITS

NEONATAL ENTERITIS IN CALVES (VACCINES)

WEANING AND POST-WEANING DIARRHEA IN PIGLETS (VACCINES)


MAY ANIMAL ROTAVIRUSES BE TRANSMITTED TO HUMANS

ARE THERE MOLECULAR MECHANISMSCONTROLLING INTER-SPECIES TRANSMISSION

DO HETEROLOGOUS INFECTIONS GENERATE VIRUSES OF EPIDEMIOLOGICAL RELEVANCE FOR HUMANS

Rotaviruses in animals

BUT NOT DETERMINED


(Doro et al., Expert Rev Anti Infect Ther. 2015)

PREVALENCE OF ROTAVIRUS G AND P TYPES IN THE POST-VACCINAL ERA (2007-2012)

G1P[8]G2P[4]G3P[8]G4P[8]G9P[8]G12P[8]

Rotaviruses in humans Rotavirusof group/species A

PREVALENCE OF ROTAVIRUS G AND P TYPES (2007-12)

OTHER ROTAVIRUS STRAINS (UNUSUAL COMBINATIONS OF G/PTYPES, RARE OR ANIMAL-LIKE TYPES)

AFRICA 8224 2323 (28.0) 1040 (12.6)

AMERICAS 6756 686 (10.1) 639 (8.2)

REGION TOTAL OTHERS (%) NT (%)

WPR 9480 638 (6.7) 907 (9.5)

SEAR 5728 911 (15.9) 1180 (20.6)

EMR 2341 276 (11.7) 336 (14.3)

EUROPE 14138 403 (2.8) 760 (5.3)

TOT 46667 5237 (11.2) 4862 (10.4)

Rotaviruses in humans Rotavirusof group/species A

ROTAVIRUS-LIKE PARTICLES DETECTED AT LOW FREQUENCY FROM BOTH SYMPTOMATIC AND ASYMPTOMATIC DOMESTIC CARNIVORES (MARSHALL ET AL., 1984, 1987).

DIARRHEA HAS BEEN REPRODUCED IN NEONATAL GNOTOBIOTIC DOGS INFECTED EXPERIMENTALLY WITH A CANINE RV (Johnson et al., 1983).

NOT REGARDED AS A MAJOR ENTERIC PATHOGENS IN PETS

Rotaviruses in pets Rotavirusof group/species A

PETS ROTAVIRUS ARE FREQUENTLY TRASMITTED TO HUMANS

EITHER G3P[3] OR G3P[9] RVs OF CANINE/FELINEORIGIN ARE REPORTED IN HOSPITALIZED CHILDREN

SOCIAL INTERACTIONS INCREASE THE RISKOF INFECTION OF HUMANS WITH PETS RVs

GENOME SEQUENCING OF CANINE AND FELINERVs HAS PROVIDED INTERESTING CLUES TO UNDERSTAND THIS ZOONOTIC EXPOSURE

Rotaviruses in petsRotavirus

of group/species A

VP7

VP4

Rotaviruses in pets


Rotaviruses in pets


Rotaviruses in pets

DISCOVERY OF NON-A ROTAVIRUSES IN DOGS

Rotavirusof group/species C

Rotaviruses in pets

DISCOVERY OF NON-A ROTAVIRUSES IN DOGS

Rotavirusof group/species I

Vesiviruses in cats

ULCERATIVE STOMATITIS

SYSTEMIC DISEASE

OCCASIONALLY REPORTED IN DOGSMartella et al., Vet Microbiol. 2002

Vesiviruses in dogs

NOT REGARDED AS MAJOR PATHOGENS

NOT INCLUDED IN THE DIAGNOSTIC ALGORITHMS

(Schaffer et al., 1985; Mochizuki et al., 1993)

ENTERIC DISEASE

Germany, 2003

A CALICIVIRUS (STRAIN 2117) CONTAMINATES CHO CELLS USED FOR PRODUCTION OF BIOLOGICAL PRODUCTS