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EBOLA AND MARBURG VIRUSES
HUMAN ANIMALHUMAN-ANIMAL INTERFACES
Douanier Rousseau
C.Goldsmith/S.Zaki
Second FAO-OIE-WHO consultation: Influenza
and other Emerging Zoonotic Diseases
Verona April 2010
Mononegavirales, Filoviridae, Filoviruses : 5 distinct Ebola strains : Sudan, Zaire, Reston, Côte
Ebola and Marburg Haemorrhagic Fevers
d'Ivoire, Bundibugyo2 lineages for Marburg : POP, RAVN
Reservoir: bats are strongly suspectedBSL 4 Incubation 2-21 daysCase Fatality Ratio 24-89%Case Fatality Ratio 24 89%Treatment : no specific treatment available,
careful rehydration, supportive, intensive care,
Vaccines in development
2
09 DRC 1999
07 DRC 1999
05 DRC 1999
Ravn Kenya 1987
1 1
1
1
Complete genome analysis:Filoviruses
Marburg 21% nt
Popp Uganda 1967
Zaire 1976
Ozolins Zimbabwe 1975
Musoka Kenya 1980
Zaire 1995
1379c Angola 2005
1
1
1
1
800 yrs
Reston 1989
Cote d’Ivoire 1994
Bundibugyo 2007
Zaire 1976
Sudan 2000
1
1
1
1
Ebola
32% nt
39% nt
Towner et al., PLoS Pathogens, 21 Nov 2008
3
Yambuku‘76
Nzara‘76
Zaire’79 80
Zaire‘95
I. Coast’96 97
CentralAfrican Republic
‘99 T t l
Summary of tropical African animals tested for evidence of Ebola Zaire, 1976-1999
Mammals Chiroptera 7 652Mega 4 41 125 19 189Micro 174 422 414 4 1014
Rodents 131 309 661 1759 283 163 3306Insectivores 7 53 114 398 56 628Carnivores 27 28 55Primates 267 12 27 312
Birds 67 184 533Reptiles 5 33 127 282 165
‘76 ‘76 ’79-80 ‘95 ’96-97 ‘99 Total
Pourrut et al., 2005 Microbes and Infection 7:1005-14
Reptiles 5 33 127 282 165Total vertebrates 157 499 1664 2814 1642 242 7018Arthropods 2318 27,843 30,161Test:
Virus isolation 0/2475 0/499 0/1664 0/30,657 0/1642 0/242 0/37,179
*Colobus monkey
4
Bats Bats –– the likely reservoir for the the likely reservoir for the Marburg and Ebola virusesMarburg and Ebola viruses
Epidemiologic dataEpidemiologic dataSudan ebolavirus
1976 cases; 1st 6 cases were cotton factory employees who worked in a room where bats roosted
Cote d’Ivoire ebolavirus1994; chimpanzees which developed EHF had been feeding in a fig tree together with fruit bats for two weeks before developing the disease
Reston ebolavirus1989-96; all outbreaks in primate facilities link back to a single primate export facility in the Philippines which was a former fruit orchard and animals potentially exposed to fruit bats
Marburg virus1967 imported monkeys from Ugandan locations where fruit bats prevalent1975 tourists slept in rooms where insectivorous bats were present Zimbabwe1980 and 1987; two patients in Kenya both visited a cave inhabited by batsshortly before becoming ill1998-2000; Durba DRC outbreak linked to gold mine with infected bats2007; Kitaka Uganda, two cases link to mine with infected fruit bats2008; Python cave Uganda, two cases linked to cave with infected fruit bats
5
Bats Bats –– the likely reservoir for the the likely reservoir for the Marburg and Ebola virusesMarburg and Ebola viruses
Direct lab dataDirect lab dataZaire ebolavirus
Detection of virus-specific antibody and genome RNA in 3 speciesDetection of virus specific antibody and genome RNA in 3 species of bats in Gabon
1996; Experimentally infected fruit bats shown to replicate ebolavirus without developing overt disease
Marburg virusDetection of virus-specific antibody, and genome RNA predominantly in Egyptian fruit bats (Rousettus aegyptiacus) inpredominantly in Egyptian fruit bats (Rousettus aegyptiacus) in Gabon, Durba DRC, Kitaka Uganda and Python Cave, Uganda
Multiple virus isolates from Kitaka and Python caves
Multiple diverse virus genetic lineages co-existing in R. aegyptiacus colonies; no correlation between genetic and geographic distances – likely reflecting mobility and large meta-population of host
Filovirus infection of batsFilovirus infection of bats
Marburg virus in R. aegyptiacus• virus infection (PCR) 1.6 – 5.1 %• past infection (IgG) 2.3 – 20.5 %
Zaire ebolavirus in 3 species of bats• virus infection (PCR) 2.8 – 19%• past infection (IgG) 6.8 – 23%
6
Proposed mechanisms of Ebola virustransmission to wildlife, domestic animals
(or humans) from bats
•Competition for fruit between chiropterans and non-human primates leads to spatiotemporal clustering of frugivorousprimates leads to spatiotemporal clustering of frugivorous animals leading to an increased likelihood of spillover
•Infectious virus in:• saliva
-Nipah virus (Chua et al., 2002; Reynes et al., 2005)-Hendra virus (in horse saliva-Williamson et al., 1998)
• feces (guano) or urine(g )-Nipah virus (Chua et al., 2002)-Hendra virus (Williamson et al., 1998)-Ebola virus (experimentally infected bats Swanepoel et al., 1996)-Menangle virus (Hooper et al., 2000)
• birthing fluids (blood, placental tissues etc)-Hendra virus (Young et al., 1997; Halpin et al., 2000)
Suspected modes of transmission to humans
• Contact with reservoir (bats): hunters, miners, ecologists, tourists
• Contact with secondary hosts (pigs, primates): hunters, farmers slaughter house workersfarmers, slaughter house workers
• Contact with human (patients): family, nosocomial infections, burial practices
7
02Uganda 2007sep09DRC 1999may
Rav Kenya1987aug04DRC 1999may03DRC 1999apr32DRC 2000aug19DRC 2000feb34DRC 2000aug07DRC 1999may06DRC 1999may14DRC 2000jan30DRC 2000aug01DRC 1999apr24DRC 2000apr23DRC 2000mar29DRC 2000jul27DRC 2000jul
Diversity Marburg complete genome
Uganda ‘07 humanSequences
(21% diverse)
Ravn lineage
27DRC 2000jul26DRC 2000may17DRC 2000feb16DRC 2000feb12DRC 2000jan20DRC 2000feb21DRC 2000feb22DRC 2000may18DRC 2000feb13DRC 2000jan28DRC 2000jul05DRC 1999may15DRC 2000feb
33DRC 2000aug25DRC 2000apr01Uganda 2007jul
Ozo Zimbabwe 1975feb
Durba DRC1998-2000
21.5%
09Angola 2005apr08Angola 2005apr04Angola 2005mar07Angola 2005apr05Angola 2005mar02Angola 2005mar01Angola 2005feb06Angola 2005apr03Angola 2005mar11Angola 2005may10Angola 2005apr
Pop Germany1967aug02DRC 1999apr
Mus Kenya 1980jan
50 changes
Main lineage
Angola 20050.07%
Bats- Aug ‘07
02U 2007.7
09d_1999.401k_1987.6Bat 44*
Bat 188*Bat 276Bat 288Bat 328
Bat 1013Bat 782Bat 982*
01U 2007.6Bat 772
Bat 29107d_1999.406d_1999.3
14d_2000.130d_2000.601d_1999.3
Bat 331*
02U 2007.7
09d_1999.401k_1987.6Bat 44*
Bat 188*Bat 276Bat 288Bat 328
Bat 1013Bat 782Bat 982*
01U 2007.6Bat 772
Bat 29107d_1999.406d_1999.3
14d_2000.130d_2000.601d_1999.3
Bat 331*
Uganda Bat Sequencesconcatenated
NP and VP35 frags (~700bp) Bats- May ‘08
Miners- Aug ’07Sept ‘07
Ravn lineage
Bat 331*Bat 371*Bat 427Bat 88304d_1999.303d_1999.332d_2000.619d_2000.134d_2000.6
24d_2000.323d_2000.2
29d_2000.527d_2000.5
17d_2000.116d_2000.112d_2000.020d_2000.118d_2000.121d_2000.226d_2000.405d_1999.413d_2000.028d 2000.5
Bat 331*Bat 371*Bat 427Bat 88304d_1999.303d_1999.332d_2000.619d_2000.134d_2000.6
24d_2000.323d_2000.2
29d_2000.527d_2000.5
17d_2000.116d_2000.112d_2000.020d_2000.118d_2000.121d_2000.226d_2000.405d_1999.413d_2000.028d 2000.5
•Bats sequencesidentical or near identicalto those foundin infectedminers
_22d_2000.2
15d_2000.125d_2000.3
33d_2000.702z_1975.1
96g2006.231g2005.1
48g2005.301k_1980.1
01g_1967.602d_1999.3
09a_2005.304a_2005.206a_2005.303a_2005.207a_2005.305a_2005.202a_2005.201a_2005.210a_2005.308a_2005.311a_2005.4
1 change
Maximum Parsimony
_22d_2000.2
15d_2000.125d_2000.3
33d_2000.702z_1975.1
96g2006.231g2005.1
48g2005.301k_1980.1
01g_1967.602d_1999.3
09a_2005.304a_2005.206a_2005.303a_2005.207a_2005.305a_2005.202a_2005.201a_2005.210a_2005.308a_2005.311a_2005.4
1 change1 change
Maximum Parsimony
Main lineage
8
Kitaka mine--population 112,000
5000 actively infectedbats at any one time
(~5% actively infected)
Geographic distribution of Rousettus aegyptiacus in Africa
•Geographic distribution encompassesthe location of all known Marburgthe location of all known Marburgoutbreaks
•Reproduces twice a year-(~75-80% of adult females pregnant)
•Reproductive capacity combined withthe large colony sizes (>100,000) predicts large meta-populations
•Can have long life span up toCan have long life span, up to25 years in captivity
•Up to nine subspecies withinAfrica and Asia
9
Pathogenesis in different species and ability to transmit diseases
Bats: unknownNon human primates:
laboratory: death in 5 to 7 days, very few survivorswild: death, some survivors (Gabon 2004 13% chimps IgG)
Excretion…
10
Animal model of disease and vaccine model prediction
Rapid systemic spread with high viremiaInfection and necrosis of macrophages and dendritic
cellsRelease of proinflammatory mediators, leading to
increased vascular permeability and shockMassive lymphocyte apoptosis.
These changes are seen in non-human primates, guinea pigs and mice… BUT
12 No. of deathsOther source
Suspected Ebola hemorrhagic fever by source of infection,
Zaire, 1995
0
2
4
6
8
10Ot e sou ceMW 29yo MNA 45yo F
0
9-Apr
13-Apr
17-Apr
21-Apr
25-Apr
29-Apr
3-May7-M
ay
11-M
ay
15-M
ay
19-M
ay
23-M
ay
27-M
ay
31-M
ay4-J
un8-J
un12
-Jun
16-Ju
n
20-Ju
n
24-Ju
n
Date of death (1995)
11
2008 Disease activity in pigs in 2008 Disease activity in pigs in PhilippinesPhilippines
• Porcine Respiratory and Reproductive Syndrome (PRRS) virus has caused respiratory failure in neonates or abortions in sows during sporadic PRRS outbreaks worldwide (also known as Blue Ear pig disease)
•• PRRSV is RNA virus, contains a ss positive-sense RNA genome (15kb); genus
arterivirus (same genus as SHFV !)
• Since 2006 large outbreaks of more virulent atypical PRRS swept through large areas of China and Vietnam – major economic impact
• Disease outbreaks in pigs in Bulacan, Philippines May 2007 through mid-2008. Increase in morbidity/mortality consistent with atypical PRRS, similar to Vietnam and China
• PRRS or swine influenza suspected
• Samples from 4 farms sent to USDA Plum Island facility Oct 2008 for testing• PRRS identified, but also Circo 2 virus. PRRSV does not grow on Vero cells
• One pig tissue yields a virus isolate growing on Vero cells.
• Panviral microarray developed in-house at Plum Island provides evidence of Reston ebolavirus
12
Pig disease symptomsPig disease symptoms• High fever 41C• Labored breathing• Labored breathing• thumping• Coughing, nasal discharge• Loss of appetite, Diarrhea• Skin hemorrhage/reddish discoloration
S f d i b t iti• Some found in recumbent position
• High nursery house and growing house mortalities• Sows previously affected by high fever and
abortions
Ebola Reston virus: Hypothesis of transmission
Ebola Reston virus: Hypothesis of transmission
Fruit bats Secondary
Transmission
Human
Food Chain
Pigs: Amplification
Healthcare workers
13
QuestionsQuestionsSource of virus infecting the pigs ?How common and widespread is the problem ?
Does Reston ebolavirus cause disease in pigs(alone or in combination with PRRSV) ?
Is there pig to pig transmission ? – Geelong
To what extent are humans getting infected down the Farm to Table chain ?to Table chain ?
Any evidence of human disease associated with Reston ebolavirus infection?
One World, One Health
•CDC – SPB, IDPB
•Uganda Virus Research Institute (UVRI)
Serena Reeder
Brian Amman
Jon Towner
•NICD – South Africa
•WHOAlan Kemp
Stuart Nichol
Tom KsiazekPierre Rollin
Bob Swanepoel
Eileen Farnon Andy Comer Pierre Formenty Tara Sealy
Cesar Albarino
John KayiwaStephen Balinandi
Chris Paddock
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