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Transcript of Marburgviruses and Ebolaviruses – History, Fiction, and the Facts MIT Faculty Dinner Series on...
Marburgviruses and Ebolaviruses – History, Fiction, and the Facts
MIT Faculty Dinner Series on Biosecurity
September 29, 2005
Jens H. Kuhn
The Media and Public Perception
The Preston-“Outbreak” Scenario1. An ebolavirus emerges in Africa and is imported
into the U.S. by its monkey host or a sick patient
2. The virus is highly contagious, spreads quickly and infects thousands of people en route
3. The infections are characterized by “crashing” patients with liquefying organs; patients die from extensive blood loss
4. The military acquires the virus and builds the “perfect biological weapon”
Phylogeny, Endemicity, Human and Animal Case Numbers
Filovirus Hosts, Transmission, Clinical Presentation, and Treatment
Initiation of coagulation cascade
Activation of antioxidation
systems (decrease of
malonic dialdehyde amount
on day 3) and follow ing
exhaustion
Development of lethal coagulation disorders (decrease of prothrombin index, bleeding, sporadic hemorrhages in internal organs)
Consumption of blood platelets on day 7-9
Activation of f ibrinolytic system (appearance of
paracoagulation products in plasma on day 5-9)
Non-adequate presentation of Zaire
Ebola virus antigens to T lymphocytes
Breach of kidney functions (rise of
blood urea level and beta-lipoproteids amount on day
7-9 )
Strengthening of lipid peroxidation (raise of malonic dialdehyde amount on day 5-6)
Activation of B lymphocytes (single
mitoses in lymphoid cells in the blood on day 3)
Release of TNF-
alpha and other
cy tokines into
blood
Ac
tiva
tion
of b
on
e m
arro
w c
ells
Export of juvenile thrombocytes on
day 5-9
Export of juvenile
granulocytes on day 5-9
Zaire Ebola virus
on neutrophils
Decrease of lymphocyte
amount in blood and lymph nodes
on day 5-7
Breach of phagocytic
mechanisms of neutrophils
Necroses in liver and breach of its
functions (raise of sGOT and sGPT
activities on day 5-9)
Reproduction in macrophages
Release of toxic products into the
blood
Damage of tissues and cells
(endotheliocy tes)
Reproduction in liver
M
Export of juvenile
lymphocytes on day 3-9
Reproduction in endotheliocytes and fibroblasts
Imm
un
olo
gic
al d
iso
rders
Сo
ag
ula
tion
dis
ord
ers
Sig
ns o
f
hep
ato
ren
al
syn
dro
me
Export of eosinophils
on day 9
Suppressive factor settling on neutrophils (sGP?)
Imbalance of cytokine amount
in blood
Apoptosis of cells
Production of antibodies capable to
form immune complexes
Settling of immune complexes on different tissues and cells :
on lymphocyteson liver cells
on kidney cells on platelets
Production of autoantibodies with
great potential to destroy cells
B
T
Breach of neutrophil-macrophage interaction
on macrophages
Breach of macrophage
functions
Generalized destruction of macrophages
Pathogenesis
Filovirus Particle Characteristics
RNA
L
NP
VP35
VP40 VP30
Membrane
VP24
GP1,2
?
Molecular Biology
OR
GP VP30
IRIR
VP40
3‘-HO
NP VP35
IR
l
IR1
IR
t
19,104
P -5‘
LVP24
Biosafety and Biosecurity Classification
Preston and “Outbreak“ RevisitedTrue Filoviruses are endemic in
Africa and could be imported
False Primates are filovirus hosts Filoviruses are very
contagious Filoviruses are very stable
entities Hemorrhages and liquefying
organs are typical symptoms
Filoviruses are perfect biological weapons
The Media and Professional Perception
The Alibek Scenario
The Soviet KGB acquires marburgviruses covertly by recovering corpses of the 1967 marburgvirus disease outbreak in Germany
Military work begins immediately to create powerful bioweapons
A laboratory accident provides extremely virulent “strains U and V“
At the end of the 1980s, “chimeras“ of these strains and variola virus are created
12
Soviet Filovirus Research
Some Publications of Concern Volchkov V. E., et al. (2001) Recovery of Infectious Ebola Virus from
Complementary DNA: RNA Editing of the GP Gene and Viral Cytotoxicity. Science 291: 1965-1969
Towner J. S., et al. (2005) Generation of eGFP expressing recombinant Zaire ebolavirus for analysis of early pathogenesis events and high-throughput antiviral drug screening. Virology 332: 20-27
Vorontsova L. A. (1992) Electron microscopic studies of Marburg virus and pathological changes in animal organs caused by this virus. Dissertation to obtain the degree Candidate of Biological Science. SCRVB "Vector" Russia
Zelenkov V. N., et al. (1990) Cultivating Marburg virus on Vero cell monolayers treated with 1-chloromethylsilatran and 1-etoxysilatran. In: Biological activity of compounds containing silicon, germanium, and tin. Abstract collection of the 4th All-Union conference, June 12 - 14, U.S.S.R. Academy of Sciences, Irkutsk Institute of Organic Chemistry, U.S.S.R., pp 6
Frolov V. G. (1994) Study of the factors determining stability and dynamics of thermoinactivation of Marburg virus in freeze-dried media. Development of an "accelerated storage" test for prediction of Marburg virus activity during long-term storage. Dissertation to obtain the degree Candidate of Technological Science. SRCVB "Vector“, Russia
Alibek Revisited
True Soviet laboratory
infection provided opportunity to characterize new filovirus strain
False KGB acquired
filoviruses All filovirus research
was classified Strains U and V were
basis of developed Soviet bioweapons?
Filovirus chimeras were created at the end of the 1980s
Summary
Overall human filovirus infection case numbers and their properties should make these viruses a low research priority (HIV-1, TB!)
Filoviruses are interesting bioweapon candidates for state-sponsored programs because of new possibilities for manipulation developed in the West in recent years
However, manipulation of filoviruses demands highly skilled researchers. The development of an efficient filovirus bioweapon still requires overcoming major obstacles such as instability and ineffective transmission