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” Scenario
1.
2.
3.
4.
An ebolavirus emerges in Africa and is imported
into the U.S. by its monkey host or a sick patient
The virus is highly contagious, spreads quickly and
infects thousands of people en route
The infections are characterized by “crashing”
patients with liquefying organs; patients die from
extensive blood loss
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
Breach of
macrophage
functions
M
Reproduction in
liver
Export of
juvenile
granulocytes
on day 5-9
Activation of B
lymphocytes (single
mitoses in lymphoid cells
in the blood on day 3)
Production of
antibodies capable to
form immune
complexes
on neutrophils
T
Decrease of
lymphocyte
amount in blood
and lymph nodes
on day 5-7
B
Production of
autoantibodies with
great potential to
destroy cells
Reproduction in
endotheliocytes
and fibroblasts
on lym phocytes
on liver cells
Settling of immune complexes on different
tissues and cells :
Imbalance of
cytokine
amount
in blood
on platelets
on kidney cells
Dam age of tissues
and cells
(endotheliocy tes)
Release of toxic
products into the
blood
Apoptosis of cells
Strengthening of lipid
peroxidation (raise of
m alonic dialdehyde
am ount on day 5-6)
Activation of
antioxidation
systems
(decrease of
malonic
dialdehyde amount
on day 3) and
follow ing
exhaustion
Export of juvenile
throm bocytes on
day 5-9
Initiation of coagulation
cascade
Activation of fibrinolytic
system (appearance of
paracoagulation products in
plasma on day 5-9)
Consumption of blood platelets
on day 7-9
Development of lethal coagulation disorders
(decrease of prothrombin index, bleeding, sporadic hemorrhages in internal organs)
Сoagulation disorders
Breach of kidney
functions (rise of
blood urea level and
beta-lipoproteids
amount on day
7-9 )
Export of
juvenile
lym phocytes
on day 3-9
Activation of bone marrow cells
Necroses in liver and
breach of its
functions (raise of
sGOT and sGPT
activities on day 59)
Release of TNFalpha and other
cy tokines into
blood
Export of
eosinophils
on day 9
Breach of
phagocytic
mechanisms of
neutrophils
Breach of neutrophilmacrophage interaction
Non-adequate
presentation of Zaire
Ebola virus antigens to
T lymphocytes
on m acrophages
Suppressive factor settling
on neutrophils (sGP?)
Immunological disorders
Generalized
destruction of
macrophages
Signs of
hepatorenal
syndrome
Pathogenesis
Zaire Ebola virus
Reproduction in
macrophages
Filovirus Particle Characteristics
Molecular Biology
VP40
RNA
VP30
NP
VP24
?
GP1,2
Membrane
L
VP35
VP24
l
NP
VP35
VP40
VP30
GP
3‘-HO
IR
IR
IR
IR
OR
t
P -5‘
IR
1
L
19,104
Biosafety and Biosecurity Classification
Preston and “Outbreak“ Revisited
True
 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
Soviet Filovirus Research
2
1
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 AllUnion 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