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Current Molecular Medicine
ISSN: 1566-5240
Current Molecular Medicine
Volume 5, Number 8, December 2005
Contents
Emerging Viruses: Advances and Challenges
Executive Editor: Thomas W. Geisbert
Editorial Pp.733
Novel Antiviral Strategies to Combat Human Arenavirus
Infections Pp.735
Stefan Kunz and Juan C. de la Torre
[Abstract]
Crimean-Congo Hemorrhagic Fever Virus
Pp.753
Ramon Flick and Chris A. Whitehouse
[Abstract]
Ebola and Marburg Viruses: Pathogenesis and Development
of Countermeasures Pp.761
Lisa E. Hensley, Steven M. Jones, Heinz Feldmann, Peter
B. Jahrling and Thomas W. Geisbert
[Abstract]
Hantaviruses: Molecular Biology, Evolution and
Pathogenesis Pp.773
Svetlana F. Khaiboullina, S.P. Morzunov and Stephen C.
St. Jeor
[Abstract]
Emerging Influenza Viruses: Past and Present
Pp.791
Darwyn Kobasa and Yoshihiro Kawaoka
[Abstract]
Hendra and Nipah Viruses: Pathogenesis and Therapeutics
Pp.805
Bryan T. Eaton, Christopher C. Broder and Lin-Fa Wang
[Abstract]
Countermeasures to the Bioterrorist Threat of Smallpox
Pp,817
Peter B. Jahrling, Elizabeth A. Fritz and Lisa E. Hensley
[Abstract]
Rift Valley Fever Virus Pp.827
Ramon Flick and Michle Bouloy
[Abstract]
Recent Advances in the Molecular Biology of West Nile
Virus Pp.835
David W.C. Beasley
[Abstract]
Abstracts
[Back to top]
Editorial
Emerging infectious diseases are classically defined as infections
that have newly appeared in a population or that have existed
previously and are increasing in occurrence or geographic
range. Viruses are among the most prominent and important
examples of emerging pathogens. These viruses have in fact
been threats to mankind for centuries. Archetypical examples
include the importation of smallpox into North America, which
had devastating effects on the Aztec population in the 1500’s
and the Amerindian civilizations in the 1600-1800’s,
and the 1918 influenza pandemic. However, for much of the
20th century improvements in hygiene and control of vector
species coupled with successes in the development of vaccines
fostered a state of complacency regarding the peril of emerging
viruses. It was not until the discovery of AIDs in 1983 and
the burgeoning pandemic that rapidly ensued, that a renewed
awareness of emerging infectious diseases began to be more
fully realized. Not long after the emergence of AIDS, the
notoriety of emerging and re-emerging viruses was dramatically
enhanced and catapulted into the limelight when Richard Preston
penned “THE HOT ZONE” and made Ebola a household
word in North America in 1994. Gruesome details of infected
victims bleeding from every orifice captured the public’s
attention and enthrallment. Knowledge that the former Soviet
Union had been exploring the use of some of these viruses
as potential bioweapons further fanned a fire freshly ignited
by Preston’s prose.
The current outbreak of Marburg hemorrhagic fever in Angola
has thus far claimed over 300 lives, amassed a staggering
mortality rate of approximately 88%, and is but the most recent
example of a continuum of emerging and re-emerging viruses
to cause concern for public health on a global level. As is
the case for Marburg virus, there are no vaccines of treatments
available for many of the emerging and re-emerging viruses.
Historically, efforts to study these agents have been slowed
as most of these viruses require special biocontainment for
safe research. Clearly, the landscape has changed noticeably
since Karl Johnson led the effort to adapt the principles
of biosafety level 4 biocontainment, originally developed
by biodefense workers at Fort Detrick, into the first fully
integrated spacesuit laboratory in 1978. At the time, the
global importance of rare exotic viruses and the need for
such containment facilities was not as apparent as today.
Thankfully, these early efforts by Johnson, C.J. Peters, and
many others to promote and develop these facilities laid the
groundwork for a landscape that would in fact change. Indeed,
increased concern about both the natural or unnatural introductions
of these viruses has driven increased investment in basic
research and the construction of a network of biocontainment
laboratories.
Caption: Biosafety Level 4 containment is
required to work with many of the emerging and re-emerging
viruses covered in this issue including Hendra virus, Nipah
virus, Ebola virus, Marburg virus, Lassa virus, and Crimean-Congo
hemorrhagic fever virus.
The collection of articles in this issue focuses on viruses
that have emerged or re-emerged in the human population during
the last decade. In particular, these articles bring us up
to date on understanding the mechanisms of how viruses emerge
and re-emerge, the mechanisms of how these viruses cause disease
in man, and finally on the recent progress that has been made
to develop vaccines and therapies against these pathogens.
Several shared themes emerge among this collection of nine
review articles. As an example, many of these viruses contain
genes that have anti-interferon strategies to counteract host
defenses. Also, similar approaches are being exploited to
elucidate the molecular mechanisms of pathogenesis and to
develop countermeasures against these viruses. In particular,
reverse genetics systems have been developed for a number
of viruses addressed in this issue. This relatively new technology
is proving to be a powerful tool allowing investigators to
manipulate these agents in order to evaluate the effects of
introduced changes. Not only does this technology aid in dissecting
out how these agents emerge and cause disease, but it has
significant potential as a device to develop safe and effective
vaccines and therapies. In fact, Kobasa and Kawaoka describe
how a reverse genetics system for influenza virus is being
used as part of an effort to develop improved and rapid vaccine
strategies against the highly virulent H5N1 influenza viruses.
Criticism of the attention given and resources committed
to emerging and re-emerging viruses is sometimes expressed
by those that view many of these exotic pathogens as less
of a global threat than more common human diseases such as
cholera or malaria. This viewpoint is recognized, but the
destructive potential of these emerging and re-emerging viruses,
and the associated economic consequences and panic that ensue
must also be weighed against risk in such discussions. Not
only are many of these viruses considered as agents of importance
for bioterrorism, e.g., smallpox as discussed by Jahrling
and colleagues, but it is also important to consider that
ever increasing changes in ecology, demographics, and ease
of intercontinental air travel, can rapidly change the dynamics
and perspective of what agents present the most immediate
threat to public health. Likewise, encroachment of these viruses
on populations with no herd immunity can have devastating
consequences and equally warrants concern.
A primary challenge in combating these emerging and re-emerging
viruses will be to develop broad-based countermeasures as
opposed to focusing solely on univalent solutions. As many
of these pathogens are RNA viruses, they have the inherent
ability to adapt quickly to conventional preventive vaccines.
The future will favor vaccine platforms that are amenable
to rapid development and production. Because many of the diseases
caused by classes of these agents have similar features it
is logical to speculate that similar mechanisms of pathogenesis
may be involved. For example, the viral hemorrhagic fevers
as a group produce similar clinical features characterized
by severe coagulation abnormalities. Identifying and targeting
common pathways in the development of this coagulopathy is
but one approach that has utility in treating and mitigating
the lethal effects of this particular class of agents. Together
with improved surveillance and diagnostics, a better understanding
of the molecular biology and pathogenesis of emerging and
re-emerging viruses will play a pivotal role in managing future
outbreaks.
Footnote
Opinions, interpretations, conclusions and recommendations
are those of the author and are not necessarily endorsed by
the U.S. Army.
Thomas W. Geisbert
USAMRIID
Attn: MCMR-UIV
1425 Porter Street
Fort Detrick, MD 21702-5011
USA
E-mail: tom.geisbert@amedd.army.mil
[Back to top]
Novel Antiviral Strategies to Combat Human Arenavirus
Infections
Stefan Kunz and Juan C. de la Torre
Arenaviruses merit significant attention both as tractable
model systems to study acute and persistent viral infections,
and as clinically important human pathogens. Evidence indicates
that LCMV remains present in the USA and Europe and capable
of causing significant morbidity in infected individuals,
likely being a neglected human pathogen. Moreover, new arenaviruses
are being discovered in the Americas on the average of one
every three years, with some of them causing severe hemorrhagic
fever. In addition, weaponized forms of these viruses pose
a real threat as agents of bioterrorism. Therefore, it is
important to develop effective vaccines and better antiviral
drugs to combat the dual threats of naturally occurring and
intentionally introduced Arenavirus infections.
The development of arenavirus reverse genetic systems is
allowing investigators to conduct a detailed molecular characterization
of the viral cis-acting signals and trans-acting factors that
control each of the steps of the Arenavirus life cycle, including
RNA synthesis, packaging and budding. We will discuss how
this new knowledge is facilitating the establishment of novel
assays to identify and characterize compounds capable of interfering
with specific steps of the virus life cycle. Likewise, the
ability to generate predetermined specific mutations within
the arenavirus genome, and analyze their phenotypic expression,
would significantly contribute to the elucidation of arenavirus-host
interactions, including the bases of their ability to persist,
as well as to cause severe HF (hemorrhagic fever) disease
in humans. These approaches could also lead to the development
of novel potent and safe Arenavirus vaccines.
[Back to top]
Crimean-Congo Hemorrhagic Fever Virus
Ramon Flick, and Chris A. Whitehouse
Crimean-Congo hemorrhagic fever virus (CCHFV) is an important
human pathogen, which is the cause of a tick-borne illness
occurring in many areas of Africa, Asia, and Europe. CCHF
is characterized by a sudden onset of high fever, chills,
and severe headache. Other symptoms can include gastrointestinal
disorders, such as nausea, vomiting, and diarrhea. In severe
cases, hemorrhagic manifestations can occur and often present
as large areas of ecchymosis, rather than frank bleeding.
Exposure to ticks, particularly those in the genus Hyalomma,
or direct contact with virus-infected animals or people
are considered the major risk factors. Studies on CCHFV are
impeded by the biocontainment needed for their manipulation.
However, the increasing worldwide medical awareness, the enormous
interest of the media in hemorrhagic fever diseases, and their
potential to be used as a bioweapon, have greatly spurred
on research on this important virus, as evidenced by many
new developments including the development of a reverse genetics
system which should greatly enhance future research with this
virus.
[Back to top]
Ebola and Marburg Viruses: Pathogenesis and Development
of Countermeasures
Lisa E. Hensley, Steven M. Jones, Heinz Feldmann, Peter
B. Jahrling and Thomas W. Geisbert
Ebola and Marburg viruses, family Filoviridae, are
among the best known examples of emerging and re-emerging
pathogens. Although outbreaks have been sporadic and geographically
restricted to areas of Central Africa, the hemorrhagic fevers
caused by these viruses are remarkably severe and are associated
with high case fatality rates often exceeding 80 percent.
In addition to humans, these viruses have decimated populations
of wild apes in Central Africa. Currently, there are no vaccines
or effective therapies available for human use. Progress in
understanding the geneses of the pathophysiological changes
that make filoviral infections of humans so destructive has
been slow, primarily because these viruses require special
containment for safe research. However, an increasing understanding
of the molecular mechanisms of filoviral pathogenesis, facilitated
by the development of new tools to elucidate critical regulatory
elements in the viral life cycle, is providing new targets
that can be exploited for therapeutic interventions. In addition,
substantial progress has been made in developing recombinant
vaccines against these viruses.
[Back to top]
Hantaviruses: Molecular Biology, Evolution and Pathogenesis
Svetlana F. Khaiboullina, S.P. Morzunov and Stephen C.
St. Jeor
Hantaviruses are tri-segmented negative sense single stranded
RNA viruses that belong to the family Bunyaviridae.
In nature, hantaviruses are exclusively maintained in the
populations of their specific rodent hosts. In their natural
host species, hantaviruses usually develop a persistent infection
with prolonged virus shedding in excreta. Humans become infected
by inhaling virus contaminated aerosol. Unlike asymptomatic
infection in rodents, hantaviruses cause two acute febrile
diseases in humans: hemorrhagic fever with renal syndrome
(HFRS) and hantavirus pulmonary syndrome (HPS). The mortality
rate varies from 0.1% to 40% depending on the virus involved.
Hantaviruses are distributed world wide, with over 150,000
HFRS and HPS cases being registered annually. In this review
we summarize current knowledge on hantavirus molecular biology,
epidemiology, genetic diversity and co-evolution with rodent
hosts. In addition, special attention was given in this review
to describing clinical manifestation of HFRS and HPS, and
advances in our current understanding of the host immune response,
treatment, and prevention.
[Back to top]
Emerging Influenza Viruses: Past and Present
Darwyn Kobasa and Yoshihiro Kawaoka
Influenza is an example of a disease for which the viral
pathogen has emerged into the human population many times
over past centuries, sometimes with devastating consequences
[1]. Historical records provide vivid descriptions of past
influenza outbreaks, and the viruses that caused the pandemics
of the last century remain subjects of great interest. It
is almost certain that a new pandemic, caused by the zoonotic
transmission of a new influenza virus into humans, will occur.
The recent outbreaks of the highly pathogenic H5 and H7 subtype
viruses in poultry and their limited transmission into humans,
as well as transmission of H9 subtype viruses, have raised
concerns that conditions are developing for the generation
of a new pandemic virus. In this paper, we review past pandemics,
viral determinants of cross-species transmission of viruses,
molecular factors that contribute to disease, and preventative
measures to reduce the impact of a future pandemic.
[Back to top]
Hendra and Nipah Viruses: Pathogenesis and Therapeutics
Bryan T. Eaton, Christopher C. Broder and Lin-Fa Wang
Within the past decade a number of new zoonotic paramyxoviruses
emerged from flying foxes to cause serious disease outbreaks
in man and livestock. Hendra virus was the cause of fatal
infections of horses and man in Australia in 1994, 1999 and
2004. Nipah virus caused encephalitis in humans both in Malaysia
in 1998/99, following silent spread of the virus in the pig
population, and in Bangladesh from 2001 to 2004 probably as
a result of direct bat to human transmission and spread within
the human population. Hendra and Nipah viruses are highly
pathogenic in humans with case fatality rates of 40% to 70%.
Their genetic constitution, virulence and wide host range
make them unique paramyxoviruses and they have been given
Biosecurity Level 4 status in a new genus Henipavirus
within the family Paramyxoviridae. Recent studies
on the virulence, host range and cell tropisms of henipaviruses
provide insights into the unique biological properties of
these emerging human pathogens and suggest approaches for
vaccine development and therapeutic countermeasures.
[Back to top]
Countermeasures to the Bioterrorist Threat of Smallpox
Peter B. Jahrling, Elizabeth A. Fritz and Lisa E. Hensley
Variola, the agent of smallpox, is a bioterrorist threat,
as is monkeypox virus, which also occurs naturally in Africa.
Development of countermeasures, in the form of improved vaccines,
antiviral drugs, and other therapeutic strategies are a high
priority. Recent advances in molecular biology and in animal
model development have provided fresh insight into the virulence
determinants for smallpox and the pathophysiology of disease.
The complex replication cycle for orthopoxviruses, and the
pivotal role for viral-specific immunomodulatory proteins
which contribute to escape from immunologic surveillance,
provide many unique targets for therapeutic intervention.
The “toxemia” of smallpox has been elucidated
in part by variola-infected primate studies which revealed
the central role of apoptosis and the evolution of a cytokine
storm leading to hemorrhagic diathesis, resembling fulminent
“black” smallpox. This suggests a potential role
for therapeutic strategies developed for septic shock, in
treatment of smallpox. Drugs licensed for other viruses which
share molecular targets with orthopoxviruses (e.g. Cidofovir)
or cancer drugs (e.g. Gleevec and other tyrosine kinase inhibitors)
have immediate application for treatment of smallpox and monkeypox
and provide leads for second generation drugs with higher
therapeutic indices. Recent advances in identification of
virulence determinants and immune evasion genes facilitate
the design of alternative vaccines to replace live vaccinia
strains that are unsuitable for a large proportion of individuals
in a mass immunization campaign.
[Back to top]
Rift Valley Fever Virus
Ramon Flick and Michle Bouloy
Rift Valley fever is considered to be one of the most important
viral zoonoses in Africa. In 2000, the Rift valley fever virus
spread to the Arabian Peninsula and caused two simultaneous
outbreaks in Yemen and Saudi Arabia. It is transmitted to
ruminants and to humans by mosquitoes. The viral agent is
an arbovirus, which belongs to the Phlebovirus genus
in the Bunyaviridae family. This family of viruses
comprises more than 300 members grouped into five genera:
Orthobunyavirus, Phlebovirus, Hantavirus,
Nairovirus, and Tospovirus. Several members
of the Bunyaviridae family are responsible for fatal
hemorrhagic fevers: Rift Valley fever virus (Phlebovirus),
Crimean-Congo hemorrhagic fever virus (Nairovirus),
Hantaan, Sin Nombre and related viruses (Hantavirus),
and recently Garissa, now identified as Ngari virus (Orthobunyavirus).
Here are reviewed recent advances in Rift Valley fever virus,
its epidemiology, molecular biology and focus on recent data
on the interactions between viral and cellular proteins, which
help to understand the molecular mechanisms utilized by the
virus to circumvent the host cellular response.
[Back to top]
Recent Advances in the Molecular Biology of West Nile
Virus
David W.C. Beasley
Since the mid-1990s, West Nile virus (WNV) has emerged as
a significant agent of arboviral encephalitis in several regions
of the world. In 1999, WNV was introduced into the northeastern
United States and was associated with an outbreak of encephalitis
affecting humans, birds and horses. Subsequently, the virus
has spread across the country, and across southern Canada,
and in 2002 and 2003 was associated with the largest outbreaks
of arboviral encephalitis recorded in the Western hemisphere.
Interestingly, the more recent spread of WNV into Mexico,
Central America and the Caribbean has not been associated
with the high levels of clinical disease observed in North
America. This review addresses the most recent results from
studies investigating the molecular biology and evolution
of WNV, as well as progress in the development of diagnostic
and therapeutic reagents.
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