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Editorial overview: Viral pathogenesis
Luca G Guidotti and Matteo Iannacone
Current Opinion in Virology 2015, 11:xx–yy
http://dx.doi.org/10.1016/j.coviro.2015.03.003
1879-6257/# 2015 Elsevier B.V. All rights reserved.
Luca G Guidotti1,2
1
Division of Immunology, Transplantation
and Infectious Diseases, IRCCS San Raffaele
Scientific Institute, Milan 20132, Italy
2
Department of Immunology & Microbial
Sciences, The Scripps Research Institute, La
Jolla, CA 92037, USA
e-mail: [email protected]
Luca G Guidotti has spent two decades as
faculty of The Scripps Research Institute in
La Jolla, California and is currently the
Deputy Scientific Director of the San Raffaele
Scientific Institute in Milan, Italy. He has
devoted most of his scientific career to the
study of viral pathogenesis in animal models,
in particular the pathogenesis of hepatitis B
virus (HBV) infection and its complications.
Matteo Iannacone1
1
Division of Immunology, Transplantation
and Infectious Diseases, IRCCS San Raffaele
Scientific Institute and Vita-Salute San
Raffaele University, Milan 20132, Italy
e-mail: [email protected]
Matteo Iannacone trained at The Scripps
Research Institute and at Harvard Medical
School prior to establishing his laboratory at
San Raffaele Scientific Institute. He uses
hepatitis B and other viruses as a convenient
excuse to study basic elements of
immunology, cell biology and pathology.
Viral pathogenesis studies the mechanisms whereby a virus causes
disease. More broadly, however, viral pathogenesis encompasses all the
processes that occur when a virus infects a host, independently of
whether disease is induced or not. Indeed, the process of infection is
of interest per se, regardless of disease outcome. Moreover, it is becoming
increasingly clear that viruses can interact with their hosts independently
of their role as pathogens, for instance by establishing mutualistic
symbiotic relationships that benefit the hosts. This is perhaps best
epitomized by recent work from the Virgin’s lab at Washington University showing that chronic infection of mice with a noncytopathic gherpesvirus increases resistance to subsequent bacterial infections via
prolonged production of IFN-g.
Virus–host interactions that determine the infection outcome comprise a
wide range of possibilities. In the simplest scenario, a single viral or host
factor is responsible for phenotypic variation, such as when genetic disruption of a specific antiviral pathway causes severe virus-induced disease. In
more complex cases, however, specific interactions among viruses, host
allelic variations and additional environmental factors can lead to phenotypes not observed with either the virus or the host variation alone (as
highlighted by another work from the Virgin’s lab indicating that persistent
murine norovirus infection interacting with both allelic variants of autophagy genes and commensal bacteria eventually induces intestinal pathology).
In this review series, Garcı́a and Pallás nicely capture the full spectrum of
virus–host relationships that determines pathogenesis. By providing examples from the world of plant viruses, they show how sometimes a single
viral factor can be the main contributor to the pathogenic process. In this
case, the cause of the disturbance effect can be intrinsically associated to
the function of such factor in viral replication (as it occurs for instance with
some RNA silencing suppressor); alternatively, the activities of the viral
factor supporting infection and promoting pathogenesis are completely
independent of each other, with only some of the viral isolates (those
harboring particular variants of the pathogenicity factor) causing disease,
as it occurs with the elicitors of most hypersensitive response-related
symptoms. Often the phenotype of many plant virus infections are,
however, much more complex, involving interactions between numerous
viral and host factors that are influenced by multiple environmental
conditions.
Scientists deal with the complexity of such pathogenic processes in two
complementary ways. On one hand, they use reductionist approaches to
study specific aspects of either the viral life cycle or the host response to
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2 Viral pathogenesis
infection. On the other hand, they take advantage of
systems biology approaches to integrate complex interactions and build models that better represent virus–host
relationships. Utilizing the example of West Nile Virus
infection, Lazear and Diamond nicely illustrate power
and limitation of both approaches. For instance, the
initial use of type I interferon receptor-deficient mice
has been critical to demonstrate an essential role for this
molecule in controlling West Nile virus, but the specific
mechanisms whereby this antiviral effect was exerted
had remained elusive until large-scale ectopic expression or gene silencing screens were applied. Such
approaches led to the identification of numerous novel
interferon-stimulated genes (ISGs) and, nowadays, systems biology approaches are being critical for developing
testable hypotheses from these complex datasets.
The type I interferon system is a key component of the
antiviral immune response. This cytokine is induced
when germ-line encoded sensors recognize specific features associated with incoming viruses. Habjan and
Pichlmair review how cytoplasmic sensor proteins detect
the presence of some of the best-studied pathogen associated molecular patterns (PAMPs), that is, viral nucleic
acids. Induction of the expression of type I interferons by
these sensors utilizes at least two distinct pathways that
involve either the adaptor proteins mitochondrial antiviral-signaling protein (MAVS) or the stimulator of interferon genes (STING). Besides inducing interferon
expression, these cytoplasmic sensors modulate cellular
functions to limit viral spread and directly target viral
nucleic acids to degradation or sequestration.
data that suggest that CD4+ T cells might provide direct
non-cytotoxic control of HAV.
Swanson and McGavern discuss how viruses cause disease of the central nervous system (CNS). As in other
anatomical districts, tissue damage and pathology are
either a direct or an indirect consequence of viral infections. Direct killing of CNS cells by viruses can be the
consequence of viral subversion of cell metabolism or the
induction of cell-intrinsic programmed cell death pathways (including apoptosis) by specific viral factors. Examples of neurotropic viruses that directly kill CNS cells
include poliovirus and Eastern, Western and Venezuelan
equine encephalitis viruses. Indirect consequences of
viral infection leading to tissue damage and pathology
include a number of cell-extrinsic mechanisms initiating
apoptosis or lysis of infected cells through the action of
soluble mediators often released by inflammatory leukocytes. For instance many CNS infections induce common
pathogenic cascades leading to the release of detrimental
cytokines (e.g. TNF-a and type I interferons) that can
cause neurotoxicity and can potentially serve as therapeutic targets to lessen the tissue damage. Also, immune
cells such as CD8+ T cells can not only directly kill
infected cells but also contribute to the recruitment of
innate myelomonocytic cells that greatly amplify pathology.
Despite the remarkable capacity of host cells to detect the
presence of incoming viruses and induce antiviral immune responses, some viruses escape immune control
and cause pathology. Lahaye and Manel discuss the
remarkable ability of HIV-1 to escape host-encoded innate sensing pathways. Although several factors in HIV-1
are directly recognized by innate sensors, numerous viral
proteins interact with host factors to prevent innate
sensing. The comparison between cytosolic sensing in
dendritic cells and macrophages also reveals how innate
sensors and the resulting innate immune responses show
a high degree of cell-type specificity.
Since Francis Peyton Rous began his famous cancer virus
transmission experiments in chicken in 1909, numerous
viruses have been shown to cause cancers in susceptible
hosts. Indeed, the International Agency for Research on
Cancer recently estimated that up to one in five cancer
cases worldwide are caused by viruses. The most commonly held view is that viral tumourigenesis is a byproduct of the molecular parasitism by viruses to promote
their own replication. Viruses can cause cancer either by
expressing viral oncogenes that directly contribute to cell
transformation or indirectly by inducing chronic infection
and inflammation that eventually lead to carcinogenic
mutations in host cells. Wendzicki et al. discuss the most
recently discovered human oncogenic virus, Merkel cell
polyomavirus, and the elegant work that led to the rapid,
detailed characterization of how the viral gene products
impact tumorigenesis.
Walker et al. summarize new findings in hepatitis A virus
(HAV) pathogenesis that demand a rethinking of how the
immune system controls this infection. Since HAV
evokes a minimal activation of the innate immune
responses and is released from infected hepatocytes
cloaked in host membranes (thereby hidden from neutralizing antibodies), control of this virus relies on T cells.
These cells can directly kill infected cells, but they can
also produce antiviral cytokines. While this noncypathic
control of virus replication is well established for CD8+ T
cells in other infections, the authors discuss intriguing
Many of the viral pathogens that cause infectious diseases
in humans have a narrow host range, often limited to
humans or closely related human and non-human primates. As the use of these large animal models in biomedical research is hampered by ethical, financial and
logistical constraints, there is a pressing need for more
tractable small animal models to study human viruses.
Gaska and Ploss discuss how humanized mice are a
potential solution to this problem. They show how humanized mice can be generated by either genetic humanization (the expression of human genes, such as entry
Current Opinion in Virology 2015, 11:1–3
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Please cite this article in press as: Guidotti LG, Iannacone M: Editorial overview: Viral pathogenesis, Curr Opin Virol (2015), http://dx.doi.org/10.1016/j.coviro.2015.03.003
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Editorial overview Guidotti and Iannacone 3
factors, required for viral infection) or by engrafting
human hematopoietic stem cells and/or tissues into immunodeficient recipients. Their paper discusses recent
progresses and challenges in the development of humanized mice for four groups of human-tropic viruses–HIV,
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Dengue virus, herpesviruses and hepatitis viruses. Humanized mice have also proven useful for handling
emerging viral threats, as exemplified by the rapid development of mouse models for studying Middle Eastern
Respiratory Syndrome (MERS) and Nipah viruses.
Current Opinion in Virology 2015, 11:1–3
Please cite this article in press as: Guidotti LG, Iannacone M: Editorial overview: Viral pathogenesis, Curr Opin Virol (2015), http://dx.doi.org/10.1016/j.coviro.2015.03.003