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Interference with Virus Infection
Michael Gale, Jr.
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Copyright © 2015 by The American Association of
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Print ISSN: 0022-1767 Online ISSN: 1550-6606.
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Supplementary
Material
J Immunol 2015; 195:1909-1910; ;
doi: 10.4049/jimmunol.1501575
http://www.jimmunol.org/content/195/5/1909
The
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Journal of
Immunology
Interference with Virus Infection
Michael Gale, Jr.
I
Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington School of Medicine, Seattle, WA 98109
Address correspondence and reprints requests to Dr. Michael Gale, Jr., 750 Republican Street E360, Seattle, WA 98109. E-mail address: [email protected]
Abbreviation used in this article: IAV, influenza A virus.
Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501575
and described its virus-induced, cell-derived, and soluble nature
and defined antiviral actions that interfere with virus infection
(2, 3). Hence, they assigned the name “interferon” to what is
now known as the IFN family of cytokines.
How did they discover the interferon? At the time, Alick
Isaacs was studying the infection properties of IAV and other
RNA viruses, including a variety of mosquito-transmitted
viruses, such as West Nile virus. Working at the National Institute for Medical Research in London, he met a research fellow named Jean Lindenmann who was learning the ropes in the
upstart field of virology. It had just been realized that viruses
were different from bacteria in that they replicated through
a means beyond binary fission within animal cells. This replication occurred during what the early virologist Leslie Hoyle
described as the eclipse phase in his studies of IAV, by which
he defined a noninfectious phase of viral growth (6). Indeed,
the eclipse phase is a period of viral disassembly and synthesis
occurring right after virus entry into the host cell during acute
infection, thus reflecting the specialized and parasitic virus life
cycle. Additionally, a previous advance spearheading the ability
to study viruses in tissue was applied by Isaacs and Lindenmann
to culture IAV when they used Thomas Goodpasture’s (7)
methods described for the culture of fowlpox virus in chorioallantoic membranes of chicken embryos. Isaacs and other
investigators also figured out that one could heat inactivate
virus stocks to render them noninfectious while retaining properties of tissue interaction. Using methods of IAV culture in
chorioallantoic membranes, Isaacs and Lindenmann produced IAV stocks. They then heat inactivated a set of IAV
stocks to use for studies of infection competition between nontreated, infectious IAV and inactivated IAV.
In their first series of experiments, Isaacs and Lindenmann
exposed chorioallantoic membranes to inactivated IAV for various times at 4 or 37˚C prior to exposure to infectious IAV at
4 or 37˚C. These were the primordial days of tissue culture
wherein cultures were little more than crude slices of membrane
of approximately equal size floating in a glass dish of saline
solution in a slightly warmed oven without additional CO2. In
these experiments, the membranes were exposed to inactivated
IAV. Heat-inactivated IAV can still be internalized into the target cell at 37˚C but not at 4˚C, and the membranes were further
incubated to allow inactivated virus internalization. Membranes
were then washed in saline solution to remove residual IAV
particles and placed back in culture for exposure to infectious
IAV for 48 h, after which supernatants were collected. Dilutions
of supernatants were then mixed with chicken RBCs. IAV can
agglutinate RBCs, so the number of IAV particles produced by
the infected chorioallantoic membrane culture was determined
by assessing heme agglutination activity of the supernatant.
These studies revealed that, when conducted at 37˚C, a
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n eukaryotes, type 1 IFN is essential for defense against
virus infection and is a major component of antimicrobial
defenses and the innate immune response. The discovery
of IFN was driven by the new field of virology (1) and studies
of influenza A virus (IAV) in the 1950s through which the
interferon was defined by Alick Isaacs and Jean Lindenmann.
These investigators revealed IFN as a soluble agent that was
made from infected cells and could suppress IAV infection (2,
3). The discovery of IFN serves as a cornerstone from which
the foundation for the discipline of innate immunity developed within the field of immunology.
Today, we know that IFNs make up an important family of
cytokines that have antimicrobial, proapoptotic, immunomodulatory, and antiproliferative actions. There are three types
of IFN, each encoded by unique gene(s) and named based on
their order of discovery and related biology. The major type 1
IFNs include IFN-a and IFN-b. In humans, there are
multiple IFN-a genes encoding highly related, but unique,
IFN-a subtypes and a single IFN-b gene, all clustered on
chromosome 9 (4). Each can be expressed from most nucleated
cells of the body and encodes a protein that binds to a common
IFN-a/b receptor. The type 1 IFNs also include minor subtypes
IFN-v, IFN-t, and IFN-k. These IFNs were discovered after
IFN-a/b, are categorized as type 1 IFNs, and are selectively
expressed among cell types and species (4). IFN-g is the sole
type 2 IFN and is encoded by a single gene expressed by
activated immune cells. IFN-g binds to the IFN-gR
expressed by many cell types, including immune cells and
tissue parenchyma cells. Type 3 IFNs are now known as
IFN-l and, in humans, include three subtypes with a receptor
chain combination that is selectively coexpressed by myeloid
cells and by parenchymal cells of the liver and gut. During
virus infection of epithelial cells, IFN-b is typically induced
first, followed by signaling events that drive the expression of
IFN-a subtypes. Virus infection also induces IFN-l expression
and, in certain cell types, the additional type 1 IFNs can be
produced. These actions mark the innate immune response and
the first stage of the global immune response to virus infection.
In addition to antiviral actions, the IFNs serve to regulate the
quality and actions of the adaptive immune response by
modulating immune effector cell activation and function (5).
Isaacs and Lindenmann discovered what we know as type 1 IFN
1910
IAV, similar to how defective virus particles can stimulate IFN
production when viral pathogen-associated molecular patterns
are revealed during the eclipse phase of the infection and are
sensed by pattern recognition receptors in the target cells. Their
discovery of IFN, now 58 y ago, led to the identification of
other IFNs, the IFNRs, JAK-STAT signaling pathways,
IFN regulatory factors, IFN genes, and the pattern recognition
receptors, such as TLRs and the RIG-I–like receptors that
induce intracellular signaling to activate IFN regulatory factors
to drive IFN production and the innate immune response to
virus infection. Moreover, this work led to studies that
identified plasmacytoid dendritic cells as the major IFNproducing cell and provided the foundation for studies that
defined other IFN-producing cell subsets. We know that IFN
actions are mediated by hundreds of IFN-stimulated genes and
that specific IFN-stimulated gene actions suppress infection by
IAV and other viruses. Today, pharmacologic IFNs serve as
effective therapeutics for treating virus infection, cancer, and
autoimmune disease (10–13). The work of Alick Isaacs and
Jean Lindenmann opened the door for these discoveries and
products, with great impact on immunology, virology, microbiology, and public health.
Disclosures
The author has no financial conflicts of interest.
References
1. Van Helvort, T. 1996. When did virology start? American Soc. Micro. News 62:
142–145.
2. Isaacs, A., J. Lindenmann, and R. C. Valentine. 1957. Virus interference. II. Some
properties of interferon. Proc. R. Soc. Lond. B Biol. Sci. 147: 268–273.
3. Isaacs, A., and J. Lindenmann. 1957. Virus interference. I. The interferon. Proc. R.
Soc. Lond. B Biol. Sci. 147: 258–267.
4. Chen, J., E. Baig, and E. N. Fish. 2004. Diversity and relatedness among the type I
interferons. J. Interferon Cytokine Res. 24: 687–698.
5. Coccia, E. M., and A. Battistini. 2015. Early IFN type I response: Learning from
microbial evasion strategies. Semin. Immunol. 27: 85–101.
6. Hoyle, L., and W. Frisch-Niggemeyer. 1955. The disintegration of influenza virus
particles on entry into the host cell; studies with virus labelled with radiophosphorus.
J. Hyg. (Lond.) 53: 474–486.
7. Goodpasture, E. W. 1983. Use of embryo chick in investigation of certain pathological problems originally published in Southern Medical Journal, May 1933.
South. Med. J. 76: 553–555.
8. Lindenmann, J., D. C. Burke, and A. Isaacs. 1957. Studies on the production, mode
of action and properties of interferon. Br. J. Exp. Pathol. 38: 551–562.
9. Isaacs, A., and M. A. Westwood. 1959. Duration of protective action of interferon
against infection with West Nile virus. Nature 184(Suppl. 16): 1232–1233.
10. McNab, F., K. Mayer-Barber, A. Sher, A. Wack, and A. O’Garra. 2015. Type I
interferons in infectious disease. Nat. Rev. Immunol. 15: 87–103.
11. Rafique, I., J. M. Kirkwood, and A. A. Tarhini. 2015. Immune checkpoint blockade
and interferon-a in melanoma. Semin. Oncol. 42: 436–447.
12. Marziniak, M., and S. Meuth. 2014. Current perspectives on interferon Beta-1b for
the treatment of multiple sclerosis. Adv. Ther. 31: 915–931.
13. Gonzales-van Horn, S. R., and J. D. Farrar. 2015. Interferon at the crossroads of
allergy and viral infections. J. Leukoc. Biol. 98: 1–10.
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15-min pre-exposure to inactivated IAV resulted in membrane interference or resistance to infectious virus at 37˚C, because
only input or lower levels of virus were generated after infectious IAV exposure. In these studies, the peak of interference
occurred after a 6-h pre-exposure. Moreover, when pre-exposure was conducted at 4˚C, followed by exposure to infectious IAV at 37˚C, no interference against infectious IAV was
observed, indicating that tissue metabolic events were necessary
for viral interference to occur. Thus, a synthetic product from
the chorioallantoic membrane was likely mediating the interference against infectious IAV. Further experiments to treat fresh
membranes with ground-up membranes or supernatant from
membranes that had been exposed to inactivated IAV for 6 h
revealed that interference was generated from membrane exposure to a soluble product from the virus-exposed membranes.
Thus, the soluble product was named “interferon.”
Isaacs and Lindenmann, with Burke and Valentine (2, 8),
conducted follow-up studies to evaluate the properties of IFN.
They scaled up their chick embryo chorioallantoic membrane
culture system to produce larger quantities of IFN-containing
supernatant by exposing membranes to inactivated IAV for 3 h,
washing the membranes in saline, and then culturing them
for 24 h in fresh media, after which the media was collected as
the IFN preparation. This preparation was then used to treat
membranes and assess their resistance to infection by Sendai
virus and Newcastle disease virus (both are paramyxoviruses
related to the contemporary human pathogen respiratory syncytial virus) and to vaccinia virus (a derivative of smallpox
virus). In additional studies, Isaacs and Westwood (9) similarly assessed IFN actions on West Nile virus infection. Upon
pretreatment of membranes with IFN supernatant, in each of
these studies it was found that membranes could resist the
virus infection. Moreover, the studies showed that the IFN
effect was titrated away upon serial dilution of the IFN supernatant. Thus, IFN actions were dose dependent. It also
was determined that IFN was heat labile and was not neutralized
by anti-IAV Abs. It was concluded that IFN was produced
from infected cells, either as a fragment of the virus that then
stimulates interference with new infection or as a reaction product of the cell, such as a cellular enzyme. Isaacs proposed the
hypothesis that IFN was a product of the heat-inactivated IAV,
in which the inactivated virus feeds into the cell insufficient
information for orderly virus replication, instilling a dysregulated viral-replication process that interferes with the infection, and that the IFN that is produced could block viral
replication. Isaacs and Lindenmann were absolutely correct.
Today, we understand that Isaacs and Lindenmann had
observed the production of type 1 IFN induced by inactivated
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