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Journal of Virology, October 2001, p. 9596-9600, Vol. 75, No. 20
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.20.9596-9600.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Interleukin-12- and Gamma Interferon-Dependent Innate
Immunity Are Essential and Sufficient for Long-Term Survival of
Passively Immunized Mice Infected with Herpes Simplex Virus Type
1
Sabine
Vollstedt,1
Marco
Franchini,1
Gottfried
Alber,2
Mathias
Ackermann,1 and
Mark
Suter1,*
Institute of Virology, University of Zurich,
Zurich, Switzerland,1 and Institute of
Immunology, Faculty of Veterinary Medicine, University of Leipzig,
Leipzig, Germany2
Received 16 April 2001/Accepted 12 July 2001
 |
ABSTRACT |
Interferon (IFN) type I (alpha/beta IFN [IFN-
/
]) is very
important in directly controlling herpes simplex virus type I (HSV-1) replication as well as in guiding and upregulating specific immunity against this virus. By contrast, the roles of IFN type II (IFN-
) and
antibodies in the defense against HSV-1 are not clear. Mice without a
functional IFN system and no mature B and T cells (AGR mice) did not
survive HSV-1 infection in the presence or absence of neutralizing
antibodies to the virus. Mice without a functional IFN type I system
and with no mature B and T cells (AR129 mice) were unable to control
infection with as little as 10 PFU of HSV-1 strain F. By contrast, in
the presence of passively administered neutralizing murine antibodies
to HSV-1, some AR129 mice survived infection with up to104
PFU of HSV-1. This acute immune response was dependent on the presence
of interleukin-12 (IL-12) p75. Interestingly, some virus-infected mice
stayed healthy for several months, at which time antibody to HSV-1 was
no longer detectable. Treatment of these virus-exposed mice with
dexamethasone led to death in approximately 40% of the mice. HSV-1 was
found in brains of mice that did not survive dexamethasone treatment,
whereas HSV-1 was absent in those that survived the treatment. We
conclude that in the presence of passively administered HSV-1-specific
antibodies, the IL-12-induced IFN--dependent innate immune response
is able to control low doses of virus infection. Surprisingly, in a
significant proportion of these mice, HSV-1 appears to persist in the
absence of antibodies and specific immunity.
| |
INTRODUCTION |
Control of acute as well as
persistent herpes simplex virus type I (HSV-1) is believed to require
interferons (IFN), natural killer (NK) cells, virus-specific
CD4+ and CD8+ T cells, and
virus-specific antibodies (8, 29). IFN type I (alpha/beta
IFN [IFN-/]), which is produced by many cells, is crucial for
the immediate control of initial HSV-1 replication and powerfully
initiates innate and specific immune responses (12, 19,
28). IFN-, which is secreted mostly by NK and T cells, can
also directly interfere with virus replication, but the main role of
IFN- is believed to be indirect by regulating more than 200 genes
(3). For IFN- secretion, NK cells need to be activated
by IFN-/, which is induced directly by virus infection or by
IL-12 or tumor necrosis factor alpha secreted by infection of
monocytes/macrophages (6, 10, 33). In addition, NK
cells can be activated by binding immunoglobulins through their Fc
receptor (CD16) located on the cell surface (13, 27).
In vitro the biological effect of antibody specific to HSV-1 can be
neutralization to prevent virus infection, whereas in vivo the
biological effect may further include aggregation of antigen followed
by complement activation. The antibody-aggregated virus facilitates
uptake by phagocytes. Antigen-bound antibodies may help to activate
macrophages or NK cells (16, 17). However, in the absence
of IFN, the effect of neutralizing antibodies in defending against
HSV-1 is unknown.
To directly address these questions, we made use of mice with the IFN
receptor and recombination-activating gene (RAG) deleted. Animals
termed AGR129 mice have no functional receptors for IFN type I
(IFN-/) or IFN type II (IFN-) and carry a third deletion (RAG)
that does not allow these mice to produce mature T and B cells
(12). By contrast, AR129 mice have a functional IFN- system but a deleted IFN type I system and no mature T and B cells (10). Using these two mouse strains without specific
immunity, the biological effect of neutralizing antibody to HSV-1 in
the absence of a functional IFN system in AGR129 mice or in the
presence of IFN- in AR129 mice was analyzed.
(This publication is in partial fulfillment of the requirements for
Sabine Vollstedt's doctoral thesis from the Faculty of Veterinary
Medicine, University of Zurich.)
| |
MATERIALS AND METHODS |
Animals and virus.
Six- to 8-week-old mice with
gene-targeted disruptions of IFN receptor types I and II as well as RAG
(AGR129) and congenic 129Sv/Ev mice with targeted disruptions of IFN
receptor type I and RAG (AR129) were used (10, 12). Thus,
AGR129 mice have no functional IFN system and no mature T and B cells,
whereas AR129 mice have no functional type I IFN (IFN-/) system
and no mature T and B cells but have an intact IFN- system. Mice were bred and maintained under specific-pathogen-free conditions in the
Labortierkunde, Universität Zurich, Zurich, Switzerland.
The HSV-1 F strain was originally obtained from B. Roizman (University
of Chicago) and was propagated on Vero cells (9). For all
experiments purified virus particles from the same batch were used.
Purification of infectious particles was performed by
ultracentrifugation on a sucrose density gradient, and the virus titer
was determined as described previously (32).
Production of neutralizing murine antibodies, serology, and
passive immunizations.
For the production of neutralizing murine
antibodies, groups of C57BL/6 and 129Sv/Ev mice were injected with a
sublethal dose of 106 PFU of the HSV-1 F strain.
At 3 to 4 weeks after immunization mice were bled, and the sera were
pooled and analyzed for in vitro virus neutralization capacity and
enzyme-linked immunosorbent assay (ELISA) titer as described
previously, using peroxidase-conjugated polyclonal anti-mouse
immunoglobulin G1 and immunoglobulin G2a antibody (Southern
Biotechnology, Birmingham, Ala.) (32).
For the calibration of passive immunization with antibodies, different
amounts of immune sera were administered intraperitoneally
(i.p.) to
naive AGR or AR129 mice to obtain a neutralization titer
of 60 to 80/ml
and an ELISA titer of approximately 10
4/ml in the
sera of these mice as determined 24 h later. For some
experiments,
sera from passively immunized animals were analyzed
at later time
points (see Table
1 for details). For controls,
sera from naive C57BL/6
specific-pathogen-free animals, or no
serum, were used. To determine
the biological significance of
IL-12 p75, 100 µg of neutralizing
monoclonal antibody (10F6) specific
to this cytokine was administered
i.p. to mice on days
1, +1,
+3, and +5 of the infection experiment
(
23). Monoclonal antibody
10F6 used under these conditions
is not toxic but can neutralize
nanogram amounts of IL-12 p70 to
prevent death after induction
of shock (reference
23 and
unpublished
observations).
HSV-1 infection and reactivation protocol.
Before infection,
mice were injected with neutralizing antibodies or sera from naive
animals or were left untreated (see above). Twenty-four hours later,
AGR129 or AR129 mice were infected i.p. with 102
or 104 PFU of HSV-1 F strain, or in some
experiments this was done 1 or 3 weeks after passive
immunization. After 3 to 4 months, mice that survived HSV-1 infection
were treated with corticosteroids. Mice were given dexamethasone
(Veterinaria AG, Zurich, Switzerland) in two doses of 3 mg each within
2 days. Three milligrams of dexamethasone contains 1 mg of
dexamethasone sodium phosphate and 2 mg of dexamethasone phenylpropionate. Dexamethasone sodium phosphate is immediately released and lasts for 48 h, whereas dexamethasone
phenylpropionate lasts for 8 days. This dose is not lethal to
HSV-1-negative control mice but enables virus reactivation of
HSV-1-infected wild-type animals.
Resection of trigeminal and spinal ganglia and PCR.
Trigeminal and spinal ganglia were isolated to probe for HSV-1 DNA by
PCR. Trigeminal ganglia were separated from brain tissue after opening
and removing the skull. Spinal ganglia were surgically removed by
opening the spinal cord under microscopic control. To detect the HSV-1
genome in spleen, liver, lung, kidney, or brain, DNA was isolated by
standard procedures and HSV-specific genes were amplified by PCR.
Primers were directed to the HSV glycoprotein B (gB) gene. The forward
primer was 5'-TCC CGG TAC GAA GAC CAG, and the reverse primer was
5'-AGC AGG CCG CTG TCC TTG. Conditions for PCR were as described
previously (30). Under the PCR conditions used, the lower
limit of detection is approximately 5 to 10 copies of gB per assay.
| |
RESULTS |
Neutralizing antibodies specific to HSV-1 are unable to protect
AGR129 mice against infection with HSV-1.
AGR129 mice, which lack
functional IFN (34) as well as mature T and B cells, are
very susceptible to exposure to various viruses (12). When
infected with 102 PFU of HSV-1, these mice died
within 6 to 7 days (Fig. 1). Virus was
reisolated from several organs, or the viral genome was detected by PCR
(data not shown). Animals infected with less than 10 PFU of HSV-1 also
died, indicating that mice without IFN and mature T and B cells have no
resistance against infection with HSV-1. We next tested whether
neutralizing murine antibodies with a titer of 80 (Table
1) could induce resistance against virus
infection. Mice were first injected with neutralizing antibodies
specific to HSV-1 at 24 h before infection with
102 PFU of virus, and the effect of the
antibodies was analyzed by clinical observation. The data shown in Fig.
1 illustrate that the onset of the disease was delayed somewhat, but
protection was not achieved. Infection of AGR129 mice with
approximately 10 PFU of virus and more antibodies (up to a titer of
180) delayed the onset of the disease but did not significantly protect
mice from a deadly infection (data not shown). Hence, virus-specific antibody and complement naturally present in AGR mice were not able to
directly protect mice against infection with HSV-1. In addition, in
mice without functional IFN, elements of the innate immunity such as
macrophages or NK cells were not able to cooperate with antibodies in
virus clearance, because they appeared to need activation by
IFN-/ or IFN- (20, 27).
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FIG. 1.
Neutralizing antibodies specific to HSV-1 are unable to
protect AGR129 mice against infection with HSV-1. Six AGR129 mice were
infected with 102 PFU of HSV-1 in the absence ( ) or
presence (- - - ) of HSV-1-specific antibody. The survival of mice
after virus infection is shown. Data are from a representative
experiment of three.
|
|
AR129 mice supplemented with neutralizing antibodies to HSV-1 are
resistant to infection with small amounts of virus.
In a next
step, the IFN- system was analyzed for its effect on influencing the
course of HSV-1 infection. AR129 mice have a functional IFN- system
but lack the IFN type I system and specific T and B cells. Groups of
mice were infected with 102 PFU of virus, and the
animals were analyzed for resistance against the infection. Similar to
the case for AGR129 mice, no AR129 mouse survived the virus
infection. Members of both mouse strains succumbed to the
infection within the same time frame (Fig
2). Similar to the case for AGR129 mice,
infection with less virus led to an extended survival time of the AR129
mice, but none survived longer than 2 months (data not shown). We next
analyzed whether pretreatment of AR129 mice with neutralizing antibody
specific to HSV-1 antigen allowed survival after infection with
102 PFU of virus. Interestingly, about 50% of
the infected mice survived. Increasing the virus dose to
104 PFU led to survival of about 15% of the mice
(Fig. 2). Mice pretreated with normal mouse serum and then exposed to
HSV-1 did not survive the infection. In mice that succumbed after HSV-1
infection, virus was found in brain, trigeminal ganglion, spleen,
kidney, and lung, and serum antibody specific to the virus was absent
at this time point.
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FIG. 2.
AR129 mice supplemented with neutralizing antibodies to
HSV-1 are resistant to infection with small amounts of virus. Groups of
10 AR129 mice were each infected with 102 or
104 PFU of HSV-1 in the absence () or presence
(--;····) of HSV-1-specific antibody. The
survival of mice after virus infection is shown. The data shown were
pooled from two different experiments.
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|
In the next experiment, two groups of mice were injected with the
standard amount of antiserum to HSV-1 antigen. Sera from
mice of group
1 were analyzed periodically for the presence of
antibody to HSV-1,
whereas mice of group 2 were infected with
HSV-1 at 24 h or at
weekly intervals after passive immunization,
and the health status of
the animals was monitored (Table
1).
The antibody titer to HSV-1 in
sera taken weekly from mice of
group 1 decreased gradually and was
undetectable 6 weeks after
passive administration. Fifty percent of the
mice infected with
10
2 PFU of virus 24 h
after infusion of antibodies survived the infection,
whereas only 16%
of the mice infected 1 week after infusion and
none of the mice
infected 2 weeks after passive administration
of antibodies survived.
Mice that received HSV-1 had no detectable
virus-specific antibodies 1 week after infection, irrespective
of whether the mice survived the
infection or not. Therefore,
a critical level of antibody to HSV-1 was
required to confer protection
against acute infection with a given
amount of
virus.
IL-12 is essential for the protection of AR129 mice exposed to
HSV-1 in the presence of neutralizing antibodies.
After virus
infection, IFN-/ may activate cells of the innate immune system
directly, whereas in the absence of IFN-/, induction of IFN-
requires the presence of IL-12 (7, 26). Because AR129 mice
have no functional type I IFN system, the role of IL-12 after HSV-1
infection was investigated (14). Groups of mice were given
the standard amount of antiserum to HSV-1 together with neutralizing
antibodies specific to IL-12 (23). Twenty-four hours
later, the mice were infected with 102 PFU of
virus. All mice died within 7 days (Fig.
3), similar to the case for AR129
mice not receiving antiserum specific to HSV-1. Therefore, critical
amounts of neutralizing antibody to HSV-1 together with the
IL-12-dependent IFN- system are crucial for the resistance against
HSV-1 infection in these immunocompromised mice.
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FIG. 3.
IL-12 is essential for the protection of AR129 mice
exposed to HSV-1 in the presence of neutralizing antibodies. Groups of
10 AR129 mice were each infected with 102 PFU of HSV-1 in
the absence () or presence (--;····) of
HSV-1-specific antibody or, in addition to these antibodies, with
monoclonal antibody that neutralizes IL-12p70 (····).
The survival of mice after virus infection is shown. The data shown
were pooled from two different experiments.
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|
Elimination or control of persistent virus in long-term survivor
HSV-1-infected AR129 mice.
In the presence of both sufficient
amounts of neutralizing antibody to HSV-1 and the IL-12-dependent
IFN- system, about 50% of AR129 mice were able to resist acute
infection with small amounts of virus. HSV-1-infected animals were
devoid of antibody shortly after infection, and detectable antibody was
present in noninfected animals for no more than 6 weeks (Table 1).
However, some HSV-1-infected animals survived for up to 15 weeks, the
latest time point analyzed. It was possible that the mice that survived
the infection had eliminated the virus or that persistent virus
infection occurred in AR129 mice. To test for these two possibilities,
six mice that survived 102 PFU and one that
survived 104 PFU of HSV-1 infection were treated
with dexamethasone. Within 4 days after the treatment, two of the six
mice infected with 102 PFU of HSV-1 and the one
mouse infected with 104 PFU of HSV-1 died (Fig.
4). HSV-1 DNA was detected in
brain but not in other organs of the diseased animals by amplification
of HSV-1 gB-specific gene fragments by PCR. Reisolation of
replicating virus was not reproducible. Animals that resisted
dexamethasone treatment were sacrificed, and brain, ganglia, and
peripheral organs were analyzed for the presence of HSV-1 gB by PCR.
All organs tested were negative. The data indicate that in the presence of antibodies, the IL-12-induced IFN- system, possibly aided by
activated monocytes/macrophages and NK cells, appeared to eliminate HSV-1 in four out of seven cases, whereas in the remaining three cases
infection seemed to be controlled by the immune system.
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FIG. 4.
Elimination or control of persistent virus in long-term
survivor HSV-1-infected AR129 mice. AR129 mice were infected with
102 or 104 PFU of HSV-1 in the presence of
HSV-1-specific antibody. Three months after infection, the surviving
animals were treated with glucocorticosteroids ( ). The survival of
animals after treatment with glucocorticoids is shown.
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| |
DISCUSSION |
In mice without a functional IFN system or mature T and B cells,
neutralizing antibodies to HSV-1 antigen had no significant effect in
impeding infection or spread of the virus, even though in vitro these
antibodies had a neutralizing titer of 80 (Table 1). In fact, there was
no difference in the death rate when AGR129 mice were infected with
103 PFU of HSV-1 in the presence or absence of
antibodies. In vivo, HSV-1 may be able to bind to far more receptors
than in vitro and direct virus neutralization by antibodies may thus be
difficult (5). Simple mass law considerations illustrate
this point: [ligand] + [receptor] 
[ligand-receptor]. This
equation predicts that the amount of receptors on the cells is directly
proportional to the amount of virus available for interaction
([ligand-receptor]). In addition, in vivo the diversity and perhaps
the density of the receptors per cell may be higher than in vitro
(5). This makes cooperative binding of the virus to cells
more likely but direct neutralization by antibodies more difficult in
vivo than in vitro, where one defined cell line adherent to plastic as
a monolayer is used for virus neutralization by antibodies
(25). Therefore, the biological effect of antibodies bound
to HSV-1 in vivo may be more indirect by stimulating innate immune
responses. This is illustrated in newborn mice, where large amounts of
antibody are required to protect animals from relatively small amounts of virus (2, 15, 22). In these mice, the IFN system is immature and supplementation of monocytes/macrophages or NK cells from
adult animals increased protection against virus infection significantly (4). The data presented here suggest that in AGR129 mice without a functional IFN system at all or in newborn mice
with an immature IFN system, antibody is not efficient in directly
neutralizing HSV-1 infection (1). Therefore, indirect mechanisms that are dependent on IFN support the biological activity of
these molecules.
Because the IFN type I system has a profound direct effect on HSV-1
replication (19), we have analyzed whether IFN type II
(IFN-) may indirectly support the biological activity of
neutralizing antibodies. AR129 mice have a functional IFN- system
but were unable to resist HSV-1 infection of as low as 10 PFU, possibly because this virus can downregulate immune responses, at least in vitro
(18, 31). Interestingly, neutralizing antibodies passively
administered to these mice allowed them to resist acute infection,
depending on the dose of HSV-1 and the amount of passively administered
antibodies, but normal mouse serum was ineffective (Table 1).
Therefore, additional activation signals, possibly delivered by
antibody-antigen complexes together with IFN-, were necessary to
induce protection against HSV-1. In the absence of IFN-/, the
IFN- system needs activation by IL-12 (26). Treatment of AR129 mice with neutralizing antibodies against IL-12 clearly indicated that this cytokine was necessary for protection against HSV-1. Production of IL-12 by dendritic cells or granulocytes after
HSV-1 infection in mice has previously been demonstrated (14). We thus speculate that virus-containing cells that
secrete IL-12 may activate and/or attract cells able to produce
IFN-, enabling control of HSV-1 replication (24).
However, the temporal order in which the postulated HSV-1
antigen-antibody complexes, IL-12, and IFN- might operate in concert
with other cytokines and chemokines as well as the cellular members of
the innate immune system is not clear. The need for immediate cytokine
production to control herpesvirus infection was shown previously
(12). Because IL-12 is a cytokine that is produced by
monocytes/macrophages early in immune responses, we consider it likely
that HSV-1 antigen-antibody may enable these cells to produce IL-12,
activate nearby NK cells, and recruit other cells to the site of
infection (24). Antibody may further be used to focus
and/or activate NK cells against virus-infected targets (21,
27). In addition, we have previously provided evidence that CD8
+ dendritic cells from AR129 mice activate NK
cells by direct cell-to-cell contact to produce IFN- and to kill
major histocompatibility complex-negative tumor cells in vitro and
possible in vivo (10). Determination of whether a similar
mechanism is operating in HSV-1-infected AR129 mice requires further analysis.
Animals that succumbed to virus infection as well as those that
survived had no detectable antibodies to HSV-1 antigen as analyzed by
ELISA. Interestingly, animals that survived acute HSV-1 infection lived
for up to 15 weeks, the latest time analyzed. Treatment of these mice
with corticosteroids revealed two possible mechanisms of virus control
in AR129 mice. In the majority of these animals corticosteroids did not
affect the health status of the mice, and no evidence of virus was
found in the organs by reisolation or PCR. We can conclude that in
these mice virus had been eliminated by the innate immune system. In
some cases animals succumbed after treatment with corticosteroids.
HSV-1 gB DNA was found by PCR in ganglia and in brain of the diseased animals but not in peripheral organs. In these animals HSV-1 appeared to persist and hence needed control by the innate immune system provided by the AR129 mice, because AGR129 mice without the IFN- system all died after infection with HSV-1. Thus, immune cells, possibly NK cells activated by monocytes/macrophages, may be able to
control persistent virus infection in the absence of specific immunity.
Immune histological analysis and infection experiments with mouse
strains without mature T and B cells as well as NK may allow us to
address these questions (1).
These data have significance for neonatal immune responses against
intracellular pathogens that depend on IFN for defense. The effect of
maternal or colostral antibodies may be enhanced by specifically or
nonspecifically inducing IL-12 or IFN (11).
| |
ACKNOWLEDGMENTS |
We thank Cornelia Schwerdel for skillful technical assistance and
Hanspeter Nägeli, Institute for Veterinary Pharmacology, University of Zurich, for assistance in the use of corticosteroids.
This work was supported by the Canton of Zurich and a grant from the
BBW (no. 96.0046-1; EU concerted action B104-CT 96-0398). G.A. was
supported by a Socrates fellowship.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Institute of
Virology, University of Zurich, Winterthurerstr. 266a, CH-8057 Zurich, Switzerland. Phone: 41 1 635 87 17. Fax: 41 1 635 89 11. E-mail: msuter{at}vetvir.unizh.ch.
| |
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Journal of Virology, October 2001, p. 9596-9600, Vol. 75, No. 20
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.20.9596-9600.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
