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Journal of Virology, July 2001, p. 6705-6709, Vol. 75, No. 14
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.14.6705-6709.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Interleukin-12 (IL-12) and IL-18 Are Important in Innate Defense
against Genital Herpes Simplex Virus Type 2 Infection in Mice but
Are Not Required for the Development of Acquired Gamma
Interferon-Mediated Protective Immunity
Ali M.
Harandi,1
Bo
Svennerholm,2
Jan
Holmgren,1 and
Kristina
Eriksson1,*
Departments of Medical Microbiology and
Immunology1 and Clinical
Virology,2 Göteborg University, 413 46 Göteborg, Sweden
Received 8 January 2001/Accepted 25 April 2001
 |
ABSTRACT |
Using a combination of gene-targeted mice and neutralizing
antibodies, we showed that interleukin-12 (IL-12) and IL-18 are important in the innate control of genital herpes simplex virus type 2 infection but were not found to be critical, either singly or in
combination, for the development of a protective gamma
interferon-mediated immune response.
 |
TEXT |
Natural antibodies, NK cells,
neutrophils, macrophages, and complement all contribute to the innate
control of genital herpes infection (1, 5, 9, 13, 24).
Once a herpes simplex virus type 2 (HSV-2) infection is established,
virus-specific CD4+ and CD8+ T cells develop
and participate in the resolution of the infection (16).
To prevent infection, both specific antibodies and T cells are
implicated. Antibodies limit the uptake and replication of the virus
(30). Thereafter, memory T cells infiltrate the exposed area (26, 32).
Gamma interferon (IFN-
) appears to play an important role in
T-cell-mediated viral clearance (25, 33). There is a
markedly increased genital virus load in vaccinated mice treated with
anti-IFN-
antibodies (25, 33). Furthermore, lack of
protection in vaccinated CD4
/
mice correlates with
reduced IFN-
responses, and protection can be restored in vivo by
addition of exogenous IFN-
(13).
Interleukin-12 (IL-12) and IL-18 are key factors for Th1 development.
IL-12 is the dominant factor inducing IFN-
production by T cells and
NK cells (27). IL-18 synergizes with IL-12 in inducing
IFN-
by T cells and is thus required for optimal IFN-
synthesis
(18, 34, 38, 39). Previous studies in experimental animals
point to the important role of IL-12 and IL-18 in host defense against
intracellular bacteria, parasites, and fungi (6, 11, 12, 15,
20-22, 28). To assess the requirements of IFN-
, IL-12, and
IL-18 in innate immune control of genital HSV-2 infection, C57BL/6
wild-type (WT), IFN-
/
(10),
IL-12p40
/
(19), and IL-18
/
(40) mice were vaginally challenged with a lethal dose
(4 × 104 PFU) of HSV-2 strain 333 (37).
Following HSV-2 infection, vaginal fluids were collected and HSV-2
titers were determined by plaque assay, and mice were examined daily
for disease and death. Statistical analyses were done by Student's
t test or log rank test.
Innate defense against primary infection.
Three days after
viral inoculation the level of shed virus was four times higher in
IFN-
/
mice (Fig. 1A)
and these animals died significantly earlier (4 days) than WT mice
(P < 0.01) (Fig. 1B). The vaginal HSV-2 titers both in
IL-12
/
and in IL-18
/
mice were higher
than those observed for WT animals (Fig. 1A), and the animals died
significantly earlier (3 days [P < 0.05] in
IL-12
/
mice and 4 days [P < 0.01] in
IL-18
/
mice) (Fig. 1B).

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FIG. 1.
Vaginal HSV-2 titers and disease progression in mice
deficient in IFN- , IL-12, or IL-18 after primary and secondary
genital HSV-2 infections. (A and B) Naïve mice were challenged
intravaginally with a lethal dose of HSV-2, and the vaginal HSV-2
titers (A) were examined on day 3 after viral challenge (n = 6). Differences were statistically significant at P
values of <0.05 (*) and <0.01 (**) by Student's t
test compared with WT mice. The mice were monitored daily for mortality
(n 12) (B). (C and D) Effects of in vivo
administration of neutralizing anti-IL-18 antibody on vaginal HSV-2
replication and disease progression in HSV-2-challenged
IL-12 / mice. Groups of IL-12 / mice (4 mice/group) received either neutralizing anti-IL-18 antibody or
purified normal IgG2a on days 0, 2, 4, and 6 after HSV-2 challenge. At
day 3 after viral challenge, the vaginal HSV-2 titers (C) were
evaluated. *, statistically significant at P values of
<0.05 compared to control antibody-treated IL-12 /
mice. The mice were examined daily for mortality (D). (E) Survival of
vaccinated C57BL/6 WT, IFN- / ,
IL-12 / , IL-18 / (10 to 15 mice/group),
and IL-18-depleted IL-12 / mice (6 mice/group) after a
lethal challenge with HSV-2.
|
|
The most prominent function of IL-12 and IL-18 in innate defense is as
enhancers of NK cell activity including IFN-

production
(
42,
43). IL-18 can also induce intercellular adhesion molecule
1 expression by an IFN-

-independent pathway, promoting immune-cell
recruitment to the target tissue (
17). To assess the
outcome
of primary genital HSV-2 infection in the absence of both IL-12
and IL-18, we depleted endogenous IL-18 in IL-12
/
mice.
A neutralizing rat anti-mouse IL-18 antibody (R&D systems)
(20 µg/mouse) was administered intraperitoneally to
IL-12
/
mice 4 h prior to vaginal HSV-2
inoculation. An additional 10
µg of anti-IL-18 antibody was given
vaginally at the time of inoculation
followed by 20 µg of anti-IL-18
antibody given intraperitoneally
on days 2, 4, and 6 after virus
challenge. The vaginal HSV-2 titers
in anti-IL-18 antibody-treated
IL-12
/
mice were threefold higher than those in control
antibody (rat
immunoglobulin G [IgG])-treated IL-12
/
mice on day 3 postchallenge (Fig.
1C), and these mice also died
significantly earlier (3 days) (
P < 0.05) (Fig.
1D).
Thus, the
natural defense against genital HSV-2 infection is impaired
in
mice lacking IL-12 and/or IL-18.
Vaccination-induced acquired defense.
Vaginal vaccination of
mice with an attenuated strain of HSV-2 confers protection against a
lethal challenge with a virulent strain of the virus (23,
31). To examine the roles of IFN-
, IL-12, and IL-18 for the
development of vaccine-induced protective immune responses,
IFN-
/
, IL-12
/
, and
IL-18
/
mice were vaccinated with 3.6 × 106 PFU of attenuated HSV-2 strain Lyon, which contains a
partial deletion of the thymidine kinase gene (2), and
then 4 weeks later they were challenged vaginally with a lethal dose of
HSV-2. Three days after the challenge infection, no viral replication was detected in vaccinated WT mice and consequently no death was observed (Fig. 1E). In contrast, vaccinated IFN-
-deficient mice had
evidence of persistent viral replication (134 ± 47.9 [mean ± standard error of the mean] PFU) and the majority of the vaccinated IFN-
/
mice had died by day 20 (Fig. 1E). No viral
replication was observed in the vaccinated IL-12
/
or
IL-18
/
mice on day 3 postchallenge, and all these
animals survived (Fig. 1E).
Next, we examined the induction of protective immunity in the absence
of both IL-12 and IL-18. Endogenous IL-18 was depleted
in
IL-12
/
mice by using different sets of anti-IL-18
antibodies (rat and
goat) at the time of vaccination and at the
time of challenge
as described above. Similarly to what was
observed for vaccinated
WT mice, no viral replication was observed
on day 3 postchallenge
in anti-IL-18-treated IL-12
/
mice. Neither the vaccinated anti-IL-18-treated
IL-12
/
mice nor the control antibody-treated
IL-12
/
animals died or exhibited any signs of disease
throughout the
20-day observation course (Fig.
1E). These results
demonstrate
that IFN-

but not IL-12 or IL-18 is required for
development
of acquired protective immunity against genital HSV-2
infection.
Immune factors associated with protection.
The immunity levels
of mice deficient in IFN-
, IL-12, or IL-18 were compared 4 weeks
postvaccination. The production of type 1 cytokines (IFN-
and IL-2)
in vitro was examined using a cellELISA method (13).
Spleen cells from all groups of vaccinated mice responded to in vitro
recall HSV-2 antigen with a strong proliferative response (Fig.
2A) and IL-2 production (Fig. 2B), even
though the responses were lower in IL-12
/
and
IL-18
/
mice. There were significantly reduced levels of
IFN-
in spleen cells from vaccinated IL-12
/
mice
(P < 0.01), whereas the levels of IFN-
in spleen
cells from IL-18
/
mice were comparable to those of WT
animals (Fig. 2C). Thus, an appreciable Th1 type response developed in
IL-18
/
animals after vaccination whereas
IL-12
/
mice displayed an impaired Th1 type response.

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FIG. 2.
HSV-2-specific immune responses in vaccinated WT,
IFN- / , IL-12 / , and
IL-18 / mice (n = 4 to 8). (A to C)
Spleen mononuclear cells obtained 4 weeks postvaccination were cultured
in the presence of either UV-inactivated HSV-2 or mock antigen and
analyzed for HSV-2-specific production of IFN- and IL-2. Data are
expressed as a stimulation index (A), the concentration (in picograms
per milliliter) of secreted IL-2 (B), and the concentration (in
picograms per milliliter) of secreted IFN- (C) per million analyzed
spleen cells. ND, not detected. (D) HSV-2-specific DTH reactions were
measured 4 weeks after vaccination. Results are expressed as the mean
and standard error of the mean of the HSV-2-specific DTH reaction ( mm, 102) at 48 h postchallenge. (E) Ratio of
HSV-specific IgG2a to IgG1 in WT, IFN- / ,
IL-12 / , and IL-18 / mice 4 weeks after
vaccination with attenuated HSV-2. Data are expressed as the mean and
standard error of the mean. Differences were statistically significant
at P values of <0.05 (*) and <0.01 (**) by
Student's t test compared with vaccinated WT mice.
|
|
We also examined the HSV-2-specific delayed-type hypersensitivity (DTH)
4 weeks after vaccination. The specific footpad swelling
was examined
48 h after injection of UV-inactivated HSV-2 (corresponding
to
7 × 10
6 PFU) or mock antigens in the left and right
footpads, respectively.
In IL-18
/
mice, the DTH
response was of a magnitude similar to that in
vaccinated WT mice (Fig.
2D). The IL-12
/
mice had intermediate levels of DTH
response, whereas IFN-

/
mice showed an almost
completely abolished DTH response (Fig.
2D). Thus, protection in the
vaccinated animals was associated
with a maintained capacity to mount
HSV-2-specific IFN-

responses
in vitro and DTH responses in vivo.
Our results support and extend
previous findings that IFN-

production is important in protective
immunity against genital HSV-2
infection (
13,
25,
33). However,
it was evident that an
optimal Th1 response required IL-12. These
findings are in line with
other observations implying that IFN-
production and a Th1-type
immune response can be induced during
certain viral infections even in
the absence of IL-12 (
29,
36,
44). Other factors can
compensate for the lack of IL-12. IL-18
cannot induce Th1 development
by itself (
34) but can contribute
to IFN-

response
through activation of the IFN-

promoter in
T cells (
4).
The strong Th1 immune response in IL-18
/
mice was
likely induced by IL-12 in synergy with other cytokines
such as IL-15,
tumor necrosis factor alpha, and IL-1

(
3,
7,
8,
41).
HSV-specific serum IgG was measured in sera obtained
4 weeks
postvaccination using an enzyme-linked immunosorbent assay
based on a
deoxycholate-solubilized membrane fraction of HSV-1-infected
cells
(
14). The serum levels of HSV-specific IgG antibodies
were
comparable in all groups of vaccinated mice (not shown),
but the ratio
of HSV-specific IgG2a to IgG1 varied considerably.
WT and
IL-12
/
mice had high levels of HSV-specific IgG2a
resulting in a significant
IgG2a/IgG1 ratio. IFN-

/
and IL-18
/
mice, on the other hand, had impaired
HSV-specific IgG2a levels
and thus gave a diminished IgG2a/IgG1 ratio
(Fig.
2E). To our
knowledge, the role of IL-18 as an important switch
factor for
antigen-specific IgG2a subclasses in vivo has not been
demonstrated
previously. This finding correlates with the documented
role of
NK cells in the development of an IgG2a response
(
35), as IL-18
is an important activator of NK cells
(
40).
In conclusion, our results show that IFN-

plays a key role in both
innate and acquired immunity to genital HSV-2 infection,
while IL-12
and IL-18 are important for innate but not for vaccination-induced
adaptive immunity. The latter finding raises interesting questions
about the nature of factors other than IL-12 and IL-18 that are
induced
by viral infection and contribute to the development of
protective
IFN-

production in the adaptive immune
response.
 |
ACKNOWLEDGMENTS |
We are grateful to Inger Nordström for skilled technical
assistance. We also thank Pia Axelsson for breeding the gene-targeted mice. We gratefully acknowledge Shizuo Akira and Kiyoshi Takeda, Hyogo
College of Medicine, Japan, for providing the IL-18
/
mice.
This study was supported by the Swedish Medical Research Council,
SIDA/SAREC's Special Program for AIDS and Related Diseases, The
Swedish Strategic Foundation Program in Infection and Vaccinology, Socialstyrelsens Fonder, The Swedish Society for Medical Research, Wilhelm and Martina Lundgrens Science Foundation, Magn Bergvalls' Foundation, and the LUA Foundation at Sahlgren's Hospital.
 |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Medical Microbiology & Immunology, Guldhedsgatan 10A, 413 46 Göteborg, Sweden. Phone: (46) 31-3424761. Fax: (46) 31-820160. E-mail: kristina.eriksson{at}microbio.gu.se.
 |
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Journal of Virology, July 2001, p. 6705-6709, Vol. 75, No. 14
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.14.6705-6709.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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