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Journal of Virology, September 1998, p. 7703-7706, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Identification of Nitric Oxide Synthase
2 as an Innate Resistance Locus against Ectromelia Virus
Infection
Gunasegaran
Karupiah,1,*
Jian-He
Chen,1
Carl F.
Nathan,2
Surendran
Mahalingam,1 and
John
D.
MacMicking2,
Host Defense Laboratory, Viral Engineering
and Cytokines Group, Division of Immunology and Cell Biology, The
John Curtin School of Medical Research, The Australian National
University, Canberra, ACT 2601, Australia,1 and
Beatrice and Samuel A. Seaver Laboratory, Department of
Medicine, Cornell University Medical College, New York, New York
100212
Received 28 May 1998/Accepted 17 June 1998
 |
ABSTRACT |
To assess whether nitric oxide synthase 2 (NOS2) fulfills the criteria of an innate resistance locus
against an acute viral infection, we inoculated genetically deficient
NOS2
/ mice with virulent ectromelia virus (EV), the causative agent
of mousepox. NOS2/ mice proved highly susceptible to EV yet showed
no diminution in other well-characterized anti-EV immune responses,
i.e., gamma interferon secretion and NK cell and EV-specific cytotoxic
T lymphocyte activities. Thus, the NOS2 locus can be
considered a critical monogenic determinant of EV resistance
that contributes to host survival.
| |
TEXT |
Cytokine-inducible nitric
oxide synthase 2 (NOS2) belongs to a multigene family
of heme-containing flavoenzymes catalyzing the 5-electron oxidation of
L-arginine to L-citrulline plus the cytotoxic
radical gas nitric oxide (NO) (13). Rapid transcriptional expression of NOS2 in most nucleated cell types together
with its sustained, high-output production of NO endows this enzyme with broad antimicrobial properties (13). The idea that NOS2 may subserve an important host protective function against viruses has
recently been appreciated (8, 13, 19). Evidence was first
obtained in experiments using ectromelia virus (EV), vaccinia virus
(VV), and herpes simplex virus type 1 in permissive human and mouse
cell lines rendered resistant by transfection with the NOS2
gene (11) or by pharmacologic provision of NO (3,
11). Since these initial observations were made, several other
RNA and DNA viruses have been proven sensitive to the virustatic action of NO in vitro: Epstein-Barr virus, coxsackievirus type B3 (CVB3), Friend murine leukemia virus, vesicular stomatitis virus, mouse hepatitis virus, rhinovirus, Japanese encephalitis virus, and poliovirus (references 8, 13, and
19 and references therein). Some, however, like
Sindbis and tick-borne encephalitis viruses, appear to be unaffected by
NO, while others, such as human immunodeficiency virus type 1, may even
benefit from cellular NO production (8, 13, 19).
Similarly disparate results have emerged in studies of the intact
mammalian host (8, 13, 19). The differences in disease outcome could be explained in part by experimental design, where the
results with nonspecific NOS inhibitors may also reflect the indirect
antiviral contributions of NOS1 and/or NOS3 (1, 12). In an
effort to distinguish the antiviral effects of NOS2 from those of other gene family members and establish its necessity or
redundancy, we used NOS2-null (NOS2/) mice (14). Such
mice express NOS1 and NOS3 genes normally
(14). EV-induced mousepox was chosen as the infectious model
for several reasons: (i) it is strictly subject to control by gamma
interferon (IFN-
) (10), with EV replicating in many of
the same cells capable of expressing NOS2 after activation by this and
other cytokines (e.g., fibroblasts, epithelial cells, and keratinocytes
within the exanthematous lesions of the skin and resident macrophages
and hepatocytes within infected viscera [11]); (ii) it
was the first model in which IFN--induced NOS2 was attributed a
protective role against viruses (11); and (iii) it
represents a natural host-virus relationship (10). These
features appeared to make it well suited for evaluation of the
contributions of the NOS2 gene toward virus eradication.
Adult (8- to 12-week-old) male and female NOS2/ mice
(H-2b; 129/SvEv × C57BL/6J F2)
(14) and their wild-type littermates (NOS2+/+) were bred at
the SPF Unit, John Curtin School of Medical Research, Australian
National University. They were infected intravenously (i.v.) with
virulent EV (Moscow strain) that had been propagated in BS-C-1 cells
and purified on sucrose density gradients as outlined elsewhere
(10). In some cases, both mutant and control mice were
treated daily with 5 mg of the NOS inhibitor
N
-methyl-L-arginine
(L-NMA; Sigma) or its inactive D-enantiomer (D-NMA) in 200 µl of phosphate-buffered saline
administered intraperitoneally, a regimen previously shown to be
efficacious (11). At selected times postinfection (p.i.),
aseptically removed organs were homogenized in phosphate-buffered
saline and serial dilutions were assayed for PFU on BS-C-1 cell
monolayers (10). On days 0, 3, and 6 p.i., plasma
NO3
and splenocyte
NO2 levels were also determined via nitrate
reductase-linked and -nonlinked diazotization assays (14,
15). The assay sensitivity was 4 µM for both
NO3 and NO2. At the
same times, standard 51chromium-release assays were
enlisted for the activity measurements of splenic NK cells and
cytotoxic T lymphocytes (CTL) (7, 9). YAC-1 cells were used
to measure NK cell killing, while EV-infected and uninfected MC57G
cells served as targets for the measurement of EV-specific, class I
major histocompatibility complex (MHC)-restricted CTL activity. IFN-
levels in plasma samples from infected mice and in supernatants from
2.5 × 106 EV-infected mouse splenocytes coincubated
for 48 h with 5 × 105 EV-infected,
mitomycin-treated (50 µg/ml) MC57G cells were measured by a sandwich
enzyme-linked immunosorbent assay (10). Recombinant murine
IFN- (Genzyme) served as the standard, with an assay detection limit
of 3 U/ml. Concanavalin A (ConA) was added to positive control cultures
at 4 µg/ml (Sigma, St. Louis, Mo.). For flow cytometry, the following
fluorochrome-conjugated monoclonal antibodies (MAbs) were used
for single-color analysis of 106
splenocytes: for T cells, biotinylated rat anti-CD3 (clone
145-2C11), anti-CD4 (clone GK1.5), and anti-CD8 (clone 53.6.7);
for B cells, phycoerythrin-conjugated anti-CD45R/B220 (clone RA3-6B2)
(Pharmingen, San Diego, Calif.); for macrophages, anti-F4/80 (clone
F4/80). Biotinylated primary MAbs were detected with
streptavidin-fluorescein isothiocyanate conjugate (Amersham
International, Amersham, United Kingdom). After erythrocytes and dead
cells were gated out, 
2 × 104 events were collected
via a FACScan flow cytometer by using LYSIS II software (Becton
Dickinson, San Jose, Calif.).
Heightened susceptibility of NOS2/ mice to EV infection.
At 104 or 105 PFU of EV, all NOS2/ mice
succumbed between days 5 and 10 p.i. (mean ± standard error
of the mean, 8.1 ± 0.2 or 7.2 ± 0.7 days, respectively),
while wild-type controls survived throughout the 21-day period of
observation (Fig. 1a; n = 16 to 17 per group at each dose). Only at the highest inoculum
tested (106 PFU) did the NOS2+/+ group become
vulnerable, dying at around the same time as their
NOS2-deficient counterparts (6.0 ± 0.3 and 6.2 ± 0.4 days, respectively). Markedly increased viral burdens were
found within target organs such as the spleen, liver, and lungs of mutant mice just prior to death, similar to those of NOS2+/+
mice treated daily with the NOS inhibitor L-NMA (Fig. 1b).
The latter treatment also led to early mortality at an i.v. dose of
104 PFU (7.4 ± 0.5 days, n = 5) (data
not shown). In contrast, wild-type controls given the biologically
inactive D-NMA effectively restricted virus replication, as
illustrated by the 2,511-fold reduction in liver viral titers, 100-fold
reduction in spleen viral titers, and 20-fold reduction in lung viral
titers between days 3 and 6 p.i. (Fig. 1b).
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FIG. 1.
Absence of NOS2 confers susceptibility to
primary EV infection. (a) Mortality in female NOS2+/+ or NOS2/ mice
inoculated i.v. with EV and monitored for 21 days (n = 17 per group at each dose, except for 105 PFU, in which
case 16 NOS2+/+ mice were used). Data represent three independent
experiments. (b) Viral titers in liver, lung, and spleen of
D-NMA- or L-NMA-treated NOS2+/+ and NOS2/
mice given 104 PFU of EV i.v., determined at day 3 (n = 4 per group) and 6 (n = 9 per
group) p.i. Data represent three experiments and are expressed as the
mean log10 virus titer per gram of tissue ± standard
error of the mean *, significantly different from value for
D-NMA-treated group at P < 0.01 (unpaired
t test).
|
|
C57BL/6 and 129/Sv parental inbred strains (obtained from the SPF Unit,
John Curtin School of Medical Research) displayed
identical survival
patterns as those of otherwise-resistant NOS2+/+
(129/SvEv × C57BL/6J F
2) hosts over a 10
2 to
10
6 dose range (
n = 8 per group at each
dose), except at 10
5 PFU of EV, at which dose 50% of the
C57BL/6 mice died (Fig.
1a
and data not shown). All three groups were
rendered susceptible
at the highest dose (10
6 PFU), with a
mean time to death of 6.0 ± 0.9 and 6.6 ± 0.7 days
for B6
and 129 strains, respectively, versus 6.0 ± 0.3 days seen
earlier
for NOS2+/+ 129/SvEv × C57BL/6J F
2 mice (Fig.
1a).
Further,
the administration of anti-murine IFN-
or anti-murine
CD8 T-cell-depleting
MAbs led to all three groups becoming susceptible,
as previously
established for the C57BL/6 strain (references
9 and
10 and
data not shown).
Hence, it appears unlikely that contaminating
genes derived from either
background account for the susceptibility
of hybrid NOS2
/
hosts.
Specificity of the NOS2 defect: other anti-EV responses
are intact and noncompensatory in mutant mice.
Aside from
NOS2 (reference 11 and data from the preceding
section), at least two additional components of host immunity are
thought necessary to eliminate EV: IFN- (10) and class I
MHC-restricted CD8+ CTL (9). Others belonging to
either the innate (NK1.1 cells) or acquired (class II MHC-restricted
CD4+ helper T lymphocytes) branches of the immune response
also participate, although to a lesser extent (9). Partial
protection is similarly conferred by tumor necrosis factor acting
predominantly via TNF receptor 2 (22), a process that with
IFN- may help signal NOS2 expression (13). Indeed, the
NOS2 pathway could be detected within the plasma of wild-type hosts
as early as day 3 p.i. following i.v. inoculation with
104 PFU (Fig. 2a). This was
accompanied by a ~50-fold elevation in circulating IFN- (Fig.
3c) and robust NK cell activity (Fig. 3a). Plasma NO3 levels further increased by
day 6 p.i., coincident with the decline in viral titers, at which
time NOS2 activity was readily evident in explanted splenocytes either
without (control, ConA-treated, uninfected stimulators) or with further
antigen-specific stimulation (Fig. 2b). This differed from results for
both mutant animals and wild-type mice given L-NMA (Fig.
2); the former failed to exhibit inducible
NO2 or NO3 levels,
in agreement with earlier studies of infectious disease (14,
15), while NOS2 inhibition in L-NMA-treated mice
ranged between 51 and 76% in plasma and 85 and 93% in splenocytes
during the same period (Fig. 2). However, as in
D-NMA-treated NOS2+/+ animals, NK cell activities together
with systemic and splenic IFN- release were heightened in these two
groups (Fig. 3a and c).
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FIG. 2.
EV-induced expression of the immunologically responsive
NOS2 pathway. (a) Plasma NO3 levels in
D-NMA- or L-NMA-treated NOS2+/+ mice and
NOS2/ mice during i.v. infection with 104 PFU of EV.
Symbols represent individual samples assayed in triplicate; horizontal
bars represent group means. (b) Explanted splenocyte supernatant
NO2 levels (mean ± standard error of
the mean) in the same mice left untreated (control) or incubated with
uninfected splenocytes, EV-infected stimulators, or ConA for 48 h.
Data represent two independent experiments. NT, not tested.
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FIG. 3.
Other anti-EV immune components are intact in NOS2/
mice. (a and b) Splenic NK cell activity (day 3 p.i.) (a) and
EV-specific CTL activity (day 6 p.i.) (b) in D-NMA- or
L-NMA-treated NOS2+/+ mice and NOS2/ mice infected i.v.
with 104 PFU of EV. Shown are group means
(n = 4 for each of two independent experiments);
standard errors of the means (SEMs) fall within the symbols.
Splenocytes from uninfected mice served as controls. E:T ratio,
effector/target cell ratio. (c) Plasma IFN- levels in the same mice
as those described for panels a and b. Individual samples were assayed
in triplicate; horizontal bars denote group means. (d) Explanted
splenocyte supernatant IFN- levels (mean ± SEM) under the same
conditions as those described in the legend to Fig. 2b. NT, not tested.
*, significantly different from value for D-NMA-treated
group at P < 0.01 (unpaired t test).
|
|
Generation of splenic EV-specific CTL activity was unaltered in the
absence of NOS2 at day 6 p.i. (Fig.
3b), the time at which
peak
cytolytic effector function is normally observed (
9).
The
proportions of CD8
+ T cells, macrophages, and other
lymphoid populations found within
the infected spleen at this time also
did not differ between genotypes
(Table
1). IFN-
secretion was, however,
increased in NOS2-null
hosts by 2.2- to 2.8-fold in plasma and 1.5- to
6.2-fold in splenocyte
cultures relative to those of NOS2+/+ controls
(Fig.
3c and d),
perhaps as a consequence of the increased viral load
in these
animals (Fig.
1b).
Based on our results,
NOS2 could be added to a list of
resistance loci considered important for recovery from EV infection
and
disease:
H-2Db (termed
rmp-3,
resistance to mousepox, on chromosome 17) (
17,
18), the
C5 genes (
rmp-2, on chromosome 2), and
Rmp-1 (
23),
recently localized to a region on
chromosome 6 encoding the NK
cell receptor NKR-P1 alloantigens
(
2). Two of these loci,
rmp-1 and
rmp-3, appear functionally unaltered by NOS2 deficiency, as
shown by the ability of mutant mice to mount robust NK cell and
EV-specific CTL responses. In the case of
rmp-1, which acts
before
an acquired response can be detected (
17), its
protective effects
may largely be mediated by two distinct mechanisms:
(i) direct
NK cell cytolysis (
18) of infected targets (e.g.,
hepatocytes)
(
23); and (ii) indirectly, via elicitation of
NOS2 through NK
cell secretion of IFN-
.
A requirement for NOS2 in the maturation of NK cell cytotoxicity and
innate IFN-
release has been recently posited in studies
of
Leishmania major infection in mutant mice (
4);
however,
the effect was apparent only within the first 24 h.
Thereafter,
IFN-
release reached or slightly exceeded that of
NOS2+/+ controls
at later time points (
4). We too, found
that NOS2
/
mice had
heightened IFN-
levels by day 3 in plasma
and day 6 in spleen
as EV infection continued to progress unabated.
Moreover, the
inability to control EV replication did not appear to be
due to
defects in lymphocyte or monocyte accumulation within infected
areas as shown by fluorescence-activated cell sorter analyses
of spleen
(Table
1). On the contrary, more precise measurements
of leukocyte
recruitment by using intravital microscopy have shown
that the absence
of NOS2 may, if anything, enhance this immigration
(
5).
For each of the immunologic parameters tested, as well as overall
susceptibility, the responses of wild-type mice given
L-NMA
quite closely resembled those of mice in which
NOS2 was
genetically
ablated. This contrasts with reports on the related
orthopoxvirus,
VV, in which results of genetic manipulation differed
from those
of phamacologic inhibition. In those studies, transfection
of
the
NOS2 gene restricted VV replication in vitro
(
11,
20)
and attenuated replication of
NOS2
encoding recombinant VV in
vivo (
20). Yet administration of
L-NMA failed to render B6,
CBA/H, or nude mice more
susceptible (
20,
21). In the latter
mouse strains, other
IFN-
-dependent pathways may have compensated
for the loss of NO, as
suggested by experiments in which healthy
NOS2-deficient animals
infected with VV become vulnerable once
they are treated with
anti-IFN-
antibodies (
11a). No such compensation
is
observed for EV, however, against which NOS2 appears to be
a critical,
nonredundant effector mechanism. A recent study of
CVB3 infection in
NOS2-deficient mice also showed increased viral
burdens and severe
myocarditis (
24), suggesting that the
NOS2 locus
is important for controlling CVB3 replication as well. However,
the
heightened virus susceptibility in NOS2
/
mice is not universal,
pulmonary clearance of influenza A (A/PR/8/34) virus is in fact
more
effective in mutant than in wild-type animals (
6). This
indicates a spectrum of antimicrobial activity for NOS2, one which
mirrors that now starting to emerge for other pathogens examined
in a
host selectively and completely deficient for this enzyme
(
13,
16).
| |
ACKNOWLEDGMENTS |
This work was supported by the National Centre for HIV Research
(G.K. and J.-H.C.) and National Institutes of Health grants HL51967 and
AI34543 (C.F.N.).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Division of
Immunology and Cell Biology, The John Curtin School of Medical
Research, The Australian National University, P.O. Box 334, Canberra,
ACT 2601, Australia. Phone: 61 2 6249 2627. Fax: 61 2 6249 2595. E-mail: Guna.Karupiah{at}anu.edu.au.
Present address: Laboratory of Immunology, HHMI, The
Rockefeller University, New York, NY 10021.
| |
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Journal of Virology, September 1998, p. 7703-7706, Vol. 72, No. 9
0022-538X/98/$04.00+0
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