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*
Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and
Veterans Affairs Hospital, Cincinnati, OH 45219
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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stands as a central
mediator of protective immunity to this fungus. In this study, we
explored the regulation of protective immunity by TNFR1 and -2. In
primary pulmonary infection, both TNFR1-/- and
-2-/- mice manifested a high mortality after infection
with H. capsulatum, although TNFR1-/- mice
were more susceptible than TNFR2 -/- mice. Overwhelming
infection in the former was associated with a pronounced decrement in
the number of inflammatory cells in the lungs and elevated IFN-
and
TNF- levels in the lungs. In contrast, IFN- levels were markedly
decreased in TNFR2-/- mice, and treatment with this
cytokine restored protective immunity. Lung macrophages from both
groups of knockout mice released substantial amounts of NO. Upon
secondary infection, TNFR2-/- mice survived rechallenge
and cleared infection as efficiently as C57BL/6 animals. In contrast,
mice given mAb to TNFR1 succumbed to reexposure, and the high mortality
was accompanied by a significant increase in fungal burden in the
lungs. Both IL-4 and IL-10 were elevated in the lungs of these mice.
The results demonstrate the pivotal influence of TNFR1 and -2 in
controlling primary infection and highlight the differences between
these receptors for regulation reexposure
histoplasmosis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Control of pulmonary infection with Hc is critically dependent on the
release of cytokines from T cells and myeloid lineage cells. Among the
endogenous cytokines that influence the outcome of both primary and
secondary infection, TNF- is a vital constituent of host defenses.
Blockade of endogenous TNF- is associated with overwhelming
histoplasmosis both in a model using i.v. or intranasal (i.n.)
inoculation of yeasts (2, 3, 4, 5). The mechanisms underlying
the inimical effects of mAb to TNF- differ between primary and
secondary infection. In the former, depletion of endogenous cytokine
causes a depression in NO production. In contrast, administration of
mAb to TNF- induces an increase in IL-4 and IL-10 levels, thus
causing a shift in the Th1/Th2 balance in secondary infection (4, 5).
The activities of TNF- are dependent on the expression of two
receptors, TNFR1 (p55) and TNFR2 (p75). TNF- engagement of these two
receptors either alone or in combination provokes a myriad of
biological effects including apoptosis, cytotoxicity, T cell
proliferation, shock, fever, and bone resorption (6, 7, 8, 9).
Because TNF- is such a key component of host resistance to Hc, we
examined the fate of mice that genetically lack either TNFR1 or TNFR2
following infection with this fungus. We demonstrated that the absence
of expression of either TNFR1 or TNFR2 modulates protective immunity in
primary infection. Although the outcome is similar, the cytokine
profiles of the lungs of these mice differ. In secondary
histoplasmosis, only TNFR1 is indispensable in host resistance.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TNFR1-/-, TNFR2-/-, and C57BL/6 mice (5 wk of age) were purchased from The Jackson Laboratory (Bar Harbor, ME). All animal experiments were done in accordance with the Animal Welfare Act guidelines of the National Institutes of Health.
Preparation of Hc and infection of mice
Hc yeasts were prepared as described (10). To produce infection in naive mice, animals were infected i.n. with Hc yeasts in a 30-µl volume. For secondary histoplasmosis, mice were initially inoculated with 104 yeasts i.n. Six to 8 wk later, previously exposed animals were rechallenged i.n. with 2.5 x 106 yeasts.
Organ culture for Hc
Recovery of Hc was performed as described previously (10). The fungus burden was expressed as mean CFU per whole organ ± SEM. The limit of detection is 102 CFU.
Treatment with mAb or cytokine
Endotoxin-free anti-TNFR1 mAb (clone 55R-170, hamster IgG)
was purchased from PharMingen (San Diego, CA). Mice were given 100 µg
of mAb 24 h before infection and 3 and 7 days postinfection.
Hamster IgG was purchased from Pierce (Rockford, IL). Recombinant
murine IFN- (rmIFN-) was purchased from PeproTech (Rocky Hill,
NJ). The cytokine was diluted in PBS to 5 µg/ml, and mice were
injected with 1 µg i.p. daily for 2 wk. Subsequently, mice received
0.5 µg i.p. every other day until day 30.
Isolation of mononuclear cells from lungs
To isolate mononuclear cells from lungs, mice were sacrificed and lungs were flushed with 20 ml of HBSS by inserting a catheter into the right heart. The lungs were excised and teased apart with forceps and homogenized by sequential passage through 16-gauge, 18-gauge, and 20-gauge needles. Mononuclear cells were isolated by separation on a 40–70% Percoll (Pharmacia, Piscataway, NJ) gradient (10).
FACS analysis
Lung cells were adjusted to 5 x
105/200 µl in PBS containing 2% BSA and 0.02%
sodium azide and stained with 0.5 µg of one of the following FITC- or
PE-labeled mAbs (PharMingen): anti-CD4 (clone RM4-5), anti-CD8
(clone 53-6.7), anti-Ly-6G (Gr-1; clone RB6-8C5, which recognizes
polymorphonuclear cells), or Mac-3 (clone M3/84, detects tissue
macrophages (M
) or isotype-matched rat IgG mAb). The samples were
washed and fixed in 2% paraformaldehyde until analyzed on a flow
cytometer. Because cells other than blood lineage cells were present
within the FACS analysis, the data were normalized to represent
hemopoietic lineage cells within the gate by multiplying by the
percentage of CD45+ cells. On average, the mean
percentage of CD45+ cells exceeded 90% for all
samples (10).
Reactive nitrogen intermediates (RNI) assay
Mononuclear cells from wild-type (wt) and
TNFR1-/- and -2-/- mice
(n = 6/group) were obtained on day 7 of primary
infection and were seeded at 5 x 105 cells
per well in 96-well plates in DMEM supplemented with 10% FBS.
Nonadherent cells were removed after 2 h, and monolayers were
stimulated with Escherichia coli O111:B4 LPS (Sigma, St.
Louis, MO) and rmIFN- (1 µg and 100 ng/ml respectively).
Supernatants were collected 48 h after seeding, filtered, and
nitrite was measured by Griess reaction using Cayman’s nitrate/nitrite
assay kit (Alexis, San Diego, CA).
Cytokine measurement
Lungs from infected mice (n = 5–6) were removed
on either days 5 and 7 of primary infection or days 3, 5, and 7 of
secondary infection. In primary infection, we chose to assay only on
days 5 and 7 because our earlier work indicated that there is virtually
no difference in any cytokine level between controls and experimental
groups at day 3 (5). Tissue was homogenized in 10 ml of
RPMI 1640, centrifuged at 1500 x g, filter sterilized,
and stored at -70°C until assayed. Protein concentrations between
groups did not vary for each day that was assayed (data not shown). The
protein content of the homogenates ranged from 0.91 to 2.46 mg/ml among
the various samples. Commercially available ELISA kits were used to
measure IFN-, IL-4, GM-CSF, TNF- (Endogen, Cambridge, MA),
and IL-10 (R&D Systems, Minneapolis, MN). IL-12 was assayed by sandwich
ELISA (PharMingen) specific for mouse IL-12 p70 protein. The
sensitivity was >100 pg/ml.
Histology
Lungs were removed and tissues were fixed in 10% formalin and embedded in paraffin blocks. Sections (5 µm) were stained with hematoxylin and eosin. Analysis of the sections was performed in a "blinded" fashion.
Statistics
Student’s t test was used to compare groups if the data achieved normality, otherwise the Wilcoxon rank sum test was used. Survival data was analyzed using the log rank test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TNFR1-/- and -2-/- mice and wt controls were exposed i.n. to 2.5 x 106 yeasts, which is a sublethal inoculum in wt (10, 11). All TNFR1-/- and -2-/- mice succumbed to Hc infection within a nearly identical time frame, whereas 100% the infected controls survived for 45 days (p < 0.001). In companion experiments, we determined if survival could be correlated with inoculum size. Groups of TNFR1-/- and -2-/- mice and wt controls were challenged i.n. with 104 or 105 Hc yeasts and followed for up to 45 days. All TNFR2-/- and wt mice survived for 45 days (p > 0.05). At this time, mice were sacrificed and assessed for fungal burden. Lungs and spleens from both groups contained <200 CFU, the limit of detection. In contrast, all TNFR1-/- mice (n = 8/group) expired following exposure to either inoculum. The mean survival time was 25 ± 4 days (p < 0.001) and 20 ± 5 days (p < 0.001) for the 104 and 105 inocula, respectively.
To ensure that the knockout mice were not becoming ill merely from exposure to the environment, groups (n = 5) of uninfected TNFR1-/- and -2-/- mice were observed for 30 days. None of the mice demonstrated signs of illness such as weight loss, huddling, or ruffled fur.
We determined if the absence of TNFR1 or -2 influenced the course of
secondary infection. TNFR2-/- mice and wt
controls were exposed to 104 yeasts i.n. and 8 wk
later challenged with 2.5 x 106 yeasts.
TNFR1-/- mice were extremely susceptible to Hc;
even treatment with amphotericin B, 5 mg/kg, three times per week
failed to sterilize tissues, and mice succumbed to overwhelming
histoplasmosis. Accordingly, C57BL/6 mice were immunized with
104 yeasts, and they were given 100 µg mAb to
TNFR1 i.p. 24 h before infection and 3 and 7 days postinfection.
This dosage of mAb to TNFR1 was sufficient to block the effects of
LPS-mediated death in mice (Ref. 12 and data not shown).
Upon reexposure to Hc, all mice administered mAb to TNFR1 expired,
whereas infected controls and TNFR2-/- mice
survived for 45 days (Fig. 1
B).
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To assess if mortality of knockout mice or mAb to TNFR1 recipients
was associated with a higher fungal burden, CFU were determined in
lungs and spleens of wt, TNFR1-/-, and
-2-/- mice exposed to 2.5 x
106 yeasts. At day 7 of primary infection, the
number of CFU in the lungs of either knockout strain was dramatically
higher (p < 0.001) than in lungs of wt
controls (Fig. 2A). The burden
in lungs of TNFR1-/- mice exceeded
(p < 0.001) that of
TNFR2-/- mice. In spleens, fungal recovery
differed (p < 0.01) between wt and
TNFR1-/- and between
TNFR2-/- and wt mice (p
< 0.001) (Fig. 2B).
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, A and
B). On day 45, all survivors were sacrificed, and lungs and
spleens were assessed for fungal burden. No CFU (<200) were detected
from either TNFR2-/- or wt animals. The burden
of Hc in lungs and spleens of mice administered mAb to TNFR1 at day 7
of infection was markedly elevated (p < 0.01)
when compared with infected controls (Fig. 3, C and
D).
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Lung cells from wt, TNFR1-/-, and
TNFR2-/- mice were analyzed 7 days
postinfection to determine whether there was perturbation in the
infiltration of cell populations into mice. There was a striking
decrement (p < 0.01) in the total number of
lung cells from TNFR1-/- mice as compared with
wt or TNFR2-/- animals (Table I). Nevertheless, the proportion of cells
expressing CD4, CD8, Gr-1, or Mac-3 did not differ among the
groups.
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). Histopathology of lungs of mice infected with Hc
Lung tissue of infected wt, TNFR1-/-, and -2-/- mice was examined at week 1 of primary infection to determine whether the inflammatory response to Hc differed among these three groups. Mild to moderate perivascular lymphoid cuffing was observed in lung parenchyma of infected controls. An admixture of neutrophils and granulomatous inflammation was present involving between 30% and 60% of the lung tissue.
In lungs of TNFR1-/- mice, there was a severe pneumonitis with destruction of nearly all the pulmonary architecture. Cellular infiltration, which was less than in controls, consisted predominantly of neutrophils and mononuclear phagocytes. Lymphocyte cuffing was limited to the perivascular and peribronchiolar regions. Analysis of lungs from TNFR2-/- animals demonstrated a severe pneumonitis with 50–75% destruction of the normal architecture. The infiltrate consisted primarily of neutrophils and mononuclear phagocytes, but lymphocyte cuffing of perivascular and peribronchiolar regions was less prominent than in TNFR1-/- mice. Granulomatous inflammation was present in both groups of knockout mice.
Lung tissue from rechallenged mice was examined on day 7 of infection.
In mice given hamster IgG, there was moderate to severe peribronchial
infiltration of a similar number of lymphocytes and M. Only a few
neutrophils were present in lungs. Granulomatous inflammation involved
20–30% of lung tissue. In mice given mAb to TNFR1, fewer cells were
present in lungs, but there was an equal admixture of lymphocytes and
mononuclear phagocytes. Neutrophils were sparse. The extent of
granulomatous inflammation ranged from 30 to 50% of the pulmonary
parenchyma.
Cytokine analysis of lungs from Hc-infected animals
Wt, TNFR1-/-, and
TNFR2-/- mice were infected with Hc, and lungs
were assayed for the presence of IFN-, TNF-, GM-CSF, and IL-4,
-10, and -12 on days 5 and 7 of infection. These cytokines were
selected because of their known immunomodulatory effects on the course
of Hc infection (4, 5, 11, 13, 14). Lungs of
TNFR1-/- mice contained exceedingly higher
levels of IFN- than those of infected controls or of
TNFR2-/- mice (p <
0.005) on days 5 and 7. IFN- levels in lungs of
TNFR2-/- mice were substantially lower than
that found in infected controls (p < 0.01) on
both time points (Fig. 4). TNF- levels
were higher in TNFR1-/- mice than in infected
controls or TNFR2-/- mice only on day 5
(p < 0.01). GM-CSF, IL-12, IL-4, and IL-10
levels did not vary significantly among the groups
(p > 0.05).
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and GM-CSF did not differ (p > 0.05)
from that of infected controls. IFN- levels in lungs of mice given
mAb to TNFR1 were significantly greater (p <
0.05) than infected controls on days 5 and 7. IL-4 and IL-10 levels
also were increased (p < 0.01) on days 5 and 7
postinfection (Fig. 5).
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from TNFR1-/- and
-2-/- mice
Generation of NO is crucial for the development of protective
immunity in primary infection with Hc (5, 13). To
determine whether mortality in TNFR1-/- and
-2-/- mice was accompanied by a decrement in
release of RNI, lung M from mice infected for 7 days were incubated
with or without LPS and IFN-, and NO was measured. Cells from each
group of mice released NO above that found in unstimulated cells. The
responses by TNFR2-/- lung M stimulated with
LPS plus IFN- exceeded (p < 0.01) those of
cells from wt or TNFR1-/- mice (Table II). A comparison of NO release by
TNFR1-/- and wt M revealed no differences
(p > 0.05).
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alter the course of histoplasmosis in
TNFR2-/- mice?
Endogenous IFN- is requisite for control of primary infection
with Hc in mice (11, 13). The depressed levels of IFN-
in TNFR2-/- mice raised the possibility that
this deficiency contributed to the aggressive course of infection.
Therefore, we sought to determine whether exogenous administration of
this cytokine might restore the protective immune response.
TNFR2-/- mice were administered 1 µg of
rmIFN- i.p. or an equal volume of PBS daily. At day 7 of infection,
mice were sacrificed and CFU were determined. There were no differences
(p > 0.05) in CFU in lungs or spleens between
the two groups (Fig. 6). Separate groups
of mice treated with IFN- or diluent were followed for survival. All
mice receiving diluent died by day 14. Administration of rmIFN-
prolonged survival over a 30-day observation period; 67% of them
survived (p < 0.01). At day 30, the survivors
were sacrificed, and lungs and spleens were assessed for Hc CFU. The
number of CFU in lungs ranged from 3 x 102
to 2 x 103 CFU and in spleens from
102 to 103 CFU.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in the generation of a protective immune response in mice
exposed to Hc either i.v. or i.n. (2, 3, 4, 5, 15). In this
study, we have examined the influence of TNFR in regulating the
generation of a protective immune response in primary and secondary
pulmonary infection. The absence of either TNFR1 or -2 abrogated
effective control of primary infection in mice exposed to 2.5 x
106 yeasts. In primary infection, mice deficient
in TNFR1 are susceptible to a number of microbes including
Mycobacterium tuberculosis, Candida albicans, Leishmania major,
Toxoplasma gondii, Listeria monocytogenes, and Streptococcus
pneumoniae (16, 17, 18, 19, 20, 21, 22). In contrast,
TNFR2-/- mice control T. gondii and
L. major (18, 20), but manifest a slight but
increased susceptibility to L. monocytogenes and C.
albicans (8, 17). These results contrast with the
present findings. TNFR2-/- mice were as
vulnerable as TNFR1-/- to a sublethal challenge
with Hc. The relative significance of the two receptors could only be
discriminated when we challenged mice with very low inocula of this
fungus. Unlike the findings in other experimental models, the data
indicate that signaling through TNFR2 is critically important for
limiting Hc.
Resistance to primary Hc infection requires the development of a
Th1-type response that includes production of IL-12 and IFN-
(10, 11, 13, 15). We have demonstrated that neutralization
of TNF- did not diminish generation of either of these cytokines. In
fact, IFN- levels in the lungs of mice given mAb to TNF- were
elevated compared with controls (5). Unexpectedly, the
absence of TNFR1 or TNFR2 resulted in discordant generation of IFN-
levels in the lungs. TNFR1-/- infected with Hc
produced markedly elevated levels of this cytokine as compared with
controls. Likewise, TNFR1-/- mice infected with
L. major develop a Th1 response (18). In
contrast, TNFR2-/- mice failed to make an
appropriate Th1 response; IFN- levels were markedly diminished
compared with controls and to TNFR1-/- animals,
but the blunted levels of IFN- were not caused by poor production of
IL-12. The biological significance of impaired IFN- levels was
attested to by demonstrating that rmIFN- treatment of
TNFR2-/- mice restored protective immunity to
67% of animals. The salutary effects of this cytokine required
prolonged treatment because no differences in CFU were apparent between
the two groups at day 7 of infection.
Recent evidence suggests that TNF- can promote activation of the
IFN- signaling complex. Elaboration of IFN- is dependent on
activation of Jak-1 and -2 and phosphorylation of STAT1 (23, 24). TNF- treatment increases Jak-2 kinase activity and STAT1
phosphorylation (25). Murine TNF- induces Jak-1 and -2
activity and phosphorylation of STAT1, -3, -5, and -6, and the
bioactivity of TNF- is mediated by TNFR1 (26). In Hc
infection, TNFR2 seems to be key in the generation of the appropriate
signals to synthesize IFN-. Although the nature of this interaction
remains to be elucidated, the current findings support the contention
that there is a link between TNFR and IFN- production.
Hc-immune mice that were treated with mAb to TNF- manifested
increased susceptibility to infection in conjunction with elevated
levels of IL-4 and IL-10 in their lungs (5). The inimical
consequences of these increases was mitigated by treating
TNF--neutralized mice with mAb to IL-4 and IL-10 (5).
The present findings define the influence of TNFR1 in both the
regulation of protective immunity and the generation of elevated levels
of IL-4 and IL-10 in secondary infection. Blockade of TNFR1 by
mAb led to excess mortality and increased levels of IL-4 and -10 in the
lungs of rechallenged mice. One potential explanation for the
dichotomous influences of TNF- and IL-4 and -10 in Hc infection is
modulation of apoptosis. In certain models of mycobacterial infection,
apoptosis promotes host resistance (27, 28, 29). A postulated
mechanism is that uptake of apoptotic bodies containing viable
organisms by uninfected phagocytes triggers a signal cascade that
promotes growth inhibition. IL-10 and IL-4 oppose the
apoptosis-inducing effect of TNF- (28, 29).
Conceivably, the lack of TNF- or an inability to signal through
TNFR1 combined with increases in IL-4 and IL-10 reduce apoptosis in Hc
infection, thus exacerbating infection.
TNF- exerts proinflammatory activity either directly or through
regulation of chemokine synthesis (30, 31), and expression
of TNFR may influence the character of the inflammatory response.
TNFR1-/-/2-/- mice
exhibit reduced inflammation in immune complex uveitis
(32). Conversely, TNFR1-/- mice
mount a vigorous inflammatory response in Escherichia coli
pneumonia (33). Analysis of inflammatory cell constituents
recovered from lungs of TNFR1-/- mice or those
given mAb to TNFR1 revealed a marked depression in the absolute number
of cells as compared with controls or TNFR2-/-
mice. However, the proportion of cell subpopulations was similar
between controls and TNFR1-/- mice or those
given mAb to TNFR1. These results were surprising in light of our
previous findings in which mice treated with mAb to TNF- did not
manifest any pronounced differences in either the numbers or
proportions of cells expressing CD4+, CD8+,
Gr-1+, or in the number of M (5). These
data clearly expose an apparent dichotomy between the ability of TNFR1
and TNFR2 to evoke inflammation.
TNF- is reported to be necessary in some models for generation of
granulomatous inflammation (34, 35). We have demonstrated
that in TNF--neutralized mice, the character of the inflammatory
response to Hc was similar to that of infected controls as measured
histopathologically (5). In primary infection, analysis of
the lung pathology in TNFR1-/- and
2-/- mice revealed the presence of
granulomatous inflammation, although the extent of the inflammation was
more pronounced than in infected controls. Similarly, the inflammatory
response in Hc-immune mice given mAb to TNFR1 was similar to that of
controls. Thus, the absence of a functional TNFR did not perturb the
development of granulomatous inflammation in response to this fungal
pathogen.
There exists a paradox between the severity of the lung pathology in TNFR1-/- mice or those given mAb to TNFR1 and the reduced number of inflammatory cells. The quantity of obliterated lung tissue was not commensurate with the number of cells recovered from lungs. The altered architecture may have been a consequence of cells that express a heightened activation state in an attempt to control the increased burden of Hc. The toxic products of neutrophils and mononuclear phagocytes (e.g., oxygen radicals and/or nitrogen intermediates) may harm the host more than Hc. This contention is supported by the finding that Hc survives the respiratory burst (36). An additional possibility is that the increased number of Hc in the TNFR1-/- mice or those given mAb to TNFR1 contributed to the disrupted lung architecture.
Generation of NO is a major host resistance mechanism for primary but
not secondary infection with Hc and TNF- is requisite for synthesis
of optimal amounts (4, 5). Hence, we determined if
production of NO was modulated in TNFR1-/- or
-2-/- mice. Lung M from either knockout
strain released amounts of NO comparable to or exceeding those of
infected controls. Others have found that NO production is not impaired
in TNFR1-/- or
TNFR1/2-/- mice who are chronically infected
with T. gondii or who are exposed to L. major
(18, 19). Conversely, in acute toxoplasmosis, NO release
is diminished in TNFR1-/- mice
(20). The findings herein were unexpected because blockade
of TNF- was accompanied by diminished NO generation by alveolar M
in response to LPS plus IFN- (5). Moreover,
TNFR2-/- mice release NO in the absence of a
vigorous IFN- response. Collectively, the results suggest that
impaired NO production requires either the absence of both TNFR or a
lack of appropriate signals for these receptors or both.
One explanation for the differences in NO production between mice
treated with mAb to TNF- and TNFR1-/- or
TNFR2-/- mice is that alveolar M were
assayed in the former and parenchymal M were analyzed in the
knockout mice (5). This consideration is unlikely because
parenchymal M from Hc-infected mice given mAb to TNF- also
manifest depressed NO release. For example, the mean µM of
NO2 from lung leukocytes of 1-wk-infected mice
(n = 6) given rat IgG stimulated with LPS plus IFN-
(48.3 ± 6.2) was more (p < 0.01) than
that from cells of infected mice (n = 6) treated with
mAb to TNF- (8.3 ± 1.7) (R. Allendoerfer and G.
Deepe, unpublished observations).
In summary, we have delineated the relative importance of TNFR1 and -2
on control of pulmonary histoplasmosis. Our data demonstrate that the
absence of either receptor renders mice susceptible to primary
infection. Differences in the mechanisms of susceptibility to primary
infection were identified between TNFR1-/- and
TNFR2-/- mice. The former manifested a marked
impairment in the quantity of inflammatory cells within the lungs.
Overwhelming Hc infection in naive TNFR2-/- was
associated a reduced generation of IFN-. Only TNFR1 is required for
maintenance of secondary immunity. Blockade of this receptor results in
disease exacerbation and increases in IL-4 and -10. These findings
provide a greater understanding of the influence of TNF- on host
resistance to Hc.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. George S. Deepe, Jr., Department of Medicine, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0560.
3 Abbreviations used in this paper: Hc, Histoplasma capsulatum; i.n., intranasal; M, macrophage; RNI, reactive nitrogen intermediates; wt, wild type; rm, recombinant murine.
Received for publication March 28, 2000. Accepted for publication June 14, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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