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and Its Receptor CCR1 Control Pulmonary Inflammation and Antiviral Host Defense in Paramyxovirus Infection
*
Department of Pediatrics, State University of New York Upstate Medical University, Syracuse, NY;
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Department of Biological Sciences, University of Warwick, Coventry, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(MIP-1). Here we
examine the role of MIP-1 in the pathogenesis of this disease using
mice deficient in MIP-1 or its receptor, CCR1. The inflammatory
response to PVM in MIP-1-deficient mice was minimal, with 
10–60
neutrophils/ml and no eosinophils detected in bronchoalveolar lavage
fluid. Higher levels of infectious virus were recovered from lung
tissue excised from MIP-1-deficient than from fully competent mice,
suggesting that the inflammatory response limits the rate of virus
replication in vivo. PVM infection of CCR1-deficient mice was also
associated with attenuated inflammation, with enhanced recovery of
infectious virus, and with accelerated mortality. These results suggest
that the MIP-1/CCR1-mediated acute inflammatory response protects
mice by delaying the lethal sequelae of
infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To study the antiviral effects of eosinophils and their secretory
RNases in vivo, we have extended our studies to investigate the
inflammatory responses of mice to infection with pneumonia virus of
mice (PVM). PVM is a paramyxovirus, subfamily pneumovirus, that
naturally targets a rodent host (17, 18, 19) and replicates
many of the acute inflammatory responses described for RSV in humans
(20, 21). Easton and colleagues (22, 23, 24, 25) have
characterized the genome of this virus, documenting similarities in
gene order and among specific primary sequences and demonstrating that
PVM is the phylogenetically nearest known relative of RSV. They have
also demonstrated that BALB/c mice are readily infected by intranasal
inoculation with PVM strain J3666 (20). We have
characterized the inflammatory response to this virus in mice, which
includes prominent pulmonary eosinophilia and neutrophilia. We also
noted elevated local production of the chemokine, macrophage
inflammatory protein-1 (MIP-1), which suggested a molecular
mechanism for the observed cellular response (21).
MIP-1 is a member of the CC subfamily of chemokines and is a
chemoattractant for neutrophils and eosinophils in vitro as well as in
several mouse models of disease (26, 27, 28, 29). MIP-1 has
been detected in response to RSV infection both in tissue culture
(7, 11) and in human subjects (11, 30, 31).
Cook et al. (32, 33) have generated a MIP-1-deficient
gene-deleted mouse strain that displays reduced inflammatory response
to infection with influenza virus. Similarly, Salazar-Mather et al.
(34) have described reduced inflammatory and protective
responses in livers of MIP-1-deficient mice infected with murine
cytomegalovirus. The major receptor for MIP-1 on neutrophils and
eosinophils is CCR1 (35, 36, 37, 38, 39, 40); Gao et al. (41)
have generated a CCR1-deficient gene-deleted mouse strain that
responded to infection with the fungus, Asperigillus
fumigatus, with accelerated mortality. Gerard et al.
(42) described a second CCR1-deficient mouse strain that
also demonstrated a role for this receptor in systemic inflammatory
responses.
In this work, we examine the role of MIP-1 and its receptor
CCR1 in promoting and sustaining the inflammation observed in mice in
response to infection with PVM. In experiments performed with either
the MIP-1 or CCR1 gene-deleted mouse strains, we found that both
elements were crucial for recruiting the vast majority of the
neutrophils and all of the eosinophils that accumulated in response to
infection with PVM. Furthermore, deficiency of either MIP-1 or CCR1
resulted in recovery higher levels of infectious virus during the
course of active infection compared with fully competent mice, and that
deficiency of CCR1 correlated with reduced survival of PVM-infected
mice. These data suggest that the antiviral inflammatory response
protects mice from the lethal sequelae of viral infection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male and female mice (6–20 wk old) were used in all
experiments. C57BL/6 mice with a targeted disruption of the gene
encoding MIP-1-/- described by Cook et al.,
(32) were obtained from The Jackson Laboratory (Bar
Harbor, ME). Mice with a targeted disruption of the gene encoding CCR1
(CCR1-/-) and littermate controls
(CCR1+/+) described by Gao et al.
(41) were backcrossed to the C57BL/6 background for six
generations and are maintained at the National Institutes of Health.
Stocks of PVM (strain J3666) at 3 x 105
PFU/ml were stored in liquid nitrogen. All procedures were reviewed and
approved by the National Institutes of Health Animal Welfare Review
Board (protocol LHD8E).
Establishing lower respiratory tract infection
To facilitate infection, mice were placed under anesthesia
for 1 min by inhalation of 15% halothane (Ayerst Laboratories,
Philadelphia, PA) diluted in mineral oil. Mice infected with PVM
received a single intranasal dose of 80 µl containing varying amounts
of virus (10- 200 PFU) diluted from concentrated stocks in IMDM (Life
Technologies, Gaithersburg, MD). Mice described as "uninfected"
were inoculated with 80 µl IMDM; mice contributing to "day 0"
points were not inoculated.
Examination of the lung tissue: microscopic analysis, ELISA, and determination of viral titer
Lungs to be sectioned for microscopic analysis were
inflated transbronchially with 0.3 ml 10% formalin before removal
from the body cavity. Inflated lungs were fixed in 10% formalin before
sectioning, slide preparation, and staining with standard hematoxylin
and eosin stains (American Histolabs, Gaithersburg, MD). Lungs to be
processed for ELISA and viral titer determination were removed from the
body cavity under aseptic conditions and immersed in prechilled tissue
culture medium (IMDM). Lung tissue was homogenized (Tissumizer, Tekmar,
Cincinnati, OH), and cellular debris was removed by low speed
centrifugation. Clarified supernatants were flash frozen in a dry
ice-ethanol bath and stored at -80°C. Viral titers were determined
by standard plaque assay using the BS-C-1 epithelial cell line
(American Type Tissue Collection, Manassas, VA). MIP-1
concentrations in homogenized lung tissue were determined by ELISA
(Quantikine, R&D Systems, Minneapolis, MN) according to the
manufacturer’s instructions. Total protein was determined by the
Bradford colorimetric assay.
Isolation and analysis of bronchoalveolar lavage (BAL) fluid
After dissection to expose the trachea and lungs, the lungs were inflated transbronchially with 0.8 ml PBS containing 0.25% BSA. The fluid was collected and the process was repeated, with a recovery of 1.2–1.5 ml bronchial washings per mouse. Total cells were determined by either hemocytometer counts or, in the cases in which very few cells were recovered, from direct counts from cytospin preparations. Differential leukocyte counts were assessed by visual inspection of Diff-Quik-stained cytospin preparations. CD8+ lymphocyte counts were assessed by fluorescent microscopic inspection of cells stained with polyclonal rabbit anti-CD8 (H-160, Santa Cruz Biotechnology, Santa Cruz, CA) followed by TRITC-tagged goat anti-rabbit IgG (Pierce, Rockford, IL).
Statistical analysis
All data points represent the average ± SEM of samples from 2–3 mice unless otherwise indicated. Statistical significance was determined by paired and unpaired Student t tests.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In previous work, we described the infection of 6- to 8-wk-old
BALB/c mice with PVM strain J3666, and identified pulmonary
eosinophilia as an early response to PVM infection. This inflammatory
response was accompanied by local production of the leukocyte
chemoattractant MIP-1 (21). We show here that wild-type
C57BL/6 mice responded to this virus in a similar fashion. The data in
Table I
demonstrate that lethal infection
in C57BL/6 mice was established with as few as 20 PFU of virus.
Furthermore, the time elapsed between inoculation and the onset of
death (ultimately reaching 100% mortality in all cases shown) was
directly related to the viral titer in the inoculum in a manner similar
to that shown for BALB/c mice. Likewise, the lower respiratory tract
infection established in C57BL/6 mice was accompanied by eosinophil and
neutrophil recruitment (see below) and by local production of MIP-1
(Table II).
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in the pathogenesis of PVM infection
Levels of MIP-1 were measured in lung homogenates of
MIP-1+/+ and
MIP-1-/- mice that were inoculated
intranasally with PVM (200 PFU). No MIP-1 was detected in lung
homogenates of either +/+ or -/- mice before inoculation (day 0;
Table III). At days 4 and 5
postinoculation, MIP-1 was detected in lung homogenates from all
+/+, but not from any of the -/- mice.
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Tissue sections of lung from MIP-1+/+ and
MIP-1-/- mice harvested on day 3 after
inoculation with 200 PFU PVM are shown in Fig. 1. As early as day 3 after inoculation,
we observed numerous inflammatory foci in the lungs of the
MIP-1+/+ wild-type mice (Fig. 1A).
A higher power view of this field is shown in Fig. 1B; two
of the many eosinophilic leukocytes recruited to this inflammatory
focus are indicated by arrows. In contrast, no inflammatory foci were
observed in sections of lung tissue prepared from infected
MIP-1-/- mice (Fig. 1C).
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An analysis of total leukocytes and leukocyte subpopulations
recruited to the lungs of MIP-1+/+ and
MIP-1-/- mice in response to infection with
PVM is shown in Table IV. The
inflammatory response in the MIP-1+/+ mice was
rapid and sustained, with >106 leukocytes/ml
detected in BAL fluid harvested on day 3, remaining elevated through
day 6. The predominant cell type at all time points tested is the
neutrophil (polymorphonuclear leukocyte), although lymphocytes are
present in significant numbers at days 3 and 6 postinoculation. From 10
to 15% of the lymphocytes detected at day 3 in wild-type mice were
CD8+. Interestingly, the absolute eosinophil
count varied substantially during the course of infection. The number
of eosinophils present in the lungs rises from virtually 0 to 1.4
x 105/ml between days 2 and 3 postinoculation
(at which point they represent 10% of the total leukocyte count),
and then declines rapidly 10-fold (to 104/ml)
by day 6 (p < 0.05). In contrast, only a
minimal inflammatory response was observed in the PVM-infected
MIP-1-/- mice. Only 50 total leukocytes
were detected in 1 ml BAL fluid harvested from
MIP-1-/- mice on day 3 postinoculation, a
number that likewise remained stable thereafter. Virtually all the
cells accumulating in response to infection in the
MIP-1-/- mice were neutrophils; few
lymphocytes and no eosinophils were detected in any of the samples
evaluated. Interestingly, eosinophils can be elicited in normal numbers
in response to i.p. thioglycolate treatment of
MIP-1-/- mice (data not shown).
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Viral titers (PFU PVM x 106/g)
recovered from lungs harvested from MIP-1+/+
and MIP-1-/- mice on days 3, 4, and 5 after
inoculation with 200 PFU PVM are shown in Fig. 2. Statistically significant differences
were observed at day 5 after inoculation, with recoveries
calculated at 1.4 ± 0.08 x 106 PFU/g
from MIP-1+/+ mice and 11 ± 2 x
106 PFU/g from
MIP-1-/- mice (p <
0.05).
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As shown in Table V, the CCR1 ligand
MIP-1 was present in lung homogenates from
CCR1+/+ and CCR1-/- mice
infected with 200 PFU PVM. MIP-1 expression was somewhat delayed in
the CCR1-/- mice, although the peak response
observed exceeded that of their CCR1+/+
counterparts. Although the significance of this observation remains
unclear, we can conclude that both CCR1+/+ and
CCR1-/- mice are able to generate this
proinflammatory mediator in response to viral infection.
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An analysis of total leukocytes and leukocyte subpopulations
recruited to the lungs in CCR1+/+ and
CCR1-/- mice in response to infection with PVM
is shown in Table VI. As anticipated from
earlier results (Table IV
), the peak leukocyte count in
CCR1+/+ mice (5 x
105/ml) was sustained through day 5 and was
composed of predominantly neutrophils, with eosinophils peaking
(10%) at day 3, and 10% of the lymphocytes as
CD8+. Similar to the observations made with the
MIP-1-/- mice, the peak leukocyte count in
the CCR1-/- mice was dramatically reduced
(>103-fold to 150 cells/ml total) and
eosinophils were not detected.
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Viral titers (PFU PVM x 107/g)
recovered from lungs harvested from CCR1+/+ and
CCR1-/- mice on days 3, 4, and 5 after
inoculation with 200 PFU PVM are shown in Fig. 3. Statistically significant differences
were observed at two of the three time points, with recoveries
calculated at 0.8 ± 0.12 x 107 and
5.2 ± 1.6 x 107 PFU/g from
CCR1+/+ mice and 19 ± 5 x
107 and 41 ± 14 x
107 PFU/g from CCR1-/-
mice on days 4 and 5 postinoculation, respectively
(p < 0.05).
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When CCR1-/- and age-matched
CCR1+/+ littermates were each infected with 10
PFU PVM, the first death of the CCR1-/- group
occurred on day 6, with an average time until death calculated to be
7.8 ± 0.48 days after inoculation (Fig. 4). The first death of the
CCR1+/+ group occurred on day 8, with an average
time to death calculated at 9.2 ± 0.42 days
(p < 0.001). These results suggest a
protective function for CCR1 in antiviral host defense, most likely due
to its role in recruiting eosinophils and neutrophils to the lung
during the earliest stages of acute viral infection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is a major determinant
of the inflammatory response to PVM in mice, apparently acting via its
receptor CCR1 on eosinophils and neutrophils. The presence of MIP-1
demonstrates a striking parallel between PVM infection in mice and
acute RSV infection in humans, in that several groups have detected
MIP-1 in supernatants of RSV-infected cultured epithelial cells
(7, 11), and MIP-1 has been detected in both upper
(30, 31) and lower respiratory tract secretions (7, 31) of infected children.
The inflammatory response to paramyxovirus infection is generally
considered to be an unnecessary and unwanted physiologic response
serving solely to exacerbate the disease process. We show here that
MIP-1-induced inflammation may be a protective response, as the
absence of MIP-1 was associated with increased yields of infectious
virus from lung tissue compared with those obtained from
MIP-1-competent mice. Specifically, on days 4 and 5 after
inoculation with 200 PFU PVM, lung homogenates from the
MIP-1-/- mice contained 10 times as many
infectious virions as did those of their fully competent counterparts.
This observation suggests that the inflammatory response promoted by
MIP-1 may have a role in blunting viral replication the earliest
stages of this infection.
The studies focusing on CCR1, the major receptor for MIP-1 expressed
in both eosinophils and neutrophils (36, 37, 41), support
the notion of a protective role for the inflammatory response to PVM.
Similar to what we observed with the
MIP-1-/- mice, BAL fluid samples from
infected CCR1-/- mice contained
103 fold fewer neutrophils than did those from
their infected CCR1+/+ littermates, and they were
devoid of eosinophils. Interestingly, Gao et al. (41)
reported that eosinophil recruitment proceeds normally in
CCR1-/- mice with schistosome-induced
granulomata. Taken together, these results demonstrate the existence of
distinct CCR1-dependent and CCR1-independent pathways for eliciting
tissue eosinophilia in vivo, analogous to those described for CCR3 in
vitro (43). Other ligands recognized by CCR1 include
RANTES and MCP-3. Several groups have demonstrated that human
epithelial cells synthesize and secrete RANTES in response to RSV
infection (7, 8, 9, 10, 11), and RANTES has been detected in
response to RSV infection in upper and lower respiratory tract samples
in several clinical studies (7, 30, 31). However, we have
shown previously that RANTES is synthesized constitutively in mouse
lung, with no modulation seen in response to PVM infection
(21). In contrast, Becker et al. (10)
reported that no detectable MCP-3 was produced in response to RSV
infection in primary human bronchial epithelial cells; to the best of
our knowledge, MCP-3 has not been associated with this infection either
in vitro or in vivo.
Similar to our findings with MIP-1-/- mice,
deficiency of CCR1 and the concomitant reduction in pulmonary
inflammation are also associated with an increased yield of virus from
lung tissue. Furthermore, we have shown that the presence of CCR1 and
the CCR1-mediated inflammatory response correlate with prolonged
survival of PVM-infected mice. Specifically, the average time to death
of CCR1-/- mice inoculated with 10 PFU PVM on
day 0 was found to be 7.8 ± 0.48 days; the average time to death
of their CCR1+/+ littermates was 9.2 ± 0.42
(p < 0.001). Although we cannot be certain
that there is a direct causal relationship, these results indicate a
strong correlation between prolonged survival and the ability to mount
an acute inflammatory response to infection with PVM. This result is
most interesting in light of the recent findings of Uzel et al.
(44) documenting the enhanced risk and severity of RSV
infection in individuals with genetic defects in cellular inflammatory
responses.
Although antiviral activities of CD8+ cells
(24, 45) and neutrophils and their components (44, 46, 47, 48, 49) have been discussed in the literature, we are
particularly interested in the contribution of eosinophils to host
defense against respiratory viral pathogens. We have shown in our
earlier work that human eosinophils can reduce the infectivity of
respiratory syncytial virus in vitro, an activity that is directly
dependent on the activity of their unique secretory RNases, EDN and
eosinophil cationic protein (13, 14, 15, 16). Consistent with this
observation, Adamko et al. (50) reported impaired recovery
of virions of the paramyxovirus, parainfluenza virus type 3, from the
eosinophil-enriched lungs of allergen-sensitized guinea pigs. Given
these findings, it is interesting to focus on the dramatic differences
in eosinophil number and percentage when comparing the inflammatory
responses of both sets of +/+ vs -/- mice in our study. Specifically,
the highest eosinophil counts for both sets of +/+ mice occurred on day
3 after inoculation, peaking at 10% (1.4 x
105/ml and 0.42 x
105/ml; Tables IV and VI, respectively). In
contrast, no eosinophils (0%, 0 cells/ml) were detected in any BAL
fluid samples from either the MIP-1-/- or
the CCR1-/- mice. Although the large reduction
in the number of neutrophils precludes any strong conclusions on the
role of eosinophils in antiviral host defense, it remains possible that
some (if not all) of the enhanced recovery of infectious virions and
the earlier demise of the CCR1-/- mice may be
attributable to the absence of these eosinophils. To the best of our
knowledge, this is also the first study to provide genetic evidence
linking MIP-1 and CCR1 to eosinophilic inflammation in
vivo.
In conclusion, our results indicate that MIP-1 and its specific
receptor CCR1 are host factors contributing to the inflammatory
response to paramyxovirus infection in the lung as well as to control
of viral replication and to the rate of disease progression. Moreover,
our results suggest that leukocyte recruitment to the lung is
beneficial in that it controls both the viral burden and clinical
outcome. Additional work will be needed to define specific roles of
neutrophils and eosinophils in the pathogenesis of pulmonary infection
by paramyxoviruses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Helene F. Rosenberg, Laboratory of Host Defenses, Building 10, Room 11N104, National Institute of Allergy and Infectious Diseases/National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892.
3 Abbreviations used in this paper: RSV, respiratory syncytial virus; EDN, eosinophil-derived neurotoxin; PVM, pneumonia virus of mice; MIP-1, macrophage inflammatory protein-1; BAL, bronchoalveolar lavage; MCP-3, monocyte chemoattractant protein-3.
Received for publication February 15, 2000. Accepted for publication June 20, 2000.
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C. Cataisson, E. Joseloff, R. Murillas, A. Wang, C. Atwell, S. Torgerson, M. Gerdes, J. Subleski, J.-L. Gao, P. M. Murphy, et al. Activation of Cutaneous Protein Kinase C{alpha} Induces Keratinocyte Apoptosis and Intraepidermal Inflammation by Independent Signaling Pathways J. Immunol., September 1, 2003; 171(5): 2703 - 2713. [Abstract] [Full Text] [PDF]
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A. Panoskaltsis-Mortari, J. R. Hermanson, E. Taras, O. D. Wangensteen, J. S. Serody, and B. R. Blazar Acceleration of idiopathic pneumonia syndrome (IPS) in the absence of donor MIP-1alpha (CCL3) after allogeneic BMT in mice Blood, May 1, 2003; 101(9): 3714 - 3721. [Abstract] [Full Text] [PDF]
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M. J. Trifilo, C. C. Bergmann, W. A. Kuziel, and T. E. Lane CC Chemokine Ligand 3 (CCL3) Regulates CD8+-T-Cell Effector Function and Migration following Viral Infection J. Virol., April 1, 2003; 77(7): 4004 - 4014. [Abstract] [Full Text] [PDF]
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T. R. Johnson, R. A. Parker, J. E. Johnson, and B. S. Graham IL-13 Is Sufficient for Respiratory Syncytial Virus G Glycoprotein-Induced Eosinophilia After Respiratory Syncytial Virus Challenge J. Immunol., February 15, 2003; 170(4): 2037 - 2045. [Abstract] [Full Text] [PDF]
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P. C. Reading, J. A. Symons, and G. L. Smith A Soluble Chemokine-Binding Protein from Vaccinia Virus Reduces Virus Virulence and the Inflammatory Response to Infection J. Immunol., February 1, 2003; 170(3): 1435 - 1442. [Abstract] [Full Text] [PDF]
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C. A. Bonville, A. J. Easton, H. F. Rosenberg, and J. B. Domachowske Altered Pathogenesis of Severe Pneumovirus Infection in Response to Combined Antiviral and Specific Immunomodulatory Agents J. Virol., December 20, 2002; 77(2): 1237 - 1244. [Abstract] [Full Text] [PDF]
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J. B. Domachowske, C. A. Bonville, A. J. Easton, and H. F. Rosenberg Pulmonary eosinophilia in mice devoid of interleukin-5 J. Leukoc. Biol., June 1, 2002; 71(6): 966 - 972. [Abstract] [Full Text] [PDF]
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J. Melchjorsen, F. S. Pedersen, S. C. Mogensen, and S. R. Paludan Herpes Simplex Virus Selectively Induces Expression of the CC Chemokine RANTES/CCL5 in Macrophages through a Mechanism Dependent on PKR and ICP0 J. Virol., February 22, 2002; 76(6): 2780 - 2788. [Abstract] [Full Text] [PDF]
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A. Nansen, J. P. Christensen, S. O. Andreasen, C. Bartholdy, J. E. Christensen, and A. R. Thomsen The role of CC chemokine receptor 5 in antiviral immunity Blood, February 15, 2002; 99(4): 1237 - 1245. [Abstract] [Full Text] [PDF]
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H. F. Rosenberg and J. B. Domachowske Eosinophils, eosinophil ribonucleases, and their role in host defense against respiratory virus pathogens J. Leukoc. Biol., November 1, 2001; 70(5): 691 - 698. [Abstract] [Full Text] [PDF]
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S. W. Chensue Molecular Machinations: Chemokine Signals in Host-Pathogen Interactions Clin. Microbiol. Rev., October 1, 2001; 14(4): 821 - 835. [Abstract] [Full Text] [PDF]
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E. J. McMahon, D. N. Cook, K. Suzuki, and G. K. Matsushima Absence of Macrophage-Inflammatory Protein-1{alpha} Delays Central Nervous System Demyelination in the Presence of an Intact Blood-Brain Barrier J. Immunol., September 1, 2001; 167(5): 2964 - 2971. [Abstract] [Full Text] [PDF]
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H. A. Haeberle, W. A. Kuziel, H.-J. Dieterich, A. Casola, Z. Gatalica, and R. P. Garofalo Inducible Expression of Inflammatory Chemokines in Respiratory Syncytial Virus-Infected Mice: Role of MIP-1{alpha} in Lung Pathology J. Virol., January 15, 2001; 75(2): 878 - 890. [Abstract] [Full Text]
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) mice. Statistical significance
between the groups of +/+ and -/- mice is observed at day 5
postinoculation. *, p < 0.05.
