Published online before print July 7, 2004
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* La Jolla Institute for Allergy and Immunology, San Diego, California; and
Children’s Hospital and Harvard Medical School, Boston, Massachusetts
2Correspondence: Torrey Pines Institute for Molecular Studies, 3550 General Atomics Ct., San Diego, CA 92121. E-mail: ssarawar{at}tpims.org
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(MIP-1), MIP-1ß, MIP-3, regulated on activation, normal T expressed and secreted (RANTES), MIP-2, and interferon-inducible protein 10 (IP-10) mRNA expression was up-regulated between days 5 and 15 after infection, consistent with a role for these chemokines in leukocyte recruitment to the lung. Low levels of expression were detected for the CC chemokine receptors (CCR)2 and CCR5, whereas CXC chemokine receptor (CXCR)3 was significantly up-regulated by day 10 after infection, coinciding with peak inflammatory cell infiltration in the airways. As RANTES, IP-10, and their receptors were up-regulated during influenza virus infection, we investigated leukocyte recruitment and viral clearance in mice deficient in RANTES or CXCR3, the receptor for IP-10. Leukocyte recruitment and viral replication in influenza-infected RANTES knockout(–/–) mice were similar to that in control mice, showing that RANTES is not essential for the immune response to influenza infection. Similarly, leukocyte recruitment and viral replication in CXCR3–/– mice were identical to control mice, except at day 8 postinfection, where fewer lymphocytes, neutrophils, and eosinophils were detected in the bronchoalveolar lavage of CXCR3–/– mice. These studies suggest that although the chemokines detected may play a role in regulating leukocyte trafficking to the lung during influenza infection, some may be functionally redundant.
Key Words: RANTES • CXCR3 • inflammatory infiltrate
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Recovery from influenza infection is dependent on the recruitment of proinflammatory leukocytes to sites of infection [9 , 10 ]. In particular, virus-specific T cells are essential for the clearance of influenza virus. Differential expression of chemokine receptors by leukocyte subsets enables chemokines to regulate leukocyte trafficking to sites of infection [11 , 12 ]. Although many respiratory viruses replicate in alveolar epithelial cells, they can induce different leukocyte profiles. This may be a result of differential induction of chemokine gene expression [13 14 15 ].
A number of in vitro studies have shown that influenza virus infection of human monocytes, macrophages, or bronchiolar epithelial cells induces expression of CC chemokine genes monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1 (MIP-1), MIP-1ß, and regulated on activation, normal T expressed and secreted (RANTES) and/or the CXC chemokine interleukin (IL)-8 [13
, 16
17
18
19
]. However, given the differences between the in vitro and in vivo systems, there is a need to determine the chemokine response and function in relation to the pathogenesis of influenza in humans or animals. There are few such studies, although in a small trial evaluating the prophylactic effect of zanamivir, an inhibitor of influenza replication, on volunteers experimentally infected with influenza, Fritz et al. [20
] observed increased protein expression of MIP-1, MIP-1ß, and MCP-1 in nasal lavage fluids in response to infection. Dawson et al. [21
] showed that MCP-1, interferon (IFN)-inducible protein 10 (IP-10), and to a much lesser extent, RANTES, T cell activation gene 3 (TCA)-3, and MIP-2 mRNA expression in the lungs was elevated at day 3 after influenza infection. Although the studies of Fritz et al. [20
] and Dawson et al. [21
] showed the kinetics of chemokine expression in response to influenza infection in humans and mice, respectively, Fritz et al. [20
] did not, in parallel, investigate the kinetics of the leukocyte response to infection, and Dawson et al. [21
] only considered the chemokine response during the acute phase of a semilethal influenza infection. Therefore, in the present study, we characterized the spectrum and kinetics of chemokine expression in the lung in relation to viral replication, the inflammatory response, and recovery from a sublethal influenza infection in mice.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Viral infection and sampling
Influenza A/Puerto Rico/8/34 (A/PR/8/34; PR/8) was obtained from the American Type Culture Collection (ATCC; VR-1469, Manassas, VA), and stocks were grown in Madin Darby canine kidney (MDCK) cells (ATCC, CC chemokine ligand 34). Infectious virus titers were determined by plaque formation in monolayers of MDCK cells by the method of Tannock et al. [22
]. Mice were anaesthetized with Avertin (2,2,2-tribromoethanol) and infected intranasally (i.n.) with 30 µL virus at a concentration of 100 plaque-forming units (PFU)/mL in phosphate-buffered slaine (PBS; 
3 PFU/mouse). Control mice were mock-infected with PBS alone. At various times after infection, mice were killed by terminal anesthesia with Avertin. The inflammatory cells infiltrating the airways were harvested by bronchoalveolar lavage (BAL) via the trachea by performing three lavages with 1 mL PBS. Viable leukocyte counts were determined by Trypan blue exclusion. The lungs were removed, and a 10% (w/v) homogenate was prepared in PBS using a Tissue Tearor homogenizer (Fisher Scientific, Pittsburgh, PA).
Cytospin preparations of BAL cells
BAL cells were harvested at days 0, 3, 5, 7, 10, 15, and 30 after infection with PR/8. Cytospin preparations were performed as described previously [23
] using cell suspensions containing 1.5 x 105 cells/mL in PBS, 2% fetal bovine serum. The cytocentrifuge preparations were fixed and stained using a Leukostat staining set (Hema 3, Fisher Scientific).
Chemokine and chemokine receptor analysis
Chemokine and chemokine receptor expression was analyzed by RNase protection assay as described previously [23
]. RNA from lungs of two to four mice from each experiment was analyzed individually. Chemokine or chemokine receptor mRNA levels were determined using a RiboQuant multiprobe template mCK-5 set or a modified mCR-5 probe set that contained the additional probe templates for secondary lymphoid tissue (SLC; 6Ckine) and CC chemokine receptor 7 (CCR7). Custom murine probe template sets for CXC chemokine receptor (CXCR)2, CXCR3, CXCR4, and CXCR5 (BRL-1) or keratinocyte-derived chemokine (KC), MIP-2, MIP-3, and MIP-3ß were also used (PharMingen, San Diego, CA).
Statistical analysis
Statistical analysis was performed using the Student’s t-test or the Mann-Whitney rank sum test, depending on whether the data were normally distributed. Unless otherwise stated, asterisks denote statistically significant increases relative to that in uninfected mice: ***, P < 0.001; **, P < 0.01; *, P < 0.05.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Figure 1. Total and differential cell counts in the BAL population and virus titers in the lungs of mice during infection with influenza PR/8. C57BL/6 mice were infected i.n. with 100 PFU/mL PR/8 or were mock-infected with PBS, and lungs and inflammatory cells were collected at various intervals. (a) Infectious virus yields in the lung. Virus titers were determined in 10% lung homogenates by plaque assay on MDCK cells. (b) Cell numbers in the BAL. Cells infiltrating the lung were collected by BAL via the trachea. Viable cell counts were determined by trypan blue exclusion. (c–e) Total macrophages/monocytes (Macro/mono), lymphocytes, and neutrophils, respectively, in the BAL cell population. Differential cell counts were determined using Hema-3 (Fisher Scientific)-stained cytospin preparations. Data are means + SE from three independent experiments, using three to five mice per group, except for differential cell counts, where the data are means + SD. Asterisks denote statistically significant increases in cell populations relative to those in uninfected mice: **, P < 0.01; *, P < 0.05.
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, MIP-1ß, RANTES, and IP-10, and mRNA expression for the CXCR2 and CCR6 ligands, MIP-2 and MIP-3, respectively, was undetectable. However, the expression of these chemokines was markedly up-regulated following influenza virus infection. Expression of MCP-1, MIP-1ß, IP-10, and MIP-2 correlated with increased viral titers in the lung and an increase in the percentage of granulocytes infiltrating the airways (Figs. 2
and 3
). Mock-infected mice showed chemokine levels comparable with those in uninfected mice (data not shown). Expression of MCP-1, MIP-1ß, MIP-3, IP-10, and MIP-2 mRNAs peaked at approximately day 7 pi and returned to near constitutive levels by approximately day 15 after infection, except for MIP-3 and MIP-2 mRNA, which remained slightly elevated at day 30 pi (Fig. 2b
and 2c)
. Similarly, MIP-1 expression levels peaked at days 7–10 after infection, before returning to baseline levels. In contrast, the kinetics of RANTES expression correlated with the number of leukocytes infiltrating the inflammatory airways (Figs. 1b
and 2b)
and peaked at approximately day 10 pi, returning to near basal levels by day 30 pi.
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Figure 2. RNase protection assay showing kinetics of chemokine mRNA induction in the lungs of PR/8-infected mice. (a) RNase protection assay. C57BL/6 mice were infected with PR/8 or mock-infected with PBS. At various time intervals after infection, the mice were killed, and the lungs were snap-frozen in liquid nitrogen. Total RNA was prepared from the lungs using Trizol reagent and hybridized with 32P-labeled antisense probes generated by in vitro transcription of templates for (a) lymphotactin (Ltn), TCA-3, MCP-1, MIP-1, MIP-1ß, RANTES, eotaxin, MIP-2, IP-10, and housekeeping genes L32 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH; PharMingen). Protected probes were separated by polyacrylamide gel electrophoresis (PAGE) and visualized using a PhosphorImager. A representative assay is shown. (b and c) Densitometric analysis. RNase protection assays were performed as described in a. The resulting autoradiographs were analyzed by scanning densitometry of each lane using ImageQuant software (Molecular Dynamics, Sunnyvale, CA). Data are expressed as mean + SE of arbitrary units normalized against values for the housekeeping gene GAPDH for three to four independent experiments at each time-point. Asterisks denote statistically significant increases in expression relative to that in uninfected mice: *, P < 0.05.
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Figure 3. RNase protection assay showing kinetics of chemokine mRNA induction in the lungs of PR/8-infected mice. (a) RNase protection assay. Mice were infected with PR/8, the lungs harvested, and RNA extracted as described in the legend to Figure 2
. RNA was hybridized with 32P-labeled antisense probes generated by in vitro transcription of templates for MIP-3, MIP-3ß, KC, and MIP-2, and housekeeping genes L32 and GAPDH (PharMingen). Protected probes were separated by PAGE and visualized using a PhosphorImager. A representative assay is shown. (b) Densitometric analysis. RNase protection assays were performed as described in a. Data for MIP-3, MIP-3ß, and KC are expressed as mean + SE of arbitrary units normalized against values for the housekeeping gene GAPDH for three independent experiments at each time-point. Asterisks denote significant increases in expression relative to that in uninfected mice: **, P < 0.01; *, P < 0.05.
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Figure 4. Expression of CCRs in the lungs of influenza-infected mice. (a) RNase protection assay. Mice were infected with PR/8, the lungs harvested, and RNA extracted as described in the legend to Figure 2
. RNA was hybridized with 32P-labeled antisense probes generated by in vitro transcription of templates for SLC, CCR1, CCR1b, CCR2, CCR3, CCR4, CCR5, CCR7, and housekeeping genes L32 and GAPDH (PharMingen). Protected probes were separated by PAGE and visualized using a PhosphorImager. A representative assay is shown. (b) Densitometric analysis. RNase protection assays were performed as described in a. Data for CCR2 and CCR5 are expressed as mean + SE of arbitrary units normalized against values for the housekeeping gene GAPDH for three independent experiments at each time-point. Asterisks denote significant increases in expression relative to that in uninfected mice: *, P < 0.05.
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, MIP-1ß, and RANTES) appeared to correlate with that of their ligands, and peak CCR2 and CCR5 mRNA expression at day 7 pi was significant when compared with mRNA levels of uninfected mice (Fig. 4b)
. CXCR3 mRNA, which was constitutively expressed in the lungs of uninfected mice, was markedly increased at day 10 pi (P=0.00023) before returning to near basal levels by day 15 (Fig. 5
). CXCR2, CXCR4, CXCR5, and CCR7 were all constitutively expressed.
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Figure 5. Expression of CXCRs in the lungs of influenza-infected mice. (a) RNase protection assays were performed as described in the legend to Figure 2
, except that antisense probes were generated using templates for CXCR2, CXCR3, CXCR4, CXCR5, and housekeeping genes L32 and GAPDH (PharMingen). A representative assay is shown. (b) Densitometric analysis showing CXCR2 and CXCR3 mRNA expression. Data are expressed as mean + SE of arbitrary units normalized against values for the housekeeping gene GAPDH for three to four independent experiments at each time-point. Asterisks denote significant increases in expression relative to that in uninfected mice: ***, P < 0.001.
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, IP-10, and IFN-inducible T cell- chemoattractant, is predominantly expressed on activated T lymphocytes [25
, 26
], and RANTES acts as a chemoattractant for monocytes, eosinophils, T lymphocytes, and immature dendritic cells (DC) [27
, 28
]. Given that CXCR3 and RANTES were significantly up-regulated during the course of influenza infection and that T cells mediate clearance of influenza virus from the lungs [29
, 30
], we used CXCR3 and RANTES knockout–/– mice to determine whether RANTES or CXCR3 ligands were essential for T cell trafficking to the lungs and influenza virus clearance. Total and differential cell counts of BAL cells and virus titers showed that deletion of RANTES had no effect on the total number or types of leukocytes infiltrating the airways in response to influenza infection or on the level of replication or clearance of virus from the lungs (Fig. 6 ). However, deletion of CXCR3 leads to a significant decrease in total BAL cells at day 8 pi compared with wild-type+/+ controls (Fig. 7b ). The decrease in total BAL cell numbers at day 8 pi in CXCR3–/– mice was associated with a significant reduction in lymphocytes, neutrophils, and eosinophils (P=0.0206, 0.0464, and 0.0055, respectively), and macrophage numbers were similar between CXCR3–/– and +/+ mice (Fig. 7c 7d 7e 7f) . BAL cell populations in the lungs of PR/8-infected CXCR3–/– mice were also examined by flow cytometry as described previously by Sarawar and Doherty [31 ]; however, there was no difference in lymphocyte subset distribution when compared with +/+ controls (data not shown). Despite the apparent delay in recruitment of lymphocytes into the airways of influenza-infected CXCR3–/– mice, there was no difference in the level of virus replication or clearance of virus from the lungs in comparison with +/+ controls (Fig. 7a) .
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Figure 6. Effect of RANTES deletion on virus replication and leukocyte recruitment. RANTES–/– mice and age-matched controls were infected i.n. with 100 PFU/mL PR/8, and lungs and inflammatory cells were collected at various intervals. (a) Infectious virus yields and (b) cell numbers in the BAL. Data are expressed as the means + SD of three to eight mice per group. KO, Knockout; WT, wild-type.
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Figure 7. Effect of CXCR3 deletion on virus replication and leukocyte recruitment. CXCR3–/– mice and age-matched controls were infected i.n. with 100 PFU/mL PR/8, and lungs and inflammatory cells were collected at days 0, 6, 8, 10, and 12 after infection. (a) Infectious virus yields, (b) cell numbers in the BAL, and (c) granulocytes as a percentage of total BAL cell population were determined as described in Figure 1
. (d–f) Total macrophages/monocytes (Macro/mono), neutrophils, lymphocytes, and eosinophils, respectively, in BAL cell population. Differential cell counts were determined using Hema-3 (Fisher Scientific)-stained cytospin preparations. Data are expressed as the means + SD of four to nine mice per group. Asterisks denote statistically significant differences between knockout (KO) and wild-type (WT) mice at the indicated time-points: **, P < 0.01; *, P < 0.05.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, MIP-1ß, RANTES, and IP-10, as well as the neutrophil chemoattractant MIP-2 were up-regulated (Figs. 2
and 3)
. MIP-3, which is chemotactic for immature DC and a subset of B and T cells [34
], was also up-regulated. Similar chemokine profiles have been reported in the lungs of respiratory syncytial virus (RSV)-infected mice, although the kinetics of mRNA expression was different, and peak levels of mRNA expression occurred between 8 and 24 h after infection, compared with 7–10 days in influenza-infected mice [14
, 35
]. Pneumonia virus of mice (PVM) has also been shown to induce MCP-1, MIP-1, RANTES, MCP-3, and eotaxin expression in the lungs of mice [15
, 36
]. In a separate study, MCP-1, RANTES, and IP-10 mRNA levels were up-regulated in the lungs of mice infected with 5–10 HAU of PR/8 between days 2 and 3 after infection; however, time-points later than day 3 were not analyzed [21
]. Therefore, in the present study, the chemokine response throughout the development of the inflammatory infiltrate and resolution was analyzed. Data from our studies and those of others show that although respiratory viruses generally induce a similar range of chemokines, expression levels and kinetics can differ between viral infections. Possible explanations for these differences include differences in the rates of viral replication or in the effects of specific viral proteins on transcriptional activators of chemokine gene expression.
In influenza virus infection, chemokine induction closely follows viral replication. However, in RSV infection, chemokine expression peaks early after infection and then decreases, although viral replication is still ongoing [14, 35]. Tripp et al. [35] suggested that RSV G and or small hydrophobic proteins modify chemokine gene expression, as a mutant virus lacking these proteins induced higher levels of chemokine expression than the wild-type virus. However, chemokine gene expression was rapidly down-regulated even in the absence of these genes. Ultraviolet-inactivated RSV has also been reported to up-regulate the expression RANTES, MIP-1, MIP-1ß, MIP-2, and MCP-1 but not TCA-3, eotaxin, and IP-10 [14]. Furthermore, Domachowske et al. [36] reported that pathogenic and nonpathogenic strains of pneumovirus had greatly divergent abilities to induce chemokines, although both replicated in the lungs. Taken together, these reports show that differential chemokine gene expression cannot be explained solely by differences in viral replication.
Differential activation of transcription factors by different respiratory viruses has been shown to be associated with differential chemokine gene expression. For example, Matikainen et al. [13] showed that influenza virus was a better inducer of MCP-1 and MCP-3 in human macrophages than Sendai virus, whereas the Sendai virus preferentially induced MIP-1, MIP-1ß, RANTES, MIP-3, and IL-8. Both viruses induced the transcription factor nuclear factor-
B similarly, whereas IFN regulatory factors, signal transducers and activators of transcription, and other transcription factors involved in the regulation of chemokine gene expression were differentially activated. This may, in part, explain the differential induction of chemokine gene expression.
Furthermore, different viruses may induce up-regulation of different chemokine receptors. The pattern of chemokine expression in PR/8-infected mice indicated that influenza might induce chemotaxis of cells expressing the chemokine receptors CCR1, CCR2, CCR3, CCR5, CXCR2, and CXCR3 (Figs. 4 and 5) . However, significant increases in expression above background levels were only observed for CCR2, CCR5, and CXCR3 receptors, and CXCR2 expression was constitutive. CCR1, a receptor important in the leukocyte response to PVM infection [15 ], was not detected in the lungs of influenza-infected mice.
The inflammatory response to influenza infection in mice is comprised mainly of mononuclear leukocytes, and neutrophils contributed to 20% of the inflammatory population. MIP-1, MIP-1ß, RANTES, and IP-10 are chemotactic for T cells [37
], and their up-regulation during influenza infection correlated with viral replication in the lungs and increased inflammatory cell numbers in the airways (Fig. 1)
. Thus, it appears that in an influenza infection, MIP-1, MIP-1ß, RANTES, and IP-10 may regulate the trafficking of lymphocytes to the lungs and thereby mediate viral clearance. However, depending on the conditions, the functional activity of certain chemokines has been reported to be redundant [38
]. This was not the case for MIP-1, where the inflammatory infiltrate in response to influenza infection in MIP-1-deficient mice was attenuated, and viral titers were increased compared with wild-type controls [39
]. Nevertheless, in the present paper, it was demonstrated that the immune response to influenza infection of RANTES-deficient mice was identical to that of wild-type controls, indicating that RANTES was not required to establish a competent immune response to influenza infection.
CXCR3-deficient mice showed reduced trafficking of leukocytes to the inflammatory airways at day 8 pi, a time when virus replication in the lungs and total inflammatory cell numbers in the airways are near their peaks. The reduction or delay in leukocyte infiltration was shown to be a result of a defect in trafficking of lymphocytes, neutrophils, and eosinophils; however, this had no physiological effect on virus clearance. Given that CXCR3 is predominantly expressed on activated T cells [40 41 42 ], reduced trafficking of lymphocytes into the site of inflammation was not unexpected. Loetscher et al. [43 ] and Xanthou et al. [44 ] have shown that ligands of CXCR3 act as antagonists for CCR3, which is expressed by eosinophils, and inhibit CCR3-mediated responses of human eosinophils. The peak expression of IP-10 mRNA, a CXCR3 ligand, in influenza-infected C57BL/6 mice occurred at day 7 pi, which correlates with decreased numbers of lymphocytes and eosinophils at day 8 pi in the inflammatory airways of CXCR3–/– mice. Therefore, it is possible that in the absence of CXCR3+ cells, the production of IP-10 may prevent the chemotaxis of eosinophils into the lungs of influenza-infected mice.
In conclusion, our results demonstrate that CC and CXC chemokines are induced during influenza infection and that there may be functional redundancy amongst the chemokines induced. Data from chemokine receptor knockout mice suggests that complex relationships between different sets of leukocytes may exist. Further studies involving in vivo neutralization of chemokines or with other chemokine or chemokine receptor knockout mice will be important in further elucidating the role that individual chemokines play in leukocyte trafficking during influenza infection.
Received December 19, 2003; revised April 8, 2004; accepted May 10, 2004.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, IFN-, MxA, and IFN regulatory factor 1 genes in influenza A virus-infected human peripheral blood mononuclear cells J. Immunol. 154,2764-2774[Abstract] in lung pathology J. Virol. 75,878-890 are prominent responses to infection with pneumonia virus of mice Cell. Immunol. 200,98-104[CrossRef][Medline]herpesvirus 68 (MHV-68) infection Virology 293,54-62[CrossRef][Medline]-inducible protein-10 and monokine induced by IFN- J. Immunol. 165,1548-1556 interferon in the regional lymph nodes of mice with influenza pneumonia J. Virol. 68,3112-3119 production in LPS-stimulated neutrophils is enhanced by the chemoattractant formyl-methionyl-leucyl-phenylalanine and IFN- through independent mechanisms Eur. J. Immunol. 32,3515-3524[CrossRef][Medline] for an inflammatory response to viral infection Science 269,1583-1585This article has been cited by other articles:
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