Cytokine & Growth Factor Reviews 12 (2001) 171– 180 www.elsevier.com/locate/cytogfr
Survey
Molecular pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene expression Ilkka Julkunen a,*, Timo Sareneva a, Jaana Pirhonen a, Tapani Ronni b, Krister Mele´n a, Sampsa Matikainen a a
Department of Virology, National Public Health Institute, Laboratory of Viral and Molecular Immunology, Mannerheimintie 166, FIN-00300 Helsinki, Finland b Howard Hughes Medical Institute, MacDonald Research Laboratories, UCLA, Los Angeles, CA90095 -1662, USA
Abstract Despite vaccines and antiviral substances influenza still causes significant morbidity and mortality world wide. Better understanding of the molecular mechanisms of influenza virus replication, pathogenesis and host immune responses is required for the development of more efficient means of prevention and treatment of influenza. Influenza A virus, which replicates in epithelial cells and leukocytes, regulates host cell transcriptional and translational systems and activates, as well as downregulates apoptotic pathways. Influenza A virus infection results in the production of chemotactic (RANTES, MIP-1a, MCP-1, MCP-3, and IP-10), pro-inflammatory (IL-1b, IL-6, IL-18, and TNF-a), and antiviral (IFN-a/b) cytokines. Cytokine gene expression is associated with the activation of NF-kB, AP-1, STAT and IRF signal transducing molecules in influenza A virus-infected cells. In addition of upregulating cytokine gene expression, influenza A virus infection activates caspase-1 enzyme, which is involved in the proteolytic processing of proIL-1b and proIL-18 into their biologically active forms. Influenza A virus-induced IFN-a/b is essential in host’s antiviral defence by activating the expression of antiviral Mx, PKR and oligoadenylate synthetase genes. IFN-a/b also prolongs T cell survival, upregulates IL-12 and IL-18 receptor gene expression and together with IL-18 stimulates NK and T cell IFN-g production and the development of Th1-type immune response. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Influenza A; Chemokines; Cytokines; Transcription factors; Caspases
Contents 1. Influenza A virus and its replication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2. Regulation of host cell protein synthesis and apoptosis by influenza A virus . . . . . . . . . .
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3. Cytokine production in influenza A virus infection . . . . . . . . . . . . . . . . . . . . . . . . .
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4. Influenza A virus and activation of cellular transcription factors . . . . . . . . . . . . . . . . .
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5. Role of influenza A virus-induced cytokines in innate and adaptive immunity . . . . . . . . .
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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author. Tel.: + 358-9-47448372; fax: + 358-9-47448355. E-mail address:
[email protected] (I. Julkunen). 1359-6101/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 1 3 5 9 - 6 1 0 1 ( 0 0 ) 0 0 0 2 6 - 5
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1. Influenza A virus and its replication Infections caused by influenza viruses are a considerable threat to human health all around the world. The disease can be prevented and treated by vaccines and antiviral substances, although these are not available world-wide and their efficacy is not optimal. Therefore, further understanding of the basic biological mechanisms of influenza virus replication, mechanisms of pathogenesis and host immune responses is still needed. Influenza viruses are enveloped, negative-stranded RNA viruses of Orthomyxo6iridae family. They are classified as influenza A, B, and C types. Of these type A influenza is the most pathogenic one. Influenza A virus can infect humans of all age groups and the infection in the population ranges from sporadic cases to large epidemics or pandemics. Influenza A virus genome consists of eight RNA segments of variable size. The genes encode for 10 proteins; envelope glycoproteins hemagglutinin (HA) and neuraminidase (NA), matrix protein (M1), nucleoprotein (NP), three polymerases (PB1, PB2 and PA), ion channel protein (M2), and nonstructural proteins (NS1 and NS2) (Fig. 1) [1,2]. Influenza A viruses are classified according to
their hemagglutinin (H1–H15) and neuraminidase (N1 –N9) genes. Viruses with HA types H1, H2 and H3 and NA types N1 and N2 are epidemic in humans. Influenza A virus undergoes genetic variation by two mechanisms; genetic drift characterized by point mutations in antigenically important positions caused by selective pressure from host immune response and genetic shift characterized by a substitution of a whole gene from one subtype to another [1]. Influenza viruses replicate in the epithelial cells of the upper respiratory tract, but monocytes/macrophages and other leukocytes are also infected [3]. In vitro many other cell types are susceptible to the virus, since they have sialic acid containing cell surface glycoproteins on cell membranes that function as receptors for influenza A virus. Cellbound virus is endocytosed via clathrin-dependent endocytotic pathway. Low pH in endosomes triggers the fusion of viral and endosome membranes, which liberates viral ribonucleoprotein (vRNP) complexes (nucleocapsids) into the cytoplasm. Viral nucleocapsids are imported into the cell nucleus where primary viral mRNA synthesis is initiated by viral RNA polymerase complex consisting of PB1, PB2 and PA polymerases
Fig. 1. Influenza A virus life-cycle. (A) Influenza A virus is an enveloped single-stranded RNA virus. It has a genome of eight RNA segments with a coding capacity for 10 proteins. RNA segments are covered by nucleoprotein (NP) and they contain viral polymerase complex consisting of PB1, PB2 and PA proteins. M1 membrane protein and glycoproteins HA and NA are associated with the lipid bilayer. M2 and nonstructural protein 2 (NS2) are also found in virions, whereas NS1 is found only in virus infected cells. (B) Influenza A virus binds to sialic acid-containing receptors via the HA molecule. The virus enters the cell by the endocytic pathway followed by fusion of viral and endosome membranes. Viral ribonucleoprotein complexes (nucleocapsids) are transported into the nucleus followed by primary transcription. Viral mRNAs are transported into the cytoplasm where viral proteins are synthesized. Newly synthesized polymerases, NP, NS1, and NS2 are transported into the nucleus and viral RNA (vRNA) replication to complementary RNA (cRNA) and vRNA is taking place by viral transcriptase complex. Secondary vRNAs are transcribed to viral mRNAs followed by synthesis of structural proteins. Viral nucleocapsids are assembled in the nucleus, transported into the cytoplasm and plasma membrane, where budding and release of the virus particles take place [1,2].
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(Fig. 1). Viral mRNA synthesis is initiated by host cell pre-mRNA-derived primers generated by the endonuclease activity of the PB2 protein of the polymerase complex. The synthesis of virus specific mRNAs is catalyzed by PB1 protein. Viral mRNAs are then transported into the cytoplasm, translated, and newly synthesized polymerase proteins, NP, NS1, and NS2 are transported into the nucleus, where they regulate the replication and secondary mRNA synthesis of the virus [1,2]. PB1, PB2, PA and NP initiate the synthesis of complementary RNA (cRNA) strand synthesis from viral RNA (vRNA) followed by synthesis of new vRNA molecules. Newly made vRNAs function as templates for secondary mRNA synthesis which is also catalyzed by viral polymerase complex (Fig. 1B). At late times of infection NS1 protein regulates the splicing of M and NS mRNAs leading to the formation of M2 and NS2 mRNAs, respectively. Viral mRNAs are transported into the cytoplasm and viral structural proteins are synthesized. PB1, PB2, PA, and NP are transported into the nucleus, where the assembly of vRNP complexes occurs. M1 and NS2 proteins are also transported into the nucleus, where they interact with vRNPs and regulate the nuclear export of newly synthesized vRNPs [1,2]. At the plasma membrane vRNPM1 protein complexes then interact with the cytoplasmic part of HA and NA molecules and budding of the mature virions takes place (Fig. 1B) [1]. Productive influenza A virus infection in epithelial cells destroys host cell pre-mRNAs, inhibits translational of cellular mRNAs and kills the host cells either by cytolytic or apoptotic mechanisms [1,2,4– 6]. Virusinfected cells respond to the infection in many ways to restrict the spread of the virus. Several different transcription factor systems are activated followed by production of chemotactic, proinflammatory and antiviral cytokines. These cytokines then recruit inflammatory cells to the site of infection, mediate proinflammatory effects and establish an antiviral state against the invading virus.
2. Regulation of host cell protein synthesis and apoptosis by influenza A virus Influenza A virus infection results in host cell death by cytolytic or apoptotic mechanisms. Influenza A virus replication in cells is fast and efficient and involves suppression of host cell gene expression. In the nucleus viral polymerase protein complex binds to the 5% ends of newly synthesized cellular polymerase II transcripts followed by cleavage of the host mRNAs. 5% cap structures of host mRNAs are then used as primers during viral mRNA synthesis, whereas decapped host mRNAs are degraded [1]. Influenza A virus-encoded NS1 protein blocks the splicing of cellular pre-mRNAs and
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inhibits the nuclear export of host mRNAs [7,8]. In the cytoplasm of influenza A virus-infected cells the translation of cellular mRNAs is also drastically reduced. Instead, influenza A virus-specific mRNAs are translated efficiently, which ensures viral protein synthesis throughout the infection cycle [1,4,9]. Sequences in the 5%-untranslated region of viral mRNAs are critical in regulating the translation of influenza A virus mRNAs [4]. Another mechanism of the maintenance of efficient influenza A virus mRNA translation is downregulation of PKR activity. IFN-induced antiviral PKR is activated by dsRNA and cellular stress [10]. Activated PKR phosphorylates eukaryotic initiator factor 2a (eIF2a), which reduces translation initation and, hence, the synthesis of cellular proteins. Influenza A virus has developed two different ways to escape from the inhibitory effects of PKR. First, viral NS1 protein, which is a dsRNA binding protein, can bind to PKR and interfere with the activation of PKR by dsRNA [11]. Second, influenza A virus infection activates a latent chaperone-associated protein, p58IPK, which can interfere with PKR dimerization and activation [12,13]. Interestingly, p58IPK was recently found to be an inhibitor of apoptosis [14] and could thus play a role in regulating influenza A virus-induced cell death. Efficient virus replication, maintenance of viral protein synthesis, shut-down of host protein synthesis, and production of viral particles lead usually to cytolytic death of cells at 20–40 h of infection. Influenza A virus-infected cells also show changes typical for apoptosis [5,6]. Apoptosis is characterized with chromatin condensation, DNA fragmentation, cell shrinking, and compartmentalization to apoptotic bodies followed by clearance of apoptotic cells by phagocytic cells [15]. Increased intracellular calcium levels, elevated Fas antigen and TGF-b levels, and activation of PKR have been associated with influenza A virus-induced apoptosis [16,17]. IFN-a/b and enhanced PKR expression were found to potentiate influenza A virus-induced apoptosis [18]. Two influenza A virus proteins, NA and NS1 have also been suggested to regulate apoptosis. NA activates latent TGF-b, which may then indirectly be involved in influenza A virus-induced apoptosis [19,20]. NS1 protein also induces apoptosis when expressed in MDCK cells [16].
3. Cytokine production in influenza A virus infection Influenza A virus-infected epithelial cells and leukocytes respond to the infection by producing chemotactic (chemokines), proinflammatory, and other immunoregulatory cytokines. Chemokine family constitutes of more than 40 proteins [21,22]. They are produced by a variety of cells constitutively or in response to microbial infections. Chemokines bind to their specific cell surface
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Fig. 2. Cytokine production in influenza A virus-infected epithelial cells and macrophages. Epithelial cells of the respiratory tract and macrophages are the targets of influenza A virus infection. In response to virus infection epithelial cells produce a limited number of cytokines, such as antiviral IFN-a/b and chemokines RANTES, MCP-1, and IL-8. Macrophages, instead, produce many different chemokines and proinflammatory cytokines. Influenza A virus-infected macrophages produce IFN-a/b and IL-18, which in synergy enhance NK and T cell IFN-g production and the development of Th1-type immune response. [[3,23 –27,32,33,35–38], Nyqvist et al., unpublished results].
receptors on leukocytes, which leads to a rapid change in cell shape and behaviour enabling them to migrate from blood vessels through the vascular endothelium into the site of inflammation [22]. Chemokine receptors are expressed differently on distinct leukocyte subpopulations [21,22]. Influenza A virus-infected monocytes/ macrophages secrete MIP-1a, MIP-1b, RANTES, MCP-1, MCP-3, MIP-3a and IP-10, whereas the production of IL-8 appears to be limited [23– 25]. Epithelial cells produce RANTES, MCP-1 and IL-8 in response to influenza A virus infection (Fig. 2) [[26,27], Nyqvist et al., unpublished]. The presence of MIP-1a/b, MCP-1 and IL-8 has been detected in the nasopharyngeal secretions of influenza A virus-infected individuals [28,29]. The chemokines produced in influenza A virus infection preferentially favor the recruitment of blood mononuclear cell population to the site of infection [23,24]. Other viral infections such as respiratory syncytial virus (RSV) infection in epithelial cells has been shown to result in the production of RANTES, MIP1a, MCP-1 and IL-8 [30,31], which may lead to tissue recruitment of a more wide-spectrum inflammatory cell population compared to influenza A virus infection.
Type I interferons (IFN-a/b) are the key cytokines produced by influenza A virus-infected epithelial cells and monocytes/macrophages [3,32,33]. Experiments using IFN-a/b receptor or STAT1 gene knock-out mice have demonstrated the importance of IFN system in antiviral defence against influenza A [34]. Human lung epithelial cell lines show poor production of IFN-a/b and proinflammatory cytokines (IL-1, IL-6, TNF-a) during influenza A virus infection [[32], Nyqvist et al., unpublished]. Influenza A virus-infected monocytes/ macrophages, instead, efficiently produce large quantities of IFN-a/b, IL-1b, IL-6 and TNF-a [3,33,35–38]. Macrophages infected with influenza A virus also produce IL-18, but fail to produce IL-12 [33]. Dendritic cells, however, have been found to produce relatively high levels of IL-12 in response to influenza A virus infection or dsRNA stimulation [39,40]. Influenza A virus can also induce the production IL-15 in human PBMCs [41]. It appears that macrophages and dendritic cells are capable of producing large quantities of antiviral and immunostimulatory cytokines during influenza A virus infection.
4. Influenza A virus and activation of cellular transcription factors Virus infection activates several transcription factors that are involved in the induction of chemokine and cytokine gene expression. Nuclear factor kappa B (NFkB), activating protein (AP)-1, interferon regulatory factors (IRFs), signal transducers and activators of transcription (STATs) and nuclear factor-IL-6 (NF-IL6 or C/EBPb) have been shown to be activated in influenza A virus infection (Fig. 3) [25,32,42– 45]. Many chemokine and cytokine genes contain NF-kB binding sites in their promoters and it is likely that NF-kB activation is important in influenza A virus-induced cytokine production. Influenza A virus-induced activation of NF-kB is biphasic. Early NF-kB activation is detected at 1 h after infection while the later NF-kB activation correlates with virus replication and viral protein synthesis [32]. Expression of single influenza A virus genes can activate NF-kB possibly due to a stress response in the endoplasmic reticulum [44,45]. IFN-a/b-inducible, dsRNA-activated PKR is involved in the activation of NF-kB [46]. Recent evidence suggests that dsRNA or vesicular stomatitis virus infection activates PKR followed by activation of the b-subunit of IkB kinase (IKKb) and NF-kB [47,48]. PKR/IKKmediated NF-kB activation takes place also in influenza A virus infection [49], although influenza A virus infection can activate a cellular inhibitor of PKR, p58IPK [12]. Activation of NF-kB by Toll-like receptors (TLR) is an important mechanism of bacteria-stimulated NFkB activation [50]. Certain TLR molecules are upregu-
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lated in viral infections [Miettinen et al., unpublished results], which brings an intriguing possibility that TLRs could also be involved in virus-induced NF-kB activation. Mitogen-activated protein (MAP) kinases are important regulators of cytokine gene expression. Influenza A virus infection activates several members of MAP kinase superfamily such as the extracellular signal-regulated kinase (ERK), p38 MAP kinase, and c-Jun-NH2-terminal kinase (JNK) [49]. In human leukocytes influenza A virus-induced AP-1 activation is of short duration [43]. Apparently, AP-1 activation requires influenza A virus replication, since the expression of individual influenza A virus genes, HA, NP, or M was not sufficient to turn on AP-1 activation whereas NF-kB was readily activated [45]. Initially, IRF-1 was suggested to be an important virus-induced and virus-activated transcription factor that regulates the expression of IFN-a/b and IFN-inducible genes [51]. The basal expression of IRF-1 is low, but it is induced by IFNs, IL-1, IL-12, TNF-a, and viruses including influenza A [3,52,53]. It remained controversial, whether IRF-1 is directly involved in virus-induced IFN-a/b expression. Presently, the IRF family constitutes nine members. Of these IRF-1, IRF-3
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and IRF-7 have been associated with IFN-a/b or IFNinduced gene expression [54]. In addition, IRF-9/p48 functions as a DNA-binding component in IFN-a/b activated ISGF3 complex that binds to interferon stimulatory response elements (ISRE) in the promoters of IFN-a/b-inducible genes (Fig. 3). It was recently found that cytoplasmic, constitutively expressed IRF-3 becomes phosphorylated and activated during paramyxovirus infection. IRF-3 activation is followed by nuclear translocation and transcriptional activation of IFN-a/b genes [55–57]. However, influenza A virus does not activate IRF-3 [J. Hiscott, personal communication]. It is likely that during influenza A virus infection enhancement in IRF activity takes place indirectly via IFN-a/b production and upregulation of IRF-1 and IRF-7 gene expression (Fig. 3) [25,52,58,59]. IRF-7, which is under the regulation of IFN-a/b, also regulates the expression of various interferon genes [58–60]. STATs are also activated during influenza A virus infection [25,32]. There is no evidence that influenza A virus directly activates STAT1 or STAT2, which are IFN-a/b-specific STATs. Rather, STAT activation in influenza infection is indirect and mediated by virus-induced IFN-a/b. Of interest is the observation that both IFN-a/b and IFN-g upregulate the expression of
Fig. 3. Activation of transcription factors in influenza A virus infection. Replication of influenza A virus activates AP-1 and NF-kB transcription factors. Viral dsRNA activates PKR followed by activation of IkB kinase (IKK) and nuclear translocation of NF-kB. Virus replication may also activate MAP kinase cascades leading to JNK and AP-1 activation. At early times of infection influenza A virus-infected cells produce IFN-a/b and NF-kB activating cytokines, IL-1b and TNF-a. IFN-a/b activates, via its specific receptors, STAT1 and STAT2. Tyrosine phosphorylated activated STAT1 and STAT2 form heterodimers, translocate into the nucleus and bind to IRF-9/p48 to form ISGF3 complex. IFN-a/b also stimulates the expression of IRF-1 and IRF-7. Chemokine and cytokine genes often contain one or more regulatory elements for the transcription factors shown in the figure [25,32,42 –49,52,58–62].
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Fig. 4. Activation of caspase cascades in influenza A virus infection. Apoptosis is associated with the activation of initiator caspases-9 and 8 and effector caspases, especially caspase-3. In influenza A virus-infected macrophages caspases-1 and 3 are activated. Virus-activated caspase-1 is involved in the cleavage of proIL-18 and proIL-1b to mature IL-18 and IL-1b. Caspase-3 can also cleave proIL-18 and IL-18 to biologically inactive forms. ProIL-18 is constitutively expressed in macrophages, whereas proIL-1b is synthesized during influenza A virus infection. Influenza A virus infection also activates the p58INK protein, a cellular inhibitor of apoptosis, which was initially described as an inhibitor of PKR. [[12 – 14,18,33,38,63– 69], Pirhonen et al., unpublished results].
STAT1, STAT2 and IRF-9/p48 [52,61,62], which sensitizes the cells to IFNs and provides positive feed-back regulation in the interferon system. Activation of other transcription factors, such as NF-IL-6, has also been described in influenza A virus infection [42], but the molecular mechanisms involved in its activation are not known. Activation of several different transcriptional systems during influenza A virus infection (Fig. 3) may explain the large number of different chemokines and cytokines produced during the infection. Many chemokine and cytokine genes contain one or more binding sites to the transcription factors described above. In addition to upregulating the expression of chemokine and cytokine genes influenza A virus can control the post-translational events involved in the production of cytokines. IL-1b and IL-18 are expressed as inactive proforms and after proteolytic cleavage by caspase-1 enzyme they become biologically active (Fig. 4). ProIL-1b (34 kDa) is processed by caspase-1 to a biologically active 17 kDa form [63]. The 24 kDa proIL-18 is also cleaved by caspase-1 to a 18 kDa mature form [64– 66]. IL-18 may be further degraded by caspase-3 to apparently biologically inactive 15–16 kDa fragments [[67], Pirhonen et al., unpublished]. Monocytes/macrophages, osteoclasts and keratinocytes constitutively express IL-18 mRNA and proIL-18 [38,66,67], whereas the constitutive levels of IL-1b
mRNA and protein are usually low and efficient IL-1b production requires both transcriptional activation of the gene and the processing of the proIL-1b by caspase1 [68]. Influenza A virus-infected macrophages readily produce IL-1b and IL-18. Secretion of IL-1b and IL-18 takes place at 9–12 h after the infection [33,38] suggesting that virus-induced processing of proIL-1b and proIL-18 occurs at later times of infection, several hours after influenza A virus mRNAs and proteins start to accumulate. Apoptosis is characterized by activation of caspase cascades [15]. Multiple apoptotic signals may first activate initiator caspases such as caspases-8 and 9, followed by activation of down-stream caspases-1, 3 and 6. During apoptosis caspase-3 has multiple substrates including structural and regulatory proteins and it has been considered as the major caspase regulating apoptosis [15]. ProIL-1b and proIL-18 are substrates for caspase-1 [15,68]. Recent studies have shown that caspases-1, 3 and 8 are activated during influenza A virus infection [[18,38,69], Pirhonen et al., unpublished results]. Caspases-1 and 3 are then involved in processing of IL-1b and IL-18 as mentioned above. Caspase mRNA and proprotein expression in cells is constitutive. However, in influenza A virus-infected human macrophages caspases-1, 3, and 8 gene expression is enhanced [[38], Pirhonen et al., unpublished results]. Upregulation of caspase gene expression during influenza A virus infection appears to be mediated by virus-induced IFN-a/b [Pirhonen et al., unpublished results].
5. Role of influenza A virus-induced cytokines in innate and adaptive immunity IFN-a/b is a major antiviral cytokine, which also has antiproliferative and immunomodulatory functions [10]. IFN-a/b induces the expression of PKR, RNAaseL/2% – 5% oligoadenylate synthetase (OAS), and Mx proteins which have antiviral activities. IFN-a/b receptor and STAT1 knock-out mice demonstrate the importance of IFN-a/b system against influenza and other viral infections [34,70,71]. The clearance of virus requires both innate and adaptive immune responses and in both of these responses IFN-a/b has been shown to be important [72,73]. PKR and RNAaseL/OAS are general antiviral proteins whereas Mx proteins are more selective in their antiviral spectrum [10]. Mx proteins are GTPases, exist as oligomers and depending on animal species they reside either in the cytoplasm or in the nucleus of IFN-a/b treated cells [74–79]. Murine Mx1 is a nuclear protein which selectively inhibits the replication of influenza A and other orthomyxoviruses at the level of primary transcription [80,81]. Human MxA protein is
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cytoplasmic and in addition to inhibiting the replication of influenza A virus it can mediate resistance to other viruses such as bunyuaviruses, certain paramyxoviruses, vesicular stomatitis and Semliki forest viruses [75,79]. Like murine Mx1 protein, human MxB protein is found in the cell nucleus [82], but so far no antiviral activity has been assigned to it. It is likely that PKR has a role in inhibiting influenza A virus replication, since the virus has evolved mechanisms to inhibit the activation of PKR during the infection (see above). RNAase L/OAS may also contribute to IFN-a/b-induced antiviral actions against influenza viruses [10]. Innate antiviral mechanisms restrict the replication of influenza A virus at early times of infection, which gives the host time to activate virus-specific adaptive immune responses, that are needed for the clearance of the virus. In addition of having direct antiviral properties, IFN-a/ b modifies the host immune response in several different ways. First, IFN-a/b upregulates MCP-1, MCP-3, and IP-10 gene expression [25], which results in further recruitment of monocytes/macrophages and Th1 cells to the site of infection [21,22]. Second, IFN-a/b enhances the antigen presentation by upregulating MHC gene expression [10] and stimulates the maturation of antigen presenting cells [39,83]. Third, IFN-a/b is an important cofactor in the development of Th1 response. IFN-a/b is involved in T cell survival, upregulation of IL-12 and IL-18 receptor expression, and enhancement of IFN-g production in human NK and T cells, especially in synergy with IL-18 [33,84– 87]. The data emphasize an essential role of IFN-a/b in both innate and adaptive immunity against influenza A and other viruses [72,73]. Proinflammatory cytokines IL-1b, IL-6, and TNF-a, which are readily produced by influenza A virus-infected leukocytes, do not directly contribute to the antiviral activity of the cells [10]. IL-1b and TNF-a are involved in the enhancement of MCP-1 and MCP-3 gene expression and maturation of tissue macrophages and dendritic cells. This leads to enhanced inflammatory response and further activation of the antigen presentation. IL-18, which is produced by influenza A virus-infected macrophages [33], has also proinflammatory properties, since it enhances the production of IL-1b, TNF-a, and chemokines [88]. One important function of IL-18 is to activate NK and T cell IFN-g production, which occurs in synergy with IL-12 or IFN-a/b [33,66]. IFN-g activates macrophages and primes them for higher cytokine (IFN-a/b, IL-12 and IL-18) production followed by enhanced IFN-g production in NK and T cells by macrophage-derived cytokines. This provides a positive feed-back loop between macrophages and NK and T cells. In many viral infections the production of IL-12 seems to be limited and therefore IFN-a/b may be involved in the activation of Th1 response in viral infections [33,72]. IFN-g, which is
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produced by cytokine stimulation (IL-12, IL-18, IFN-a/ b) or via cell-cell interactions (T cell receptor stimulation), enhances the development of cell-mediated immunity, macrophage activation, antigen presentation, and chemokine gene expression. The interplay with IL-1b, TNF-a, IFN-a/b, IL-18, IFN-g, and chemokines forms a complex positive feed-back network leading to infammatory response and the development of influenza-specific Th1 response.
Acknowledgements We are grateful to Dr Tapani Hovi for critical comments of the manuscript. The original work was supported by the Medical Research Council of the Academy of Finland and the Sigrid Juselius and Finnish Cancer Foundations.
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