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. Author manuscript; available in PMC: 2012 Feb 17.
Published in final edited form as: Crit Rev Immunol. 2011;31(6):459–474. doi: 10.1615/critrevimmunol.v31.i6.20

Induction and Function of IFNβ During Viral and Bacterial Infection

Uma M Nagarajan 1
PMCID: PMC3281552  NIHMSID: NIHMS332509  PMID: 22321107

Abstract

Since the discovery of the protein “interferon” over 50 years ago, IFNβ, an antiviral cytokine has been well studied. In particular the pathways inducing this cytokine during viral infection have been characterized, leading to the discovery of multitude of pattern recognition receptors. IFNβ is also induced during bacterial infection, following recognition of bacterial ligands by the host viral and DNA sensors. However, the function of IFNβ during bacterial infection is variable and -sometimes detrimental to the host. This review discusses the currently identified receptors and pathways engaged in IFNβ induction during infection with emphasis on the role of IFNβ during bacterial infection.

Keywords: type I IFN, viral sensors, DNA sensors

INTRODUCTION

The existence of a host-produced viral interference factor had been observed since the last century, but the term “interferon” was first coined in 1957 by Isaacs and Lindenmann.1 Following incubation of heated influenza virus with chick chorio-allantoic membrane a new factor was released that induced “interference” in fresh pieces of chorio-allantoic membrane to live virus. Since then, interferons have been characterized in the following decades in great detail. Of the interferons, the group known as type I IFN specifically comprises a family of cytokines that include multiple (>11) IFNα genes and a single IFNβ gene. Other IFNs include type II IFNs (IFNγ), which has integral immune function and type III IFNs (IFNλ), also an antiviral cytokine family [reviewed in2, 3]. It is now known that type I IFNs (IFNα and IFNβ) are the major contributors in innate immunity serving as the first line of defense against viruses. They are more than just anti-virals as they play a major role in linking innate to adaptive immunity. Over the last two decades a tremendous amount of data has been generated on immune functions of type I IFNs and the pathogen recognition receptors (PRRs) involved in the induction of this important anti-viral defense. Type I IFNs are produced in response to number of viral and bacterial infections in multiple cell types including lymphocytes, macrophages, endothelial cells and fibroblasts. Leukocytes are a major source of IFNα, with plasmacytoid dentritic cells (DC) as major producers.4 Fibroblast/epithelial cells are major producers of IFNβ, though most cell types can make the cytokine upon stimulation. Both IFNα and IFNβ signal through a common receptor IFNAR that consists of IFNAR1 and IFNAR2 chains. Binding of the cytokines to the receptor leads to the activation of JAK-STAT signaling pathway, which results in direct antiviral effects of type I IFNs and expression of interferon-inducible genes and. This review is focused on IFNβ, a key interferon rapidly induced following infection. Specifically, the receptors engaged in induction of IFNβ are discussed in detail. The role of IFNβ during viral infection has been reviewed extensively previously.57 Therefore, the less defined role of IFNβ during bacterial infection is discussed. Further, the immune functions of IFNβ are reviewed in the context of an infection model to understand the disease outcomes, specifically using mice deficient for type I IFN signaling or following in vivo neutralization of IFNβ. Lastly, in order to appreciate the complexities of the different signaling pathways that induce type I IFNs, the mechanisms by which viruses target these pathways are discussed.

1. THE MAJOR PATHWAYS OF TYPE I IFN INDUCTION

A multitude of intracellular pathways can lead to type I IFN induction following viral/bacterial infection. It is likely that the major driving force in evolution for existence of several redundant pathways that induce type I IFN, is viral infections. Further, viruses can target a number of these pathways by degrading or inactivating specific components of the pathway to avoid IFN-mediated killing.810 The existence of a vast array of receptors and pathways underscores the important role of type I IFN in immune defense.

A. The pathogen sensors

A number of pattern recognition receptors (PRR) exist in the cells to detect viral infections, a majority of them evolved to sense viral DNA and RNA. Here we review the receptors specifically engaged in type I IFN induction. It is important to note that some of these receptors also induce inflammatory cytokines, such as TNFα or IL-6 during infection.

1. The TLRs

The Toll-like receptors (TLRs) are type I trans-membrane receptors with a unique pathogen recognition Leucine rich repeat (LRRs), a cysteine rich domain, a transmembrane domain, and an intracellular Toll/IL-1R (TIR) motif [reviewed in11, 12]. The TLRs are responsible for the recognition of unique microbe-associated molecular patterns (MAMP) and initiate an immediate cytokine response upon infection.13 At least 11 different TLRs are known in humans and mice, and ligands for each have been identified. 13 The TLRs involved in type I IFN induction are schematically represented in Figure. 1. TLR4 is localized in the plasma membrane and is known to traffic between the Golgi and the plasma membrane,14 bind to LPS, and induces a potent IFNβ response. TLR3 is located intracellularly in the endosomal compartment in human DCs but is expressed on the cell surface in fibroblasts15 and can bind viral dsRNA to induce IFN response. Induction of type I IFNs by cross-linking of TLR3 and TLR4 is mediated through the adaptor molecule TRIF (Toll-IL-1 receptor domain-containing adaptor inducing IFNβ, also called TICAM).1619 TLR7 and TLR9 form a subgroup within the TLR family due to their exclusive intracellular localization in endoplasmic reticulum (ER) and recognition of MAMPs (ssRNA and CpG DNA respectively) in endosomal/lysosomal compartments.20, 21 Unlike TLR3/TLR4, TLR7 and TLR9 mediate induction of type I IFNs in a MyD88-dependent manner,20, 2224 which is a common adaptor molecule25 through which all TLRs signal (except TLR3) to activate the MAP kinase/NFκB pathway. This unique ability of TLR7 and TLR9 to induce type I IFN in a MyD88-dependent manner separated from their ability to induce inflammatory cytokines is due to their ability to migrate to a specialized lysosome-related organelle by forming a complex with adaptor protein-3.26 In addition to these TLRs, TLR2 has also been reported to induce IFNβ in Ly6C high inflammatory monocytes in response to viral, but not bacterial ligands.27

Figure 1. Major pathways and sensors for IFNβ induction.

Figure 1

A. TLRs: TLR4 and TLR3 can sense bacterial LPS and ds RNA respectively, and recruit the adaptor molecule TRIF. This leads to activation of NFκB and IRF3, mediated by the respective kinases. TLR7 and TLR9 recognize ssRNA and CpG DNA respectively in the lysosomal compartments and recruit adaptor molecule MyD88, leading to activation of NFκB and IRF7 activation. B. RLR/NLR: Recognition of viral dsRNA by MDA5 and RIG-I or ssRNA by NOD2, results in recruitment and activation of MAVS, and STING, leading to IRF3 phosphorylation. C. DNA sensors: This group is comprised of structurally unrelated proteins that recognize different forms of DNA. RNA polymerase III binds to polydAdT, and transcribes it to RNA, which in turn is recognized by RIG-I. IFI16 is major DNA sensor for longer DNA (>70 bp), and functions independent of MAVS. Bacterial metabolites di-cyc-AMP and di-cyc-GMP are recognized by unknown sensors. All DNA sensors require the adaptor molecule STING for downstream activation. LRRFIP1 recognize cytosolic dsRNA and DNA, and activates β-catenin. All pathways converge to binding of phosphorylated nuclear IRF3 and p65 to the IFNβ promoter resulting in IFNβ gene transcription.

2. The NLR and RLR pathway

In addition to the TLRs, innate immune cells possess a parallel set of PRRs that reside in the cytoplasm. Cytosolic PRRs that induce type I IFN include the Rig-like receptors (RLRs) and NOD-like receptors (NLRs), which recognize double-stranded viral RNA28 and bacterial cell wall components,29 respectively. Many of the MAMPs are identical or analogous to the structures recognized by TLRs, suggesting that RLRs and NLRs might have emerged during evolution to complement the surveillance of TLRs for sensing MAMPs where TLRs cannot access. It has also been proposed that NLR signaling may be needed for redundancy when TLRs become refractory to their ligands after initial MAMP exposure, as in the case of TLR4 desensitization.30

RLRs consist of the RNA helicases Rig-I and MDA5. RIG-I and MDA5 consist of a caspase activation recruitment domain (CARD), a helicase domain and a RNA binding/repressor domain [reviewed in31]. Viral RNA binds to the RNA-binding domain to induce a conformational change in the presence of ATP. The conformational change exposes the CARD domain, which is masked by helicase and repressor domain, and allows its interaction with downstream adaptor molecule. RIG-I and MDA5 have some overlapping specificity with both being able to respond to double stranded RNA,32 yet also have distinct roles in sensing viruses.33 RIG-I is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus, and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Uncapped single stranded RNA can also be sensed by RIG-I,34 suggesting that this protein might be involved in sensing bacterial RNA in addition to viral RNA. Similar to TLRs, RLRs exhibit signaling convergence by using the adaptor protein mitochondrial anti-viral signaling protein (MAVS),35 also known as IPS-1,36 and Cardif,37 linked via homotypic caspase recruitment domain (CARD) interactions. Recognition of viral DNA by RIG-I activates MAVS, by forming large prion-like aggregates of MAVS on mitochondrial membrane.38 Aggregated MAVS associates with TRAF3, leading to potent activation of Interferon response factors (IRF) transcription factors and IFNβ expression.39 In addition to TRAF3, an ER-associated host protein called stimulator of interferon genes (STING) functions downstream of the MAVS signaling cascade and is essential for RIG-1/MDA5-mediated IFNβ induction.40 The NLR and RLR pathway inducing IFNβ are summarized in Figure 1.

The NOD-like receptor (NLR) family is very large (>20 proteins), comprised of proteins with a LRR domain, a nucleotide-oligomerization domain, and CARD domain, with diverse function. Among the NOD family of proteins, NOD1 and NOD2, have been implicated in IFNβ induction. The NOD proteins were originally thought to sense only the bacterial cell wall components γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP)29 and muramyl dipeptide (MDP),41 respectively. Unexpectedly however, it has been determined that NOD2 can also recognize structurally unrelated viral single stranded RNA.42 Upon recognition of ssRNA, NOD2 can signal via MAVS to induce IFNβ similar to RLRs. Conversely, when recognizing bacterial ligands, NOD1 and NOD2 can only utilize the adaptor protein Rip2 to activate NF-κB and MAPK43 via TRAF2 and TRAF5.44 This contributes to the NFκB activation, which is required for optimal IFNβ induction.45 The explanation for the disparate use of MAVS in one circumstance and not the other remains unknown. The vast majority of the other characterized NLRs are known to be involved in activation of caspase-1 [reviewed in46]. Unlike the viral RNA sensors, the role for NOD in IRF3 activation appears not to be critical, but NOD1/2 contributes to NFκB activation, which is required for optimal IFNβ induction.

3. The DNA-sensors

More recently a number of DNA sensors that induce type I IFN have been discovered. These sensors likely evolved to detect DNA viruses or intracellular bacterial infection. The DNA sensors discovered to date do not classify into a single family, as each have unique structure. DNA-dependent activator of IFN-regulatory factors (DAI/ZBP-1), the cytosolic DNA sensor was the first to be discovered.47 DAI can sense dsDNA and initiate association with IRF transcription factors to induce IFNβ. Recently it has been demonstrated that DAI played a specific role in inducing IFNβ during human cytomegalovirus (HCMV) infection in fibroblast cells.48 RNA polymerase III is another surprising sensor that detects cytosolic B-form DNA such as poly dA-dT and Epstein Barr virus DNA and converts them to 5′-ppp RNA to induce IFNβ through the RIG-I-MAVS pathway.47, 49 Recently, IFI16 a novel pyrin-domain containing protein, has been shown to detect ds DNA of longer lengths (70 bp).50 IFI16 with AIM251 forms a unique group of DNA sensors containing a PYRIN domain. These newly discovered DNA sensors seem to directly bind to the cytosolic DNA such as Vaccinia virus or HSV-1 ds DNA, and recruits STING resulting in IFNβ expression. IFI16 functions universally in mouse and human cells and directly recruits STING, with no involvement of MAVS. Recently, another DNA sensor, LRRFIP1, has been shown to bind DNA during VSV infection and Listeria monocytogenes infection to induce a IFNβ response via the β-catenin pathway.52 In addition to the above-mentioned specific DNA sensors, the HMG-B group of proteins is also involved in the IFNβ response.53 The function of HMG-B is upstream to activation by TLR3, TLR7 and TLR9 pathways suggesting that selective activation is downstream to promiscuous sensing by HMG-Bs.

4. Other receptors

The ambiguity present regarding a huge number of sensors that sense viral/bacterial products in the cytosol, underscores the point that the field of cytosolic receptors is in its relative infancy with new pathways still being delineated. For example, delivery of the bacterial regulators cyclic di-GMP54 or cyclic-di-AMP55 into the cytosol triggers PRR pathways leading to IFN-β expression. The specific host receptors recognizing these bacterial second messengers are not yet known. A specific pathogen triggering the cyclic di-GMP recognizing pathway has not yet been identified, but intracellular infection with Listeria monocytogenes has been shown to induce a IFNβ response through the release of cyclic di-AMP.55 Similarly, bacterial substrates such as gluconates can induce type I IFN response, as in the case of L. monocytogenes infection,56, 57 through an unknown cytosolic surveillance pathway. However, the observation that STING is involved downstream of dsDNA sensors [IFI1650, 55, 58 and DAI59], RNA sensors [RIG-I/MDA5/MAVS58] and cyclic di-nucleotide sensors60 suggests that STING serves as a major adaptor protein to many cytosolic pathways, analogous to the role of MyD88 for the TLRs.

B. Kinases and transcription factors regulating type I IFN induction

Induction of type I IFNs is regulated at the level of transcription by IRF and NFκB.61 The IRF family of transcription factors consists of nine members (reviewed in62). Three of these transcription factors, namely IRF3, ISGF3, and IRF7, have been characterized as crucial elements n the regulation of type I IFNs. IRF3 is constitutively expressed in most cell types; as discussed, specific binding of MAMP to PRRs results in IRF3 phosphorylation by the kinases TBK or IKKε, and nuclear translocation.63 Nuclear IRF3 plays an important role in initiation of IFNβ transcription in conjunction with AP-1 and NF-κB.6466 The other 2 transcription factors (IRF7 and ISGF3) contribute after autocrine or paracrine signaling of IFN-β via the IFNAR through activation of the JAK/STAT signal transduction pathways.67 IRF7 is expressed at low levels inside most cell types but can be induced several fold following initial IFN-β signaling. Unlike IRF3, which does not upregulate IFN-α genes, IRF7 has been termed as a master regulator because of its ability to regulate both IFN-β and also IFN-α genes.68 IRF7 translocates to the nucleus and binds synergistically with IRF3, c-jun, and NFκB to the IFNβ promoter, acting as a positive feedback loop.69 ISGF3 (a trimeric complex composed of STAT1, STAT2, and IRF9)70 and IRF7 are able to bind to promoters with interferon-sensitive response elements (ISRE),71 leading to the induction of ISGs and enhanced expression of IFN-β.72 The common convergence point for all receptor-ligand cross-linking pathways of type I IFN induction is the activation of TBK/IKKε kinases73 and the nuclear translocation of IRF3/IRF7.

2. MECHANISM OF TYPE I IFN INDUCTION DURING INFECTION

The field of PRRs involved in IFNβ induction is largely advanced by the study of virally-induced IFNβ. A recent review has described RNA viruses and cytosolic sensors involved in IFNβ induction in great detail.74 The DNA viruses and their receptors have also been discussed in the previous section along with the nucleic acid sensors. Hence, this section is focused mainly on the less well-characterized mechanism of type I IFN induction during bacterial infection.

It is well known that number of bacterial pathogens can induce a potent type I IFN response. [(reviewed in75, 76] However, the PRRs used by different bacteria vary significantly depending on their intracellular niche. Gram-negative bacteria, especially commensals and pathogens such as Salmonella spp. and Yersinia spp., produce LPS with hexacylated lipid A that are well-recognized by TLR4 on the cell surface to induce a potent IFNβ response via the TRIF pathway.77 Purified E. coli LPS is a potent stimulator for this pathway and routinely used as a positive control for TLR4 activation.78 However, a number of gram-negative bacteria including Chlamydia spp, Legionella spp., and Francisella spp. produce weak stimulatory LPS, which is poorly detected by TLR4 and in some cases detected by TLR2.79 In addition to LPS, other bacterial ligands can stimulate TLR4, as in the case of purified hsp60 from Chlamydia spp.80 However, during chlamydial infection, there is no role for TLR4 in IFNβ induction.81 Therefore, studying the PRR used during specific bacterial infection should be ideally determined in the context of whole bacteria and/or its mutant lacking specific MAMP, rather than purified bacterial MAMPs. Interestingly, for a number of gram-negative pathogens that induce a type I IFN response, such as Chlamydia spp, S. typhimurium, S. flexneri, and E. coli, cell invasion and in certain cases intracellular growth is a prerequisite for this response. This prerequisite would suggest that intracellular receptors would be preferred over membrane-expressed TLR4 during infection. Intracellular TLRs have been suggested to be involved in bacterial-induced IFNβ in a few instances. During infection of conventional DC with group B streptococcus, a phagosomal bacteria, IFNβ response occurs through the TLR7-MyD88 dependent pathway.82 In another instance, intracellular TLR3 signaling during Chlamydia muridarum infection induces IFNβ in a specific oviduct epithelial cell line.83 This data contradicts a previous finding that showed TLR-independent STING involvement for IFNβ induction in the same cell line,45 suggesting activation of multiple pathways during infection. These are clearly exceptions; as for a number of pathogens the route to IFNβ induction appears to be TLR-independent.

Chlamydia muridarum induces IFNβ independent of TLR2 and TLR4, and some contribution from MyD88 pathway was suggested.81 However, when the authors used macrophages deficient for both TLR4 and MyD88, the contribution from MyD88 disappeared suggesting a role for intracellular receptors.45 Subsequently, the downstream adaptor STING was demonstrated to be necessary for chlamydial-induced IFNβ induction in both HeLa cell line and mouse oviduct epithelial cells. IFNβ induction was also MAVS independent ruling out the viral RNA sensing mechanism but the specific sensor upstream of STING has not been identified. However, Chlamydia pneumoniae in HUVEC cells required MAVS for IFNβ induction, unlike C. trachomatis infection. Once again these data suggest that multiple pathways are used for IFNβ induction depending on the specific species or cell type used. Chlamydia spp. possesses type III secretion (T3S) apparatus, which appears to be essential for IFNβ induction, based on studies using T3S inhibitors.84 However, in the absence of chlamydial T3S mutants, and the fact that the inhibitors also block induction of other cytokines such as IL-6, it is not clear if the inhibitors block delivery of ligands or change inclusion membrane permeability to prevent leakage of bacterial products. The specific chlamydial product that is sensed to induce IFNβ is unknown, although one could speculate that it is nucleic acids.

Induction of type I IFN by another gram-negative pathogen, Legionella, has been well described. Induction of type I IFN by L. pneumophila requires a type IV secretion system but not the TLRs,85 and the MAMP was suggested to be DNA. However, the evidence for direct bacterial DNA translocation was not conclusive. A recent report clearly rules out the role for DNA but suggests that viral sensors RIG-I and MDA5 mediate type I IFN response during Legionella infection and, it is specifically mediated by bacterial RNA and not DNA.86 However, the question whether Legionella spp. DNA or RNA is translocated through type IV secretion system is still open. Gram-negative Fransicella tularamia follows a similar trend of not requiring TLRs but unlike Legionella spp. does not require RIG-I/MDA5 pathway for IFNβ induction.87 There is a requirement for a type VI secretion system, and it is suggested that nucleic acids escaping into the cytosol from disruption of phagosome induce an IRF3 dependent IFNβ response. This in turn is critical for activation of DNA sensing AIM2-inflammasome pathway.88

Amongst the gram-positive bacteria, Mycobacterium tuberculosis also shows a TLR-independent source for type I IFN requiring NOD2-RIP pathway.89, 90 M. tuberculosis also requires type VII secretion system for IFNβ induction.90 In several of these cases, such as Yersinia spp.,91 and M. tuberculosis that show a requirement of secretion system for IFNβ induction, direct delivery of bacterial components through the secretion system has not been demonstrated. Listeria monocytogenes is probably the most well studied gram-positive pathogen with respect to the mechanisms of type I IFN induction. Earlier it was suggested that a “cytosolic surveillance” mechanism was responsible for L. monocytogenes - induced type I IFN. These studies used Listeriolysin O-deficient mutant that fails to exit into the cytoplasm and also fails to induce type I IFN response.92, 93 Subsequently, it was shown by other investigators that IFNβ induction during L. monocytogenes infection is independent of TLR4, TLR2, RIP2, and NOD-2 activation pathways and MAVS.94, 95 Further studies showed the requirement of the downstream adaptor molecule STING for L. monocytogenes - induced IFNβ induction.96 Using genetic screening methods, a multi-drug transporter (MDR) mutant of L. monocytogenes, was shown to be defective for IFNβ production,56 suggesting transport of small molecules through these transporters could induce IFNβ induction. Using mutants that overexpressed MDR, Woodward et al. showed that secreted cyclic-di-AMP made by L. monocytogenes is a major player in inducing IFNβ.55 The specific sensor for this cyclic dinucleotide has not yet been identified although this pathway does function through downstream adaptor molecule STING. A more recent study demonstrated a role for novel cytosolic nucleic acid-sensor LRRFIP1 that induced type I IFN in a β-catenin-dependent pathway during L. monocytogenes infection.52 It was not demonstrated if STING is required for activation of this pathway. Overall during L. monocytogenes infection, multiple sensors are involved in the induction of IFNβ, but there is no role for the TLR pathway and the adaptor MAVS.

3. ROLE OF TYPE I IFN DURING INFECTION

A. A protective role in viral infection but conflicting role in bacterial infection

Type I IFNs are deleterious to viruses in a number of ways that prevent viral replication. The specific role of type I IFNs during viral infection has been well reviewed57 and includes direct killing, activation of antigen presenting DC, clonal expansion of virus-specific T cells and antibody producing B cells. Overall, the role of type I IFN during viral infection is protective.

In the case of non-viral pathogens, type I IFNs have been reported to have a highly variable role. During Pneumonitis murina fungal infection, which can cause life-threatening pneumonia in HIV-infected patients, type I IFNs have been shown to be beneficial.97 IFNAR−/− mice exhibit delayed fungal clearance and increased inflammation. Likewise, during bacterial infection the role of type I IFNs is compounded by number of factors, including infecting bacterial strain and infected tissue site. As a consequence, it has not been possible to assign a global beneficial or detrimental role for type I IFNs during bacterial infections. Few examples of beneficial role for type I IFNs include a slightly enhanced replication of M. tuberculosis in the lungs of IFNα/β receptor-deficient mice compared with WT controls.98 Studies in mice treated with purified IFN preparation or IFN neutralizing antibodies indicated increased resistance against Streptococcus pneumoniae infection,99 suggesting that type I IFN plays a critical role directly or indirectly in controlling S. pneumoniae infection. Likewise during Group B streptococcus, pneumococci and E. coli infection, type I IFN is protective as IFNAR−/− mice show decreased survival and increased bacterial load100 A marked reduction in IFNγ, (Nitric oxide) NO, and tumor necrosis factor α (TNFα) was observed in infected IFNAR−/− macrophages, suggesting that IFNα/β boosted macrophage function and improved host resistance. Another instance of protective function with type I IFNs was observed with Franscisella novicida infection, where IFNAR signaling was required for caspase-I activation, inflammasome-mediated cell death, and IL-1β/IL-18 release.87 There are also a couple of instances where type I IFN signaling affects in vitro cell function but has a minimal role in vivo due to compensation from other pathways. For instance, during L. pneumophila, infection, type I IFN has a restrictive role in vitro101 but no role in vivo.86 Similarly, no difference in bacterial load between WT and IFNAR−/− mice was observed in C. pneumoniae lung infection.102

In most other bacterial infections, particularly during intracellular bacterial infections, type I IFN is detrimental to the host. During systemic L. monocytogenes infection using IFNAR−/− mice and IRF3−/− mice, it was found that IFNAR−/− mice were 1000-fold more resistant to L. monocytogenes infection103, 104. This resistance to infection was correlated to elevated levels of IL-12 p70 and increased numbers of CD11b macrophages, owing to a block in macrophage apoptosis in the IFNAR−/− strains.103, 104 Likewise, mice lacking IFNAR are significantly protected against a lethal Staphylococcus aureus strain in comparison to WT mice,105 providing another example of detrimental role of type I IFNs. In an independent study, intra-nasal administration of IFNα/β in mice infected with a clinical isolate of Mycobacterium tuberculosis displayed increased bacterial load and reduced survival,106 which was associated with the dampening of antigen-specific Th1 response. With respect to Chlamydia muridarum infection, both in the lungs and genital tract, type I IFN was shown to be detrimental. In the lung infection model,107 IFNAR−/− mice showed less bacterial burden, weight loss and less pathology. The protection was attributed to lower macrophage apoptosis in the IFNAR−/− mice. In the genital infection, there was a slightly enhanced clearance of infection in the IFNAR−/− and significantly reduced oviduct pathology.108 The mechanism for improved bacterial clearance in IFNAR−/− mice was attributed to improved antigen specific T cell response. A similar outcome of enhanced infection clearance and reduced pathology was observed in genital chlamydial infection during IFNβ neutralization in wild-type mice, confirming the detrimental role for IFNβ.109 A surprising role for type I IFNs was also discovered in development of Lyme arthritis during Borrelia burgdoferi infection in mice, wherein type I IFN receptor blocking by antibodies dramatically reduced arthritis.110 Furthermore, during Leishmania amazonensis infection, type I IFN regulates neutrophil infection and regulates innate immunity.111 As a consequence, IFNAR−/− mice develop fewer lesions and lower tissue burden of parasites due to enhanced neurophil/monocyte recruitment. Overall, the role of type I IFN during bacterial infection appears highly diverse.

B. Immune function of IFNβ during infection

To understand the mechanism behind the conflicting role of type I IFN, the pleiotropic immune functions of this cytokine needs further understanding. Type I IFNs are a potent regulator of adaptive immunity, affecting multiple cell types, including macrophages, lymphocytes, and DCs. IFNα/β induces the expression of interferon response genes (IRG): IP-10 (Interferon inducible protein 10), MCP-5 (monocyte chemoattractant protein-5), RANTES (Regulated upon Activation, Normal T-cell Expressed and Secreted), iNOS (inducible nitrous oxide synthase), and GARG-16 (glucocorticoid attenuated response gene). The IRGs are important for Th1 maturation.112 Type I IFNs have also been implicated in the generation of cytotoxic T cells and promotion of in vivo T cell proliferation,113 and T cell survival.114 Besides its immuno-stimulatory role, type I IFNs are also known to inhibit IFNγ induced MHC class II expression,115117 a function that contradicts its TH1 stimulatory role. Type I IFNs have also been shown to inhibit maturation and activation of mouse Langerhans cells.118 IFNβ has been reported to augment119 or downregulate IL-12 and CD40 expression in DC.120 Further, therapeutic administration of IFNβ in multiple sclerosis patients led to inhibition of IL-12 and augmentation of IL-10 production.121 These paradoxical effects of IFNβ on the expression of Th1-type immune responses partly depends on the timing of DC exposure (during maturation vs. mature) to IFNβ, with a positive role if exposed during DC maturation and a negative role if exposed after maturation.112 Importantly, type I IFNs are also pro-apoptotic and induce the expression of a number of proapoptotic genes, which play a major role in pathological outcomes in number of infection modes. The proapoptotic function of type I IFNs can also have a direct role in the immune modulation, resulting in conflicting functions. In summary, type I IFNs are either favorable or detrimental to the host during bacterial infection depending on their effect on, i) pathogen killing ii) enhancing or inhibiting the Th1-type response depending on tissue site or kinetics of immune response, and/or iii) inducing an apoptotic response. Overall, the type I IFN-dependent immune response and outcome is largely pathogen- and tissue-dependent.

4. FUTURE DIRECTIONS AND PERSPECTIVES

The most fascinating feature of IFNβ inducing pathways are the resources used by the cell to detect a wide variety of pathogens and generate this important cytokine. During evolution of the immune system, viral infections are the major players in driving this arm of innate immunity to the complex form to which it presently exists. Several examples of viral inhibition of these pathways are known. For instance during HIV-1 infection, HIV-1 protease targets cytosolic RIG-I to lysosome, inhibiting IFNβ induction,8 Influenza virus polymerase also inhibits IFNβ induction by directly binding to MAVS (IPS-1).9 A number of viruses directly inhibit activation of IRF3. For instance, Varicella zoster immediate early protein 62 blocks IRF3 phosphorylation at 3 different serine residues.10 The structural protein NS5 of some members of flavivirus family function as the major antagonist for IFN-dependent STAT-1 phosphorylation as in the case of West Nile virus.122 Overall in this race between the host and the viruses, the pathogen is evolving to evade the host immune system to ultimately be less pathogenic and survive. The host on the other hand is evolving relatively slower to eradicate the pathogens as they target the host’s antiviral signaling pathways. There are no winners here until commensalism is reached. Until then the host and the pathogens drive each other’s evolutionary variations in a complementary fashion. In the case of bacterial infection, no such direct inhibition of host factors engaged in IFNβ induction has been reported. However, in instances where IFNβ is detrimental, one can speculate that the intracellular bacterial infection likely exploits this antiviral pathway to its advantage. This could be particularly relevant during bacterial-viral co-infection. For instance during co-infection of Chlamydia trachomatis with human pappiloma virus, type I IFN response resulting from the viral infection is likely to benefit C. trachomatis infection. Whether this results in persistent infection for either or both pathogens is not clear, although there is some evidence for C. trachomatis infection to be a risk factor for persistent HPV infection.123

A lot has been learnt about type I IFN induction in the past few years. However, still many unknowns exist. These include the cytosolic PRRs that function upstream to STING during several bacterial infections, the interaction between the sensors and the adaptor molecules and the cell-type specificities of these interactions. Over the following decades, we expect to see discovery of more sensors, which could be used as potential therapeutic targets during infection and autoimmunity.

Acknowledgments

Thanks to Daniel Prantner, Dr. Laxmi Yeruva and Mr. John Gregan for assistance and suggestions. U.M.N has received a grant support from NIAID AI067678.

Abbreviations

CARD

Caspase recruitment domain

IFNAR

IFN α/β receptor

IRF3

Interferon response factor 3

LRR

Leucine rich repeats

LPS

Lipopolysaccaride

MAMPs

Microbe-associated molecular patterns

MAPK

Mitogen activated protein kinase

NOD

Nucleotide oligomerization domain

NLR

NOD-like receptor

PGN

Peptidoglycan

PRR

Pathogen recognition receptors

RLR

Rig-like receptors

STING

Stimulator of IFN signaling

TBK

Tank-binding kinase

TLR

Toll-like receptors

T3S

Type III secretion apparatus

TRIF

Toll-IL-1 receptor domain-containing adaptor inducing IFN-β

WT

wild-type

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