Mechanisms of Type I Interferon Action and Its Role in Infections and Diseases Transmission in Mammals

Interferons (IFNs) are pivotal regulators of immunolog-ical processes. This paper describes mainly type I inter-ferons-α and-β and their recently recounted signaling pathways, especially connected with ISGs – interferon stimulated genes, having a crucial role in regulating IFN recruitment. Moreover, the paper shows the data on the role of interferons-α and-β in infections – not only commonly known viral infections, but also bacterial, fungal and parasitic.


INTRODUCTION
Response of an organism to infections caused by microorganisms is a highly complex process involving different types of the immune cells and different immunological mechanisms.Distinct elements and mechanisms of the immune response are activated depending on the infectious factor, and these elements are modulated by i.e. cytokines, which significantly influence the course of the immune response, including inflammation.Interferons (IFNs) belong to the group of important regulators of immunological processes.
Interferons -α and -β play an important role in regulation of the innate immune system, especially modulating the functions of macrophages and dendritic cells.In addition, these cytokines significantly influence the adaptive immune response, regulating the function of T lymphocytes, mainly CD4+ and CD8+ cells (Gessani et al., 2014;McNab et al., 2015), i.e. by influencing Th lymphocytes polarization, as well as activation of Tc, NK and B cells (Alsharifi et al., 2008;Gessani et al., 2014).IFN-I are also involved in regulation of apoptosis and autophagy -important cellular processes activated in the course of viral and bacterial infections (Trinchieri, 2010;Malireddi et al., 2013;Schmeisser et al., 2014;McNab et al., 2015).Studies showed that IFN-α and -β take part in activation of inflammasomes -functional receptors, thus regulating the IL-1 synthesis and indirectly influencing pyroptosis, an inflammatory cell death process dependent on caspase-1 which is released by inflammasomes interactions (Malireddi et al., 2013;Pothlichet et al., 2013).Both cytokines exert a pleiotropic effect by inducing antiviral immunity in infected and non-infected cells, as well as in the bystander cells, through activation of transcription of genes interacting with the virus replication cycle (McNab et al., 2015).The key factor causing activation of cell signaling pathways that lead to IFN-α and -β synthesis is recognition of the pathogen associated molecular patterns (PAMP) by the pattern recognition receptors (PRR).On the other hand both interferons induce signal transduction in the cells after binding to specific cell surface receptors: IFNAR (interferon α/β receptor), which leads to activation of transcription of IFN-stimulated genes (ISG), whose protein products play an important role in the immune response (Durbin et al., 2000;Koyama et al., 2008;Sadler & Williams, 2008;Trinchieri, 2010;Crouse et al., 2015;Durbin et al., 2013;Urban & Welsh, 2014;McNab et al., 2015).
Nod-like receptors (NLR) divided into four subfamilies (NLRA, NLRB, NLRC, NLRP) also belong to intracellular cytosolic sensors containing nucleotide oligomerization domains (NOD).NLRC: NOD1 and NOD2 contain additionally caspase recruitment domain (CARD) (Trinchieri, 2010), whereas NLRP, such as NLRP3, characterized by their PYRIN domains are involved in formation of inflammasomes and after binding viral ssRNA or dsRNA they lead to caspase-1 activation inducing pyroptosis (Koyama et al., 2008).NOD receptors recognize exogenous nucleic acids and muropeptides of bacterial walls (Trinchieri, 2010), transducing the signal via RICK (receptor-interacting serine-threonine kinase), which leads to induction of NFκB causing cytokines production i.e. during Mycobacterium tuberculosis and Helicobacter pylori infections (Trinchieri, 2010).Furthermore, RICK was shown to interact with TRAF3 and MAVS causing activation of TBK1/IKKε kinases and phosphorylation of IRF5 and IRF7 transcription factors involved in regulation of IFNβ gene expression (Trinchieri, 2010;Durbin et al., 2013).Studies showed that during infection with Newcastle disease virus (NDV) or HSV-1, high level of IRF5 expression was detected mainly in lymphoid tissue, whereas blood cells displayed low expression of this transcription factor (Malmagaard, 2004).
In addition, mitochondria of infected cells are also involved in the mechanisms of IFN-α and -β production (White & Kile, 2015).In stress conditions caused by infection mitochondrial DNA (mtDNA) is released from these organelles and binds to cyclic GMP-AMP synthase (cGAS).The mtDNA/cGAS complex activates STING, which in turn induces transcription of IFN-α and -β genes via signaling pathway mediated by TBK1 kinase and IRF3 transcription factor (White & Kile, 2015).
In addition, recent studies demonstrated that both IFNs may play a role in alternative mechanism of NLRP3 inflammasome activation resulting in the induction of pyroptosis (Malireddi et al., 2013).
Another example of indirect effect of IFN-I on T lymphocytes differentiation is the IFN-I-stimulated production and secretion of cytokines by DCs, e.g.IFNγ, which is involved in activation of Th1 lymphocytes differentiation.In addition, DCs activated by IFNα synthesize IL-15 and IL-7, whose actions induce proliferation and survival of T and NK cells.Stimulation of DCs by IFN-α and -β also results in production of IL-12 regulating Th1 cells.On the other hand high concentrations of IFN-α and -β may inhibit the activity of Th1 lymphocytes (Lopez et al., 2006;Swiecki & Colonna M, 2011;Crouse et al., 2015).Studies showed that during influenza virus and cowpox virus infections IFN-α and -β cause increased activation of NK cells and stimulate the synthesis of IFNγ via pathways mediated by STAT transcription factors, leading to regulation of Th1 cells function (Crouse et al., 2015;McNab et al., 2015).Aside from the indirect effect of IFN-α and -β on T lymphocytes, these cytokines may directly influence the functions of CD4+ and CD8+ T cells (Crouse et al., 2015;McNab et al., 2015).In the case of CD4+ T cells type I IFNs induce their differentiation into Th1 lymphocytes, which in turn synthesize IFNγ (Bonjardim 2005;Alsharifi et al., 2008;Swiecki & Colonna, 2010).IFN-α and -β also enhance the immune response of Th1 cells by inhibiting production of cytokines typical for Th2 cells, i.e.IL-4 and IL-5 (Alsharifi et al., 2008).CD4+ T lymphocytes stimulated by IFN-α and -β interact with B cells and are involved in their clonal expansion (McNab et al., 2015).On the other hand both interferons inhibit growth of CD8+ T lymphocytes through STAT1-mediated signaling pathway (McNab et al., 2015), although despite the antiproliferative function they may regulate CD8+ T cells survival and clonal expansion (Alsharifi et al., 2008;Urban & Welsh, 2014;Yesebrant de Lendock & Martinet, 2014;McNab et al., 2015).IFN-α and -β are also involved in regulation of differentiation, function and number of memory T cells (Tm) by inducing their expansion to the sites of viral infection (Alsharifi et al., 2008, Swiecki & Colonna, 2010;McNab et al., 2015;Urban & Welsh, 2014).Both interferons act positively on Tm lymphocytes function also in the case of secondary viral infections.It was demonstrated that in the course of Sendai virus infections IFN-I enhance the cytotoxic effect of Tm cells.During the immune response to lymphocytic choriomeningitis virus (LCMV) infections these cytokines induce chemokines production by Tm cells, whereas in mouse cytomegalovirus (MCMV) infections IFN-α and -β regulate IL-15 and IL-18 production exerting their effect on monocytes (Alsharifi et al., 2008, McNab et al., 2015).A significant role of IFN-α and -β was also observed during chronic LCMV infections (Ou et al., 2001).Studies using a mouse model of arenavirus infections, showed that in the course of long-term infections the cells lost their antigen-specific activity, causing repression or loss of CD8+ T lymphocytes, which are specific for this type of infections (Ou et al., 2001;Urban & Welsh, 2014).Some scientific reports also demon-strated the influence of IFN-α and -β on regulatory T cells (Treg) population, causing either a decline in the number of Tregs or induction of these cells proliferation (Hastings et al., 2015).
In addition, IFN-α and -β stimulate B lymphocytes to become antibodies producing B cells (Lopez et al., 2006;Swiecki & Colonna, 2011), although these cytokines may also decrease survival and development of the precursor and immature B cells (Alsharifi et al., 2008, Yesebrant de Lendock & Martinet, 2014).During viral infections IFN-α and -β induce the secretion of B lymphocyte stimulator (BLyS, also known as BAFF) and A proliferation-inducing ligand (APRIL) by activation of macrophages and DCs (Kiefer et al., 2012).These proteins constitute the key factors for the survival of B cells in the periphery (Kiefer et al., 2012).The positive role of both type I IFNs in activation of B lymphocytes is also connected with their ability to regulate the profile of IgG antibodies subclasses synthesized by these cells in the course of influenza virus infections (Alsharifi et al., 2008, Kiefer et al., 2012;McNab et al., 2015).Furthermore, IFN-α and -β induce production of IgM and IgA antibodies by B cells (Alsharifi et al., 2008;Swiecki & Colonna, 2010) and are required for activation of B lymphocytes in the lymph nodes, where they are additionally involved in production of TNFβ -a cytokine showing protective function towards a specific phenotype of macrophages (McNab et al., 2015).It was demonstrated that during infection of human macrophages with avian influenza virus subtype H5N1 type I interferons, especially IFNβ, are among the cytokines appearing at the earliest stages of infection (Moulin et al., 2011;Davidson et al., 2015), and can be detected before other proinflammatory cytokines and chemokines, such as: IL-12 and macrophage inflammatory protein 1β (Mip-1β) (Davidson et al., 2015).Increased level of IFNα during H5N1 virus infection is connected with augmented secretion of cytokines causing aberrations in coagulation, which was also demonstrated in the course of viral haemorrhagic fevers (Moulin et al., 2011).
IFN-α and -β not only play an important role in the regulation of the immune cells functions, but also are involved in the regulation of cellular mechanisms leading to different types of programmed cells death -caspase dependent apoptosis (Koyama et al., 2008;Davidson et al., 2015) as well as autophagy (Trinchieri, 2010;Levine et al., 2011;Durbin et al., 2013), which are activated during viral infections.Apoptosis induction requires activation of specific cell signaling pathways initialized by binding of ligands to specific surface membrane receptors.Ligands known to induce this process include cytokines, such as Apo2L protein also known as TRAIL (TNF-related apoptosis -inducing ligand), which belongs to the TNF superfamily (TNFSF10).TRAIL binds to death receptor 5 (DR5) on the cell membrane activating the extrinsic programmed death pathway.During influenza A virus infections increased levels of IFN-α and -β result in an increase in TRAIL expression in monocytes and accelerated expression of death receptors on infected epithelial cells, causing host's inflammatory re-Type I interferon action and its role in infections and diseases transmission in mammals sponse (Davidson et al., 2015;McNab et al., 2015).Increase in TRAIL and DR5 expression was also noted in the course of HIV-1 infection in pDCs (McNab et al., 2015).In addition, IFN-α and -β were shown to induce the extrinsic apoptotic pathway by regulating expression of FAS (CD95), which binds to another apoptosis inducer -FAS ligand (Crouse et al., 2015).Moreover, this programmed cell death may be induced in virus-infected macrophages via TLR4-dependent mechanisms involving synthesis of PKR regulated by ISG expression (Sadler & Williams, 2008).
On the other hand, autophagy was shown to be required for the production of IFNα by pDCs following recognition of viral antigens by TLR7 (Lee et al., 2007;Lee & Iwasaki, 2008;Swiecki & Colonna, 2010;Levine et al., 2011;Schmeisser et al., 2014).Some studies demonstrated negative regulation of RLR by IFN-α and -β, resulting from interactions of ATG (autophagy related proteins) proteins: ATG5-ATG12 involved in autophagy induction, with RIG-I domains of these receptors (Levine et al., 2011).Additionally, ATG9 was shown to negatively regulate STING (Levine et al., 2011).Other studies describe the role of IFN-α and -β in autophagy induction through the classic activation pathway mediated by IFNAR receptor, JAK and TYK kinases and STAT transcription factors (Schmeisser et al., 2014).Moreover, IFN-α and -β were shown to activate PI3K (phosphoinositide 3-kinase) pathway, which is known to negatively regulate autophagy via activation of mTORC1 (mammalian target of rapamycin complex 1) and phosphorylation of ATG proteins (Kudchodkar & Levine, 2009;Durbin et al., 2013;Schmeisser et al., 2014).Simultaneously, mTOR kinase activation by IFN-I controls cell growth and metabolism during infections with several viruses, including Epstein-Barr virus, Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV), human papillomavirus (HPV16) and retroviruses (Trinchieri, 2010;Levine et al., 2011;Durbin et al., 2013).This leads to autophagy inhibition and tumorigenesis promotion (Trinchieri, 2010;Levine et al., 2011).TBK1 constitutes another link between IFN-I and autophagy, as this enzyme is involved in activation of the complex stimulating ISG transcription, as well as regulates autophagy, which is a cellular process subjected to viral suppressive mechanisms, leading to increase in ISG expression in infected cells (Zhao, 2013).Furthermore, studies demonstrated that during infection with influenza virus, there is an accelerated production of IFN-α and -β resulting in limitation of the infection by induction of IL-5 and IL-10 secretion (Durbin et al., 2000).

IFN-α AND -β IN BACTERIAL INFECTIONS
It is commonly accepted that IFN-α and -β play a role in bacterial infections; however, detailed mechanisms of their actions have not been fully elucidated yet.Studies demonstrated that in the course of Listeria (L.) monocytogenes infection secretion of hemolytic toxin -listeriolysin O (LLO) causes increase in IFN-I production in macrophages via RLR-and STING-dependent pathways (Malireddi et al., 2013).The signal is then mediated by TBK1-IRF3 axis (Swiecki & Colonna, 2011;Malireddi et al., 2013), resulting in the synthesis of highly toxic nitric oxide (NO) (Rauch et al., 2013).Furthermore, L. monocytogenes triggers assembly of inflammasomes, such as AIM2, NLRC4 and NLRP3, and this process, connected with pyroptosis activation, is regulated by IFN-α and -β (Gonzales-Navajas et al., 2012;Malireddi et al., 2013;Pothlichet et al., 2013;Rauch et al., 2013).Type I interferons are also involved in STAT1-dependent induction of apoptosis during L. monocytogenes infection (McNab et al., 2015).It was shown that IFN-α and -β protect macrophages and lung epithelial cells infected with Legionella (L.) pneumophila through induction of MAVS and IRF3 pathway (Gonzales-Navajas et al., 2012).In addition, these cytokines were shown to induce cell death processes, including apoptosis and pyroptosis during L. pneumophila infections most probably by upregulation of pro-cell death molecules, such as BAK (BCL2-antagonist/killer 1) and TRAIL (Malireddi et al., 2013).Similar protective mechanism of IFN-I actions was demonstrated in the course of Bacillus anthracis infections.IFN-α and -β were reported to inhibit germination of B. anthracis spores (Malireddi et al., 2013;McNab et al., 2015).Francisella (F.) tularensis and F. tularensis subsp.novicida also belong to intracellular bacteria causing induction of IFN-α and -β secretion in an IRF3-dependent manner, which leads to formation of AIM2 inflammasome (Gonzales-Navajas et al., 2012;Malireddi et al., 2013;Pothlichet et al., 2013;McNab et al., 2015).During Salmonella typhimurium infections type I IFNs induce STAT4-dependent synthesis of IFNγ (Trinchieri, 2010) accelerating the cell death processes (Malireddi et al., 2013).On the other hand, during Chlamydia infections type I interferons inhibit the pathogen's growth cycle at the point of transformation of elementary body (EB) into reticulate body (RB), resulting in inhibition of Chlamydia replication (Trinchieri, 2010).It was suggested that in the case of infections with Chlamydia pneumopniae IFN-α and -β interact with IFNγ, allowing the host to effectively limit the survival of the pathogen (McNab et al., 2015).Studies conducted on mouse models showed that IFN-α and -β have protective role during Streptoccocus (S.) pneumoniae, S. pyogenes, Pseudomonas aeruginosa, Helicobacter pylori and Echerichia coli infections (Swiecki & Colonna, 2011;Malireddi et al., 2013).However, the activity of IFN-I not always brings a positive outcome for the infected organism.It was demonstrated that in the case of infections with Mycobacterium (M.) sp.elevated expression and secretion of IFN-α and -β lead to increased M. tuberculosis virulence and suppress the production of proinflammatory cytokines IL-1α and IL-1β, leading additionally to inhibition of IL-1β secretion (Ivashkiv & Donlin, 2014).Such effect can be caused by repression of the activity of NLRP 1 and NLRP3 inflammasomes in a STAT1-dependent manner, thereby inhibiting IL-1β production (Guarda et al., 2011;Gonzales-Navajas et al., 2012;Malireddi et al., 2013;McNab et al., 2015).Experimental mouse models were also used to study the effect of IFN-α and -β on the immune system in the presence or absence of the commensal bacteria (Rauch et al., 2013;Ivashkiv & Donlin, 2014;McNab et al., 2015).Lack of functional intestinal microflora, caused i.e. by antibiotic treatment, results in strong reduction of ISG expression.Moreover, in the absence of IFNAR signaling in the intestinal epithelial cells there is an increase in Paneth cells proliferation, leading to changes in the intestinal microflora.Studies showed that the commensal microbial flora of the intestines determines the basal level of IFN-α and -β production, providing the protective function and maintaining organism in homeostasis upon response to pathogenic factors (Ivashkiv & Donlin, 2014;McNab et al., 2015).P. Niedźwiedzka-Rystwej and others

IFN-α AND -β IN FUNGAL AND PARASITIC INFECTIONS
The role of IFN-I was also indicated in fungal infections.During infections with Candida (C.) albicans, Cryptococcus neoformans IFN-α and -β were shown to be involved in induction of reactive oxygen species (ROS) formation, enabling C. albicans elimination in the course of phagocytosis.In the case of Cryptococcus neoformans infections both interferons maintain the immune response of the organism by sustaining high levels of IFNγ, TNF, induced nitric oxide synthase (iNOS) and CXCL10 chemokine (McNab et al., 2015).The role of IFN-α and -β was also demonstrated during Candida glabrata and Histoplasma capsulatum infections, although the exact mechanisms of their action have not been elucidated so far (Malireddi et al., 2013;McNab et al., 2015).Nevertheless, it was documented that different forms of fungal glucans and mannans are recognized by TLR and CLR receptors activating signaling pathways which lead to cell death induction or cytokines synthesis (Malireddi et al., 2013).
The immune response of the organism is also regulated by IFN-α and -β during Leishmania (L.) major, Plasmodium (P) spp.and Trypanosoma cruzi infections.Studies demonstrated that type I IFNs induce iNOS during leishmaniasis, although too high levels of these cytokines may result in weakened iNOS induction (McNab et al., 2015;Paludan & Bowie, 2013).Furthermore, high activity of iNOS may suppress the function of macrophages, as well as formation of neutrophils and their number.This dual effect of IFN-I on the immune response was also noted in Plasmodium infections.In the case of P. berghei and P. chabaudi infections IFN-α and -β may augment the parasitic invasion suppressing the function of CD4+ T cells; whereas, during P. yoelii infections these cytokines exert a positive effect causing reticulocytosis inhibition (McNab et al., 2015) Similar results were obtained in the studies on Trypanosoma infections, as these parasites may regulate NO synthesis and negatively affect T cells producing IFNγ, the cytokine playing an important role during Trypanosoma cruzi infections (McNab et al., 2015).

SUMMARY
Despite the fact that the functions of IFN-α and -β are often described as non-immunological, their role in the immune response during viral, bacterial, fungal and parasitic infections is significant.IFN-I actions are mediated by PRR receptors expressed on the surface of the immune cells, and result in induction of cell death process, i.e. apoptosis, autophagy and pyroptosis.Furthermore, the expression of IFN-α and -β in the immune cells is tightly regulated by specific signaling pathways.