Successful defense against pathogens requires both, the eradication of the infectious agent by the immune system as well as tissue protection against the damaging effects of the immune response. Increasing evidence indicates that many if not most infectious diseases result from insufficient resilience, i.e., from a failure of the infected host to repair and regenerate destroyed tissues, rather than from inefficient pathogen clearance (1–4). Mechanisms which preserve the integrity of host tissues during the intensive inflammatory response against the pathogen remain incompletely understood. Recent studies established that successful tissue protection during infection requires systems which balance the immune response as well as mechanisms which restore tissue homeostasis. These mechanisms are often interdependent and result from messengers like growth factors, cytokines, or lipids produced by immune cells (1–4). Examples include the anti-inflammatory cytokine IL-10, the tissue regeneration promoting IL-22 and amphiregulin, the tissue remodeler TGF-β, or the pro-resolving lipid lipoxin (5–8). Remarkably, several recent studies demonstrated that type I interferons (IFNs) can also act as critical resilience-promoting cytokines during infections with several streptococcal species (9–11). Such protective functions are in marked contrast to detrimental effects of type I IFN during infections with many other bacterial species (12, 13). The reasons for the ambivalent roles of type I IFNs in bacterial infections remain poorly understood. However, it appears that the ability of type I IFNs to both suppress and stimulate immune responses is of critical importance (Table 1; Figure 1). This review focuses on the role of type I IFNs in balancing pro- and anti-inflammatory processes as well as cell survival and cell death programs during antibacterial defense and discusses how these effects determine the outcome of an infection.

Type I IFNs were described more than a half century ago as products which are secreted by virus-infected cells and interfere with virus replication in autocrine and paracrine ways (40). It is now known that type I IFNs are cytokines produced in response to viral, bacterial, and fungal pathogens, as well as parasites. The effector mechanisms of type I IFNs mainly derive from products of genes which are transcriptionally regulated by type I IFN signaling. Type I IFNs induce hundreds of interferon-stimulated genes (ISGs) through activation of the homodimeric STAT1 and the heterotrimeric STAT1–STAT2–IRF9 (i.e., ISGF3) transcription factors (41). Bacteria trigger type I IFN production mostly following the recognition of bacterial nucleic acids or the Gram-negative cell wall component lipopolysaccharide (LPS) by innate immune receptors (12, 42). The induction mechanisms have been best studied for IFN-β which belongs together with IFNα4 to the first type I IFNs produced during infection and is the driver of other type I IFN genes (43, 44). The induction of IFN-β by bacterial DNA is complex and involves different pathways. The most common mode of IFN-β induction by bacterial DNA is through the cytosolic DNA sensor cyclic GMP-AMP synthase, as described for Francisella novicida, group B streptococcus (GBS) (Streptococcus agalactiae), Legionella pneumophila, Listeria monocytogenes, Mycobacterium tuberculosis, and Neisseria gonorrhoeae (45–51). The cytosolic DNA sensor Ifi204 (IFI16 in humans) contributes to IFN-β induction in the course of F. novicida and L. monocytogenes (48, 49). The signaling events downstream of these DNA sensors involve the STING–TBK1–IRF3 pathway driving the IFN-β gene transcription. L. monocytogenes can activate this pathway also independently of DNA sensing. This alternative mechanism is driven by binding of the bacterial product c-di-AMP to STING (51, 52). The recognition of bacterial DNA through unmethylated CpG motif-containing DNA by the endosomal Toll-like receptor 9 can also contribute to IFN-β induction, although the importance and relevance of this pathway in the context of the overall IFN-β production and host response have not been entirely clarified (42). Bacterial RNA has been recently established as another key IFN-β inducer. A short and highly conserved sequence found in the bacterial 23S rRNA is recognized by the mouse TLR13 leading to Myd88- and IRF5-dependent IFN-β induction (9, 53–56). Human cells employ TLR8 as IFN-β-inducing RNA sensor rather than TLR13 which is missing in humans (9, 53, 57–59). The precise nature of bacterial RNA triggering the human TLR8 remains to be identified.

IFN-β induction by LPS occurs after binding of this ligand to the TLR4 and the following internalization into the endosome (60). Subsequently, a TRIF-dependent activation of the kinase TBK1 causes phosphorylation of the transcription factor IRF3 to stimulate IFN-β gene transcription. Endosomal signaling has been also implicated in IFN-β induction by TLR2 in response to Gram-positive bacteria, although this mechanism appears to be restricted to specific immune cells and/or pathogens (61–63). The cytosolic receptors NOD1 and NOD2 were reported to trigger IFN-β production following infection with Helicobacter pylori and M. tuberculosis, respectively (20, 64). NOD2 engagement can induce IFN-β also in responses to Staphylococcus aureus (14).

While the pathways causing IFN-β induction by bacteria are relatively well understood, more studies are needed to assess the importance of individual pathways for the overall IFN-β production in whole organism rather than cells. One of the rare studies on this topic revealed that the dominant IFN-β-inducing pathway during infection with Streptococcus pyogenes (group A streptococcus) is the TLR13-mediated RNA recognition pathway (9).

Additional work is also needed to clarify the key IFN-β producing cells, as investigated during, e.g., L. monocytogenes infections (65–67) and the reported cell type-specific features of IFN-β induction (12, 15, 16).

Type I IFNs’ ability to stimulate immune responses against viruses has been established very early after their discovery but it soon became clear that these cytokines exhibit also immunosuppressive activities. The first evidence for such immunosuppressive activities was provided in a study showing that type I IFNs were able to reduce carrageenin-induced footpad swelling (68). Thus, type I IFNs are now regarded as immunomodulatory cytokines capable of enhancing or dampening the immune response, depending on the context. This ambiguousness contributes to the disparate and still incompletely understood roles of type I IFNs during bacterial infections. Importantly, no unifying principles have been found to date: neither the beneficial nor detrimental effects of type I IFN signaling correlate with the broad pathogen classification into Gram-positive and -negative, extra- and intracellular pathogens, or the route of infection (Table 1; Figure 1).

Immunosuppressive effects of type I IFN signaling are beneficial during infection with the Gram-positive largely extracellular human pathogen S. pyogenes (9). S. pyogenes is the causative agent of mild (e.g., pharyngitis and scarlet fever) but also invasive and life-threatening infections (e.g., cellulitis, necrotizing fasciitis, and streptococcal toxic shock syndrome). Mice deficient in the type I IFN receptor IFNAR1 are more susceptible to subcutaneous S. pyogenes infection, which is a relevant model of severe invasive infection of the soft tissue (15). Type I IFN signaling promotes resistance against S. pyogenes by suppressing the transcription of the Il1b gene (9). The absence of type I IFN signaling results in an unrestricted production of IL-1β thereby causing a lethal hyperinflammation and organ damage. Importantly, type I IFN signaling balances rather than prevents Il1b transcription so that a controlled and life-saving IL-1β production is achieved (9). The key IFN-β producer and effector cells in this infection model are both LysM+ and CD11c+ myeloid cells (9).

Immunomodulation by type I IFN signaling is protective during infection with the human Gram-positive extracellular pathogen GBS (16, 17). GBS is regarded as commensal microbe asymptomatically colonizing the skin and mucosal tissues of 30% people, yet it is the leading cause of severe neonatal pneumonia and meningitis in developed countries. The absence of IFNAR1 results in increased bacterial loads during both subcutaneous GBS infection of neonate mice and intravenous infection of adult animals (16, 17). Similarly, type I IFN signaling is protective against uncontrolled bacteremia during infection with the Gram-negative intracellular bacterium L. pneumophila, which is a frequent cause of the severe pneumonia, Legionnaire’s disease (18). Type I IFN signaling inhibits in a cell-autonomous way replication of L. pneumophila inside the infected cell (18, 19). The organismal physiology of the protective effects of type I IFN signaling during infection with GBS and L. pneumophila remains to be elucidated so that it is presently unclear whether immunosuppressive or immunostimulatory effects of type I IFNs drive the resistance against these two pathogens.

Stimulation of the immune response by type I IFN signaling is advantageous in defense against the Gram-negative pathogen H. pylori (20). H. pylori is a frequent cause of chronic gastritis and is associated with increased risk of gastric ulcers and stomach cancer. Deficiency in type I IFN signaling causes increased H. pylori loads in the stomach of orally infected mice. The lack of type I IFN responses is associated with decreased levels of the chemokine CXCL10 suggesting that type I IFNs promote defense against H. pylori by stimulating CXCL10-driven inflammation (20). Immunostimulatory effects of type I IFNs are beneficial also during gastric infection with the food-borne Gram-positive intracellular pathogen L. monocytogenes (28). L. monocytogenes infects the gastrointestinal tract, where it traverses the epithelial barrier and spreads into distant organs. Deficiency in type I IFN signaling results in an increased bacterial dissemination and is accompanied by diminished production of several pro-inflammatory cytokines, including TNF and IL-6 upon gastric infection using oral gavage (28). Interestingly, type I IFN signaling plays no role in an infection model using food contaminated with L. monocytogenes (30).

Immunosuppression by type I IFN signaling is detrimental during infection with the intracellular pathogen and causative agent of tuberculosis, M. tuberculosis (22–24). Type I IFN signaling-mediated inhibition of IL-1 cytokines during M. tuberculosis lung infection blunts the antimicrobial defense and results in increased local as well as systemic bacterial loads (24). The key type I IFN effector cells are transplantable inflammatory monocyte-macrophage cells and DCs (24). The precise mechanism of IL-1 inhibition by type I IFN signaling in this infection model is not resolved but includes both direct as well as indirect mechanisms (24). The indirect IL-1 inhibition appears to be mediated by the anti-inflammatory cytokine IL-10 which is known to be upregulated by type I IFNs (69). The importance of type I IFN signaling in M. tuberculosis infections is underlined by type I IFN signaling-associated gene expression pattern found in blood cells of patients with active tuberculosis (70). The detrimental function of type I IFN signaling during M. tuberculosis lung infection is converted into a protective one if IFN-γ signaling is missing (71). Under such conditions, type I IFNs inhibit the polarization of macrophages into infection-permissive alternatively activated macrophages.

Inhibition of immune response by type I IFNs is deleterious during infection with the facultative intracellular Gram-negative bacterium F. novicida (31). F. novicida is a subspecies of Francisella tularensis which infects humans through the skin or aerosol droplets and causes ulceroglandular or pneumonic tularemia, respectively. IFNAR1-deficient mice infected intradermally with F. novicida respond by an increased IL-17 production compared to WT animals and, correspondingly, are more resistant against infection (31). Similar increase in resistance is also observed during lung infection with F. tularensis (31). The key IL-17 producers during F. novicida infection are IL-17A+ γδ T cells which show enhanced expansion in the absence of type I IFN signaling.

Interferon-β exacerbates infection with S. typhimurium by reducing the ability of the host to launch a complete immune response (34). S. typhimurium is Gram-negative intracellular pathogen associated with gastroenteritis in humans and a severe disease resembling typhoid fever in mice. Mice deficient in IFN-β are more resistant against oral infection with S. typhimurium and display enhanced expression of IL-1β and the neutrophil chemoattractants, CXCL1 and CXCL2 (34). These changes are attributable to IFN-β-mediated inhibition of these genes in macrophages and are independent of S. typhimurium-induced macrophage death.

Listeria monocytogenes-induced type I IFN signaling downregulates the expression of both type II IFN receptor subunits, IFNGR1 and IFNGR2, thereby decreasing the responsiveness of macrophages and DCs to IFN-γ (29). The suppression of the IFN-γ signaling results in an increased susceptibility to L. monocytogenes infection. Increased susceptibility to L. monocytogenes infection is also caused by type I IFN-mediated induction of anti-inflammatory IL-10 (72).

Immunosuppressive effects of type I IFNs are harmful during postinfluenzal bacterial pneumonia (36–39). The immune response during a secondary postinfluenzal infection with the Gram-positive extracellular pathogen S. pneumoniae, a key causative agent of pneumonia, is impaired. This is caused by the ability of type I IFNs to suppress production of the neutrophil chemoattractants CXCL1 and CXCL2, the macrophage chemoattractant CCL2, and the inflammation-promoting cytokine IL-17 (36–38). The resulting reduction of leukocyte infiltration in the lung diminishes the capability of the host to control bacterial growth. Similar alterations in the immune response appear to be responsible for the increased susceptibility of mice to postinfluenzal infection with S. aureus and Pseudomonas aeruginosa (39). The mechanisms of the immunosuppressive effects of type I IFN signaling during postinfluenzal bacterial infection are not well understood but they might act downstream of the type I IFN-mediated inhibition of IL-1 cytokines.

Enhancement of the inflammatory response is associated with detrimental effects of type I IFN signaling during lung infection with the Gram-positive extracellular pathogen S. aureus (21). IFNAR1-deficient mice exhibit a lower TNF and IL-6 production and decreased leukocyte infiltration in the lung compared to WT animals suggesting that type I IFN signaling causes an exacerbated tissue damage (21). The pathogenicity of S. aureus strains correlates with the levels of type I IFNs induced during infection with differently virulent strains (14).

Type I IFN signaling plays an indispensable role in the preservation of the epithelial barrier and epithelial integrity during lung infection with S. pneumoniae (10, 11). Type I IFN signaling promotes the maintenance of lung epithelial tight junctions during S. pneumoniae infection thereby reducing the passage of the pathogen from alveoli into the lung parenchyma (10). IFNAR1-deficient mice display increased permeability of the lung epithelium and enhanced invasiveness of S. pneumoniae infection associated with higher bacterial burden in distant organs. Type I IFN signaling protects the barrier function of the lung during S. pneumoniae infection also by promoting survival of the alveolar epithelial type II cells as revealed by IFNAR1 deletion specifically in this subtype of the barrier epithelium (11).

A common detrimental effect of type I IFN signaling during bacterial infections is the induction of various types of leukocyte cell death. Type I IFN-facilitated apoptosis of macrophages and lymphocytes appears to contribute to the increased susceptibility of WT mice compared to IFNAR1-deficient animals to intravenous and intraperitoneal infection with L. monocytogenes (25–27, 73). Type I IFN-facilitated death of macrophages is associated also with harmful effects of type I IFNs during infection with F. novicida and S. typhimurium (32, 33). F. novicida promotes macrophage death by type I IFN-mediated inflammasome-activation whereas S. typhimurium employs type I IFN induction to stimulate RIP-dependent macrophage necroptosis.

Ample evidence exists for the pivotal role of type I IFNs in regulation of defense against bacterial pathogens. The complex and often disparate effects of type I IFNs on the outcome of different bacterial infections provide chances to exploit type I IFNs and their inducers as well as effectors for adjuvant therapies tailored to specific infectious diseases. A prerequisite for the development of such therapies is a detailed understanding of the molecular, cellular, and organismal physiology of type IFNs in the course of bacterial infections. The following topics appear particularly important since they represent rather underexplored yet critically important areas.

All authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.