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The Yin and Yang of type I interferon activity in bacterial infection

Key Points

  • Type I interferons (IFNs), a family of around 20 members, were originally described as antiviral cytokines. Research in recent years has shown that type I IFNs also affect immune responses to bacteria.

  • IFNs are produced in response to bacterial infection when Toll-like receptor 4 (TLR4) or TLR9 are stimulated, or from within the cytoplasm when bacteria enter a cell.

  • Induction of type I IFN genes by bacteria and their products requires activation of IFN regulatory factor 3 (IRF3) and/or IRF7.

  • Most cells in the body must increase the amounts of IRF7 before transcribing the majority of type I IFN genes in response to infection. This occurs through Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling by the type I IFN receptor (IFNAR), which is stimulated by low amounts of type I IFNs produced at the onset of infection.

  • Specialized cells known as IFN-producing cells (IPCs) constitutively express IRF7 and immediately produce large amounts of type I IFNs in response to bacterial signals. These cells rapidly activate IRF7 after TLR signalling.

  • Type I IFNs increase immunity to some Gram-negative bacteria by stimulating IFN-γ production. Some studies suggest that type I IFNs inhibit the invasion of epithelial cells and that this activity limits the ability of enteric bacteria to cross the intestinal epithelium.

  • Type I IFNs influence maturation, activation, migration and survival of dendritic cells (DCs). By regulating DC activity, they can indirectly enhance both T cell and B cell-mediated adaptive immunity to bacteria.

  • Type I IFNs exert adverse effects during infection with at least some intracellular bacteria (Listeria monocytogenes and under some circumstances also Mycobacterium tuberculosis). This activity can be attributed to a sensitization of effector cells to bacteria-induced death.

Abstract

Interferons (IFNs) are cytokines that are important for immune responses, particularly to intracellular pathogens. They are divided into two structurally and functionally distinct types that interact with different cell-surface receptors. Classically, type I IFNs are potent antiviral immunoregulators, whereas the type II IFN enhances antibacterial immunity. However, as outlined here, type I IFNs are also produced in response to infection with other pathogens, and an increasing body of work shows that type I IFNs have an important role in the host response to bacterial infection. Strikingly, their activity can be either favourable or detrimental, and can influence various immune effector mechanisms.

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Figure 1: Signal transduction by the interferon (IFN) receptors.
Figure 2: Cytosolic and extracellular bacteria induce type I interferons (IFNs) through distinct receptors.
Figure 3: Activation of interferon (IFN) regulatory factor 7 (IRF7) by bacteria.
Figure 4: Type I interferon (IFN) effects on antibacterial immunity.

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Acknowledgements

Work in the authors' laboratories is supported by the Austrian Science Foundation (T.D.), the Viennese Foundation for Science, Research and Technology (M.M. and T.D.) and the Austrian Ministry of Education and Science (M.M.).

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DATABASES

Entrez Gene

IFN-α

IFN-β

IFN-γ

IFN-ε

IFN-κ

IFN-ζ

IFN-ω

IFNAR1

IFNAR2

IFNGR1

IFNGR2

FURTHER INFORMATION

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Glossary

JAK

The Janus kinases (JAKs) are a family of four protein tyrosine kinases (JAK1–3 and TYK2) with a common domain structure. JAKs associate permanently with cytokine receptors. They phosphorylate STATs, and stimulate other signalling responses.

STAT

Signal transducers and activators of transcription (STATs) are the only transcription factors that contain an SH2 (Src-homology-2) domain. This domain allows them to interact with tyrosine-phosphorylated receptor complexes and to become substrates for JAKs. The STAT SH2 domain also mediates dimerization, a prerequisite for nuclear translocation.

T HELPER 1 (TH1)-CELL

A CD4+ T cell that has differentiated into a cell that produces the cytokines IFN-γ and tumour-necrosis factor.

SRC-HOMOLOGY-2 DOMAIN

(SH2 domain). A domain that is found in signalling molecules. It binds phosphorylated tyrosine residues and thereby mediates protein–protein interactions.

IFN REGULATORY FACTORS

A transcription factor family with several members engaged in type I IFN transcription and/or the expression of IFN-inducible genes.

P38 MAPK

A member of the MAPK family that is involved in responses to stress or infection. P38 MAPK participates in the synthesis of inflammatory cytokines.

PI3K

A lipid kinase that generates membrane attachment sites for further signal transducers. PI3K signalling is important for the regulation of cellular survival.

AP1 FAMILY

A group of transcription factors forming homodimers or heterodimers through leucine zipper interfaces. The prototype AP1 subunits are Fos and Jun. The family members ATF2 and Jun contribute to the IFN-β promoter enhanceosome.

HIGH-MOBILITY GROUP

(HMG). The HMG box is a domain that is present in members of a large protein family that are small non-histone components of chromatin and function in higher-order chromatin structure.

FACULTATIVE OR OBLIGATE INTRACELLULAR PATHOGENS

Bacteria that can (facultative) or must (obligate) enter a host cell to multiply.

ENDOSOME/PHAGOSOME

Vacuolar compartments that confine bacteria after enforced endocytosis or after phagocytosis. Unless counteracted by a bacterial survival strategy, the phagosome matures into a hostile environment that is designed to kill and digest microorganisms.

GRAM-NEGATIVE BACTERIA

Bacteria that present as pink-red after exposure to Gram stain. The weak reaction with the dye is due to the thin peptidoglycan layer that is present in their cell walls.

UBIQUITIN

A small protein that is attached to other proteins by ubiquitin ligases. Depending on the mode of attachment, ubiquitin can either activate signalling function or target a protein for destruction by the proteasome.

GRAM-POSITIVE BACTERIA

Bacteria that present as blue-purple after exposure to Gram stain. The strong reaction with the dye is due to the thick peptidoglycan layer present in their cell walls.

DEXD/H BOX RNA HELICASE

An enzyme that can unwind double-stranded RNA using energy derived from ATP hydrolysis. The DExD/H box is a characteristic amino-acid signature motif of many RNA-binding proteins.

HAEMOLYSIN

A family of structurally related bacterial proteins that can lyse cholesterol-containing plasma membranes, particularly those of erythrocytes, but also membranes of intracellular compartments.

NON-METHYLATED CPG DNA

DNA that is characteristic of prokaryotes because the CpG sequence is not methylated on C as in eukaryotes.

SEPTIC SHOCK SYNDROME

Results from uncontrolled production of inflammatory cytokines owing to bacterial overload. Death might result from multi-organ failure.

ADJUVANT

An agent mixed with an antigen that enhances the immune response to that antigen after immunization.

TUNEL

An in situ method for detecting the 3′-OH ends of DNA exposed during the internucleosomal cleavage that occurs during apoptosis.

INVASIVE BACTERIA

Bacteria that can enforce endocytic uptake by a eukaryotic host cell.

CROSS-PRESENTATION

The initiation of a CD8+ T-cell response to an antigen that is not present within antigen-presenting cells (APCs). This exogenous antigen must be taken up by APCs and then re-routed to the MHC-class-I pathway of antigen presentation.

TROPISM

From the greek 'trepein', meaning to turn. Describes the directed movement of a pathogen to its preferred site of infection and/or multiplication.

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Decker, T., Müller, M. & Stockinger, S. The Yin and Yang of type I interferon activity in bacterial infection. Nat Rev Immunol 5, 675–687 (2005). https://doi.org/10.1038/nri1684

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