The dual role of type I interferons in bacterial infections: from immune defense to pathogenesis

Abstract

Type I interferons (IFNs) are crucial components of the human immune system, playing a key role in regulating immune activity. Existing literature has characterized their antiviral and proviral roles in viral contexts. Type I IFNs also exhibit a dual role in bacterial infections, functioning as defenders or disruptors or both based on factors including but not limited to such things as the bacterial species, infection stage, host immune status, and the route and site of infection. This review provides a summary of the signaling pathways associated with type I IFN responses and discusses the complex mechanisms of type I IFNs in bacterial infections. Because type I IFNs provide an important opportunity to develop personalized treatment strategies, which are expected to be transformed into efficient adjuvant therapy for specific infectious diseases, we also discuss the potential for targeting type I IFNs for therapeutic interventions.

Keywords: bacterial infection; host immunity; type I interferon.

Fig 1

Type I IFN signaling induces ISG expression. Type I IFNs bind to the IFNAR, consisting of the IFNAR1 and IFNAR2 subunits. This interaction activates TYK2 and JAK1, leading to the phosphorylation of STAT1 and STAT2. The phosphorylated STAT1 and STAT2 associate with IRF9 to form the ISGF3 transcriptional complex. ISGF3 translocates to the nucleus and interacts with ISREs in the nucleus, driving the expression of hundreds of ISGs. IFNAR, interferon-α/β receptor; TYK2, tyrosine kinase 2; JAK1, Janus kinase 1; STAT1, signal transducer and activator of transcription 1; IRF9, interferon regulatory factor 9; ISGF3, interferon-stimulated gene factor 3; ISREs, interferon-stimulated response elements; ISGs, interferon-stimulated genes. Figures were created and authorized by BioRender (http://www.biorender.com).

Fig 2

Signaling pathways inducing type I IFNs production in the context of bacterial infections. Recognition of bacterial components by pattern recognition receptors leads to the production of type I IFN. TLR2/7/8/9/13 recognizes DNA or RNA and induces type 1 IFN production through the MyD88-dependent pathway, while TLR3/4 is through the TRIF-dependent pathway. MDA-5 and RIG-I recognize RNA and interact with MAVS, which activates TBK1 and IRF to induce type I IFN production. NOD1 and NOD2 bind the downstream adaptor molecule RIP2 and activate IFN production upon recognizing specific components of bacterial peptidoglycan. DNA sensors cGAS, DDX41, and IFI16 recognize bacterial DNA or cyclic dinucleotide and induce IFN production through the STING-TBK1-IRF3 pathway, respectively. Bacteria-derived 2'3'-cGAMP could also bind STING directly and induce IFN production. ZBP1 is reported to function as a cytosolic receptor sensing Brucella abortus infection. TLR, Toll-like receptor; MyD88, myeloid differentiation primary response protein 88; MAVS, mitochondrial antiviral signaling protein; RIG-I, retinoic acid-inducible gene 1; RIP2, receptor interacting protein kinase 2; MDA-5, melanoma differentiation-associated gene 5; NOD, nucleotide-binding oligomerization domain-containing protein; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1; DDX41, DEAD-box helicase 41; IFI16, interferon gamma-inducible protein 16; ZBP1, Z-DNA binding protein 1; TRAF, TNF receptor-associated factors; TBK1, TANK binding kinase 1; IRF, interferon regulatory factor; 2'3'-cGAMP, 2'3'-cyclic GMP-AMP.

Fig 3

The PRRs involved in the production of type I IFN in Gram-positive and Gram-negative bacterial infections, respectively. The PRRs involved in the production of type I interferon by Gram-positive and Gram-negative bacteria are not exactly the same. Based on the literature reports, the differences and similarities between the two bacterial types are synthesized. The figure is not universally applicable and could be specific to certain types of bacteria.

Fig 4

Mechanisms of type I IFNs during bacterial infections. This figure illustrates the mechanisms of type I IFN during bacterial infection, including the induction of immune cell or host cell death, influencing immune cell recruitment and activation, influencing the production of inflammatory factors, antimicrobial substances, and IFN-γ. Studies have included metabolic reprogramming of type I IFN to modulate the inflammatory response during infections with Listeria monocytogenes, Staphylococcus aureus, and Mycobacterium tuberculosis.