IFN-β: A Contentious Player in Host-Pathogen Interaction in Tuberculosis

Abstract

Tuberculosis (TB) is a major health threat to the human population worldwide. The etiology of the disease is Mycobacterium tuberculosis (Mtb), a highly successful intracellular pathogen. It has the ability to manipulate the host immune response and to make the intracellular environment suitable for its survival. Many studies have addressed the interactions between the bacteria and the host immune cells as involving many immune mediators and other cellular players. Interferon-β (IFN-β) signaling is crucial for inducing the host innate immune response and it is an important determinant in the fate of mycobacterial infection. The role of IFN-β in protection against viral infections is well established and has been studied for decades, but its role in mycobacterial infections remains much more complicated and debatable. The involvement of IFN-β in immune evasion mechanisms adopted by Mtb has been an important area of investigation in recent years. These advances have widened our understanding of the pro-bacterial role of IFN-β in host-pathogen interactions. This pro-bacterial activity of IFN-β appears to be correlated with its anti-inflammatory characteristics, primarily by antagonizing the production and function of interleukin 1β (IL-1β) and interleukin 18 (IL-18) through increased interleukin 10 (IL-10) production and by inhibiting the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome. Furthermore, it also fails to provoke a proper T helper 1 (Th1) response and reduces the expression of major histocompatibility complex II (MHC-II) and interferon-γ receptors (IFNGRs). Here we will review some studies to provide a paradigm for the induction, regulation, and role of IFN-β in mycobacterial infection. Indeed, recent studies suggest that IFN-β plays a role in Mtb survival in host cells and its downregulation may be a useful therapeutic strategy to control Mtb infection.

Keywords: Mycobacterium tuberculosis (Mtb); fate of infection; interferon-β (IFN-β); interleukin-1β (IL-1β); nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3).

Figure 1

Interferon-β (IFN-β) signaling pathways and autocrine/paracrine loop. IFN-β signaling pathways may be MyD88-independent (TRIF or TLR3-4 pathways) or MyD88-dependent pathways. The pathway that is mainly triggered by TLR3 and TLR4 requires the adaptor protein TRIF, which leads to the production of type I IFNs. TRIF engages TNF receptor associated factor 3 (TRAF3) and NAP-1 (nucleosome assembly protein-1) to activate TBK1 and IKK. TBK1 and IKK lead to the induction of the transcription factor IRF3 inducing type I IFNs. On the other hand, stimulation of TLR7/8 or TLR9 leads to recruitment of MyD88 protein, IRAK4), TRAF3, and TRAF6 and results in activation of IRAK1, IKK-α, and transcription factors IRF5/IRF7, leading to the induction of type I IFNs. Once produced, IFN-β can also enhance the activation of IRF5/IRF7, leading to augmented type I IFN induction. In addition to these main pathways associated with the production of type I IFNs, there is also an autocrine/paracrine feedback loop amplifying the production of type I IFNs. This feedback loop is initiated by type I IFNs and leads to the formation of the ISGF3 complex. Binding of this ISGF3 complex to the IFN-stimulated response element (ISRE) within the ISRE-containing genes results in type I IFN induction.

Figure 2

Role of IFN-β in host–pathogen interaction in Mtb infection. Mtb gains access to the host cytosol and leads to mitochondrial stress and release of mtDNA. This mtDNA and some other unknown factors indicated by “?” trigger the cGAS–STING–TBK1–IRF3–IFN-β pathway. On the other hand, Mtb also induces NLRP3 and AIM2 inflammasomes resulting in IL-1β synthesis. These two pathways have opposite roles and outcomes in the host defense against Mtb. In addition to direct inhibition of IL-1β, IFN-β can also inhibit or diminish the production of IL-1β through inhibition of NLRP3 inflammasomes and the augmented induction of IL-10. Reciprocal inhibition of IFN-β has been reported through IL-1β-induced PGE2. A recent study demonstrated that AIM2 could also inhibit IFN-β induction by interfering with the STNG–TBK1 pathway [72]. IL-1β is recognized as beneficial for host cells with anti-mycobacterial activity while IFN-β is considered largely detrimental for host cells having pro-bacterial and replication-promoting properties.