Study Reveals Immune System’s Backup Mechanism

Researchers led by Prof. Martin Schlee from the University Hospital Bonn and the Cluster of Excellence ImmunoSensation2 at the University of Bonn have discovered why loss of TBK1 function in humans, which increases susceptibility to viral infections, is better tolerated when the protein is entirely absent. The study, published in Frontiers in Immunology, has shown that TBK1 directly affects a similar enzyme, the IKKepsilon.

TBK1 reduces the stability of IKKepsilon, which ensures that an antiviral immune response can occur despite the absence of TBK1. However, point mutations in the TBK1 gene, which may induce a loss of TBK1 function, do not prevent destabilization and degradation of IKKepsilon. Ultimately, both factors are unavailable for viral defense, increasing susceptibility to viral infections.

The body’s innate immune system plays a critical role in defense against viruses, and TBK1 is a crucial component of this system. When viral particles are detected by pattern recognition receptors (PRRs) in the cell or on the cell surface, TBK1 is activated. TBK1, in turn, activates two transcription factors that induce the transcription of interferon and cytokine genes. These messenger molecules alert neighboring immune cells and point out the viral infection, inducing an immune reaction.

TBK1 is particularly crucial in antiviral immune signaling pathways downstream of cytosolic nucleic acid receptors such as cGAS and RIG-I-like receptors. Upon activation, it phosphorylates the transcription factors IRF3 and IRF7, thereby initiating the expression of type I interferons and antiviral effectors. Point mutation-induced loss of TBK1 kinase activity results in clinical hyper-susceptibility to viral infections. However, a complete lack of TBK1 expression in humans is unexpectedly not associated with diminished antiviral responses.

These findings demonstrate that human immune cells have an important backup mechanism and can maintain an effective antiviral response even when pathogen-induced degradation of TBK1 occurs.

Additionally, this mechanism takes effect in the case of genetic loss of TBK1. Increased amounts of IKKepsilon can thus compensate for the loss of TBK1, which becomes particularly important when viruses seek to eliminate the body’s defenses. Herpes simplex virus 1 (HSV-1), human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and several bacterial species are capable of causing the degradation of TBK1.