Type I Interferons in Bacterial Infections: A Balancing Act

Abstract

Defense against bacterial infections requires activation of the immune response as well as timely reestablishment of tissue and immune homeostasis. Instauration of homeostasis is critical for tissue regeneration, wound healing, and host recovery. Recent studies revealed that severe infectious diseases frequently result from failures in homeostatic processes rather than from inefficient pathogen eradication. Type I interferons (IFN) appear to play a key role in such processes. Remarkably, the involvement of type I IFNs in the regulation of immune and tissue homeostasis upon bacterial insult may have beneficial or detrimental consequences for the host. The reasons for such ambivalent function of type I IFNs are not understood. The disparate effects of type I IFNs on bacterial infections are in marked contrast to their well-established protective roles in most viral infections. In this review, we will focus on type I IFN effector mechanisms which balance processes involved in immune and tissue homeostasis during specific bacterial infections and highlight the most important missing links in our understanding of type I IFN functions.

Engagement of Fas differentially regulates the production of LPS‐induced proinflammatory cytokines and type I interferons

“…Inhibition of immune responses by type I IFNs has been shown to be deleterious during infection with the facultative intracellular Gram‐negative bacterium Francisella novicida . Moreover, IFNβ exacerbates infection with Salmonella typhimurium by reducing the ability of the host to launch a complete immune response . These studies highlight the importance of tightly regulating IFNβ production in response to Gram‐negative bacteria in order to avoid detrimental excessive inflammation and associated pathologies.…”

Functional remodeling of lysosomes by type I interferon modifies host defense

“…Although a virtually universal antiviral immune signal, the consequences of IFN-I signaling on bacterial pathogens has remained less clear and is in many cases detrimental to the host (Kovarik et al, 2016). Several intracellular bacterial pathogens, including Listeria monocytogenes, Mycobacterium tuberculosis and Stm, appear to have decreased virulence in IFNAR1-deficient mice.…”

“…Due to the large size of the “interferome” and the complex interactions of ISGs with thousands of additional cellular proteins (Hubel et al, 2019), knowledge of the full spectrum of IFN-I-mediated changes in cellular function is incomplete. Although IFN-Is are known to have critical roles in antiviral responses, their functions in bacterial infection are less clear, and IFN-I signaling has been reported to be either protective or detrimental to the host depending on the specific bacterial pathogen (Kovarik et al, 2016).…”

TET2 regulates the neuroinflammatory response in microglia

“…We found that TET2 regulates primarily genes involved in the innate immune response and more specifically genes related to the TLR induced-Type I IFN response (e.g., Stat1, Stat3, Irf1, Irf7) (Noppert et al, 2007) (Luu et al, 2014). Traditionally, Type I IFN response was considered solely for defense against viral and bacterial infections (Stifter and Feng, 2015) (Kovarik et al, 2016). However, in the brain, and under sterile inflammatory conditions, there are increasing numbers of reports showing activation of the Type I IFN response in ischemia (McDonough et al, 2017), spinal cord injury (Impellizzeri et al, 2015) and in two different AD mouse models, the 5xFAD (Landel et al, 2014) and APP/PS1 (Taylor et al, 2014), as well as in AD patients (Taylor et al, 2014).…”