Type I Interferon Signaling Prevents IL-1β-Driven Lethal Systemic Hyperinflammation during Invasive Bacterial Infection of Soft Tissue

Abstract

Type I interferons (IFN-Is) are fundamental for antiviral immunity, but their role in bacterial infections is contradictory and incompletely described. Streptococcus pyogenes activates IFN-I production in innate immune cells, and IFN-I receptor 1 (Ifnar1)-deficient mice are highly susceptible to S. pyogenes infection. Here we report that IFN-I signaling protects the host against invasive S. pyogenes infection by restricting inflammation-driven damage in distant tissues. Lethality following infection in Ifnar1-deficient mice is caused by systemically exacerbated levels of the proinflammatory cytokine IL-1β. Critical cellular effectors of IFN-I in vivo are LysM+ and CD11c+ myeloid cells, which exhibit suppression of Il1b transcription upon Ifnar1 engagement. These cells are also the major source of IFN-β, which is significantly induced by S. pyogenes 23S rRNA in an Irf5-dependent manner. Our study establishes IL-1β and IFN-I levels as key homeostatic variables of protective, yet tuned, immune responses against severe invasive bacterial infection.

The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection

“…(Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/JCI80631DS1), implying no gross differences and/or impairment in organ function. These data are in agreement with lethal sepsis following uncontrolled bacterial dissemination rather than direct organ injury as the cause of death in this infection model (22,27,28).…”

Disease tolerance and immunity in host protection against infection

“…For example, regulation of IL-1β-induced inflammation by type I IFN prevents the lethality of systemic Streptococcus pyogenes infection, without affecting bacterial load 108 . In this case, signaling via type I IFN receptor in macrophages, DCs and neutrophils represses IL-1β transcription, through signal transducer and activator of transcription STAT1, and to a lesser extent STAT2, ultimately preventing the development of lethal IL-1β-driven inflammation 108 .…”

The Roles of Type I Interferon in Bacterial Infection

“…For example, in plasmacytoid dendritic cells (pDCs) constitutive expression of IRF7 makes it the preferred IRF (Honda et al, 2006; Prakash et al, 2005). Interestingly, IRF5 appears to play a more dominant role in the induction of type I IFNs in response to bacterial pathogens (Bergstrom et al, 2015; Castiglia et al, 2016; Gratz et al, 2011; Pandey et al, 2009; Parker et al, 2014), and to a lesser extent against viruses (Lazear et al, 2013). Following PRR stimulation, IRFs are activated in a phosphorylation dependent manner.…”

“…Initially located at the plasma membrane, TLR4, and to a much lesser extent TLR2, induce type I IFNs following endocytosis, by ligating components derived from the bacterial cell surface (Barbalat et al, 2009; Kagan et al, 2008). In immune cells, such as dendritic cells (DCs), endosomal membrane anchored TLR9 is activated by bacterial DNA, whereas single stranded RNA is sensed by TLR7 (Mancuso et al, 2009), TLR8 (Eigenbrod et al, 2015), and TLR13 (Castiglia et al, 2016) to activate type I IFN expression. All TLRs, except TLR3, activate the downstream signaling adapter, MyD88.…”

“…Streptococcus pyogenes , the group A streptococcus, causes superficial and deep tissue infections that can develop into necrotizing fasciitis. Both group A streptococci and group B streptococci ( Streptococcus agalactiae ) activate the STING-TBK1-IRF3 pathway in macrophages (Gratz et al, 2011); while in cDCs, TLR7-Myd88-IRF5 and to a lesser extent IRF1, both play a role (Castiglia et al, 2016; Gratz et al, 2011; Mancuso et al, 2009). In a mouse model of S. pyogenes cellulitis, survival of WT mice is significantly greater than IFNAR1 deficient mice (Gratz et al, 2011).…”