Abstract
The immune system depends upon combinations of signals to mount appropriate responses: pathogen specific signals in the context of co-stimulatory “danger” signals drive immune strength and accuracy. Viral infections trigger anti-viral type I interferon (IFN) responses by stimulating endosomal and cytosolic pattern recognition receptors (PRRs). However, viruses have also evolved many strategies to counteract IFN responses. Are there intracellular danger signals that enhance immune responses to viruses? During infection, viruses place a heavy demand on the protein folding machinery of the host endoplasmic reticulum (ER). To survive ER stress, host cells mount an unfolded protein response (UPR) to decrease ER protein load and enhance protein-folding capacity. Viruses also directly elicit the UPR to enhance their replication. Increasing evidence supports an intersection between the host UPR and inflammation, in particular the production of pro-inflammatory cytokines and type I IFN. The UPR directly activates pro-inflammatory cytokine transcription factors and dramatically enhances cytokine production in response to viral PRR engagement. Additionally, viral PRR engagement may stimulate specific pathways within the UPR to enhance cytokine production. Through these mechanisms, viral detection via the UPR and inflammatory cytokine production are intertwined. Consequently, the UPR response is perfectly poised to act as an infection-triggered “danger” signal. The UPR may serve as an internal “co-stimulatory” signal that (1) provides specificity and (2) critically augments responses to overcome viral subterfuge. Further work is needed to test this hypothesis during viral infections.
Highlights
TUNING AN APPROPRIATE IMMUNE RESPONSE Inappropriate activation of the immune system, as evident by toxic shock and autoimmune diseases, reveals an incredibly potent force that can wreak havoc on the human body
Endogenous products produced during concomitant tissue destruction during infection, so called “danger associated molecular patterns” (DAMPs) stimulate pattern recognition receptors (PRRs) (Matzinger, 1994; Bianchi, 2007; Tang et al, 2012)
MECHANISMS UNDERLYING unfolded protein response (UPR)-PRR SYNERGY IFN and inflammatory cytokine production is largely regulated by the nuclear availability and activation status of critical transcription factors
Summary
TUNING AN APPROPRIATE IMMUNE RESPONSE Inappropriate activation of the immune system, as evident by toxic shock and autoimmune diseases, reveals an incredibly potent force that can wreak havoc on the human body. Engagement of PRRs on macrophages and dendritic cells enhances antigen presentation, expression of T cell co-stimulatory molecules, and provides an inflammatory cytokine milieu Through these combinations of stimuli, cells are poised to respond appropriately to external threats. Infected cells must cope until an effective adaptive immune response can be mobilized Intracellular pathogens such as viruses excite immune responses by triggering endosomal and cytosolic PRRs. Host cells detect viral dsRNA via endosomally localized TLR3, cytosolic RNA-helicases such as retinoic acid inducible gene 1 (RIG-I) and melanoma differentiation associated 5 (MDA-5), and interferon induced sensors such as protein kinase R (PKR). This initial wave of IFN serves as an “alarm signal”: binding of early IFN to the type I IFN receptor (IFNAR) triggers Janus kinase 1/tyrosine kinase 2 – signal transducers and activators of transcription 1/2 (JAK1/Tyk2–STAT1/2) signaling, and an anti-viral transcriptional program (Levy et al, 2003)
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