Induction of type I interferons by bacteria

Abstract

Type I interferons (IFNs) are secreted cytokines that orchestrate diverse immune responses to infection. Although typically considered to be most important in the response to viruses, type I IFNs are also induced by most, if not all, bacterial pathogens. Although diverse mechanisms have been described, bacterial induction of type I IFNs occurs upon stimulation of two main pathways: (i) Toll-like receptor (TLR) recognition of bacterial molecules such as lipopolysaccharide (LPS); (ii) TLR-independent recognition of molecules delivered to the host cell cytosol. Cytosolic responses can be activated by two general mechanisms. First, viable bacteria can secrete stimulatory ligands into the cytosol via specialized bacterial secretion systems. Second, ligands can be released from bacteria that lyse or are degraded. The bacterial ligands that induce the cytosolic pathways remain uncertain in many cases, but appear to include various nucleic acids. In this review, we discuss recent advances in our understanding of how bacteria induce type I interferons and the roles type I IFNs play in host immunity.

Figure 1. TLR Receptors and Ligands

A. TLR2 and 4 recognize bacterial lipoprotein (BLP) and lipopolysaccharide (LPS), respectively, and signal from the cell surface via the adaptor MyD88 to activate proinflammatory cytokines including TNFα and IL-6. TLR3 recognizes double stranded RNA (dsRNA) and signals via the adaptor TRIF from an intracellular compartment to induce IFNβ. Upon endocytosis, TLR4 can also signal via TRIF to induce type I IFN. B. Plasmacytoid dendritic cells primarily express nucleic acid sensing TLRs, which are localized to intracellular compartments. pDCs produce vast amounts of IFNβ upon stimulation via a MyD88-dependent pathway. C. Conventional dendritic cells and macrophages express many TLRs. However, only cDCs have been reported to induce IFNβ via TLR7 and 9. In macrophages, TLR7 and 9 signaling induces proinflammatory cytokines such as TNFα.

Figure 2. Bacterial Induction of Type I IFN via Cytosolic Receptors and Ligands

A. In many cell types, except pDCs, cytosolic IFN-inducing receptors are expressed that sense nucleic acids, including RNA, DNA, and cyclic-di-nucleotides. AT-rich DNA can be transcribed by RNA polymerase III to generate ligands for the RNA-sensing pathway. Other sensors for DNA and c-di-nucleotides appear to exist, but remain to be identified. Cytosolic pathways that recognize bacterial cell wall fragments can synergize with nucleic acid sensing pathways to induce IFNβ. B. Extracellular or phagosomal bacteria utilizing secretion systems can leak or secrete nucleic acids that are sensed via cytosolic pathways outlined in A. Bacteria replicating in the cytosol activate type I IFN either by transport or lysis that releases IFN-inducing ligands. Degradation of phagocytosed bacteria can lead to IFN induction in many ways, and in some cases ligands generated in the phagolysosome access the cytosol via a pathway that remains to be elucidated.