Activation of toll-like receptor signaling pathways leading to nitric oxide-mediated antiviral responses

Abstract

Toll-like receptors (TLRs), well-characterized pattern-recognizing receptors of the innate arm of the immune system, are vital in detecting pathogen-associated molecular patterns (PAMPs). The TLR-PAMP interaction initiates an intracellular signaling cascade, predominantly culminating in upregulation of antiviral components, including inducible nitric oxide synthase (iNOS). After activation, various TLR pathways can promote iNOS production via the myeloid differentiation primary response-88 (MyD-88) adapter protein. Subsequently, iNOS facilitates production of nitric oxide (NO), a highly reactive and potent antiviral molecule that can inhibit replication of RNA and DNA viruses. Furthermore, NO can diffuse freely across cell membranes and elicit antiviral mechanisms in various ways, including direct and indirect damage to viral genomes. This review emphasizes current knowledge of NO-mediated antiviral responses elicited after activation of TLR signaling pathways.

Fig. 1

Common and specific TLRs in humans, mice and birds. In mammals, TLR2 can dimerize with TLR1 or TLR6, whereas in birds, TLR2 is divided into TLR2a and TLR2b and TLR1 is divided into TLR1La and TLR1Lb (due to gene duplication). TLR2s can form a heterodimer complex with TLR1Ls

Fig. 2

Illustration of potential synthesis of NO via TLR signaling leading to NO-mediated antiviral activity. The TLRs are expressed on the cell surface or inside cells. Among those expressed on the surface, TLR2, 4, 5 and 11 are well studied with respect to iNOS expression. TLR3, 7, 8 and 9/21 are expressed on the membrane of the endosomal compartment and recognize nucleic-acid-based PAMPs, leading to expression of iNOS (among many other mediators). Most of these TLRs use MyD-88 for downstream signaling, but TLR3 uses TRIF protein as an adaptor molecule. In downstream signaling, activated NF-κB or AP-1 enters the nucleus and upregulates gene transcription for iNOS, which facilitates conversion of L-arginine to L-citrulline (using NADPH as an electron donor) to generate highly reactive NO, which has various antiviral effects. TLR, toll-like receptor; LTA, lipoteichoic acid; LPS, lipopolysaccharide; CpG, CpG motif of unmethylated DNA; Poly I:C, polyinosine-polycytidylic acid; MyD-88, myeloid differentiation primary response 88; TRIF, TIR-domain-containing adaptor inducing IFN; IRAKs, IL-1 receptor-associated kinases; TRAF, TNF-receptor-associated factor; TAK1, transforming growth factor beta-activated kinase-1; IKKε, IkappaB kinase-epsilon; RIP1, receptor-interacting protein kinase 1; NF-κB, nuclear factor kappa B; AP-1, activator protein-1; iNOS, inducible nitric oxide synthase; NADPH, nicotinamide adenine dinucleotide phosphate H; NO, nitric oxide

Fig. 3

Viral components that activate TLRs signaling leading to NO-mediated antiviral activity in mammals and birds. In birds, TLR8 and TLR9 are absent; however, TLR21 replaces the function of TLR9 in mammals. TLR3, TLR7, TLR8, TLR9 and TLR21 are endosomal TLRs that recognize viral nucleic acids, whereas TLR2 and TLR4 are surface TLRs that detect viral surface molecules