Regulators of innate immunity as novel targets for panviral therapeutics

Abstract

Interferons (IFNs) have long been used as an immunomodulatory therapy for a large array of acute and chronic viral infections. However, IFN therapies have been plagued by severe side effects. The discovery of pathogen recognition receptors (PRR) rejuvenated the interest for immunomodulatory therapies. The successes obtained with Toll-like receptor (TLR) agonists in activating immune cells and as adjuvant for prophylactic vaccines against different viruses paved the way to targeted immunomodulatory therapy. Better characterization of pathogen-induced immune disorders and newly discovered regulators of innate immunity have now the potential to specifically withdraw prevailing subversion mechanisms and to transform antiviral treatments by introducing panviral therapeutics with less adverse effects than IFN therapies.

Figure 1

TLR and RLR signaling. Viral nucleic acids are recognized by endosomal and cytoplasmic PRRs. Activation of MYD88-dependant TLR7/8/9 signaling, TRIF-dependant TLR3 signaling and RIG-I/MDA5 signaling results in nuclear translocation of IRF3/7 and NF-κB transcriptional factors, leading to type I IFN and proinflammatory cytokines production. Effectors of innate immune response allow mounting of an optimal adaptive immune response. Viral evasion strategies are also identified that interfere with TLR/RLR and IFN signaling pathways. Abbreviations: AdV: Adenovirus, CSFV: Classical Swine Fever Virus, CVB3: Coxsackievirus B3, EBV: Epstein-Barr Virus, GBV-B: GB virus B, HAV/HBV/HCV/HDV: Hepatitis A/B/C/D virus, HIV-1: Human Immunodeficiency Virus type 1, HPV: Human Papillomavirus, HRV1a: Human Rhinovirus 1a, KFSV: Kaposi's Sarcoma Virus, RSV: Respiratory Syncytial Virus, SARS-CoV: SARS coronavirus, VACV: Vaccinia Virus, VSV: Vesicular Stomatitis Virus, WNV: West Nile Virus.