Novel Drugs Targeting Toll-like Receptors for Antiviral Therapy

Mira C Patel; Kari Ann Shirey; Lioubov M Pletneva; Marina S Boukhvalova; Alfredo Garzino-Demo; Stefanie N Vogel; Jorge CG Blanco


Future Virology. 2014;9(9):811-829. 

In This Article

Abstract and Introduction


Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved 'pathogen-associated molecular patterns' of invading microbes, including viruses. The activation of TLRs establishes antiviral innate immune responses and coordinates the development of long-lasting adaptive immunity in order to control viral pathogenesis. However, microbe-induced damage to host tissues may release 'danger-associated molecular patterns' that also activate TLRs, leading to an overexuberant inflammatory response and, ultimately, to tissue damage. Thus, TLRs have proven to be promising targets as therapeutics for the treatment of viral infections that result in inflammatory damage or as adjuvants in order to enhance the efficacy of vaccines. Here, we explore recent advances in TLR biology with a focus on novel drugs that target TLRs (agonists and antagonists) for antiviral therapy.


A significant advance in the field of immunology accompanied the identification of the two arms of immune responses as 'innate' and 'adaptive'. Initially, innate immunity was considered to be a relatively nonspecific and simple part of the overall immune response, while adaptive immunity was believed to provide antigen-specific protection from microbial and viral infection. However, accumulating evidence has clearly established that innate immune responses are the first line of defense against invading pathogens and also coordinate the development of a pathogen-specific adaptive immune response (reviewed in[1,2]). Despite striking differences in terms of response timing, effector cells and recognition receptors on the cells of both of these systems, there are many cellular and molecular components in common that orchestrate highly specific, integrated responses against invasive pathogens and establish long-term immune memory.

The primary receptors of innate immunity are a diverse set of germ line-encoded 'pattern-recognition receptors' (PRRs) that identify a broad spectrum of 'pathogen-associated molecular patterns' (PAMPs), which are diverse microbial structures of invading microorganisms, or 'danger-associated molecular patterns' (DAMPs), which are host-derived molecules released by stressed or injured cells (reviewed in[1]). PAMPs include diverse microbial molecules, such as lipopolysaccharides (LPSs), lipopeptides, peptidoglycans, mannans, flagellin, bacterial and viral nucleic acids and viral envelope proteins, whereas examples of DAMPs include endogenous (host) components, such as histones, nucleic acids, uric acid crystals, cytochrome C, ATP, oxidized 1-palmitoyl-2-arachidonoyl-phosphaticylcholine and HMGref-1, among others. In 1989, Janeway first proposed the concept of PRRs that recognize the molecular structures of microorganisms and link innate and adaptive immune responses.[3] Two important discoveries strengthened Janeway's concept of PRRs: the proof of the importance of Toll-mediated signaling in the induction of antifungal peptides by Drosophila in response to infection;[4] and the positional cloning of the Lps gene (now known to be Tlr4). Both C3H/HeJ and C57BL/10ScCr mice were shown to express mutations in this gene that led to LPS hyporesponsiveness in these two strains.[5,6] The importance of this research resulted in the sharing of the 2011 Nobel Prize in Physiology or Medicine.

Among the various families of PRRs (e.g., Toll-like receptors [TLRs], Nod-like receptors, RIG-I-like receptors [RLRs], c-type lectin receptors and cytosolic DNA receptors), TLRs are one of the largest and best-studied families of PRRs. The study of TLR biology has provided molecular insights into how PRRs recognize PAMPs and DAMPs, and how this leads to the activation of signaling cascades that converge in order to induce the expression of proinflammatory cytokines, chemokines and antiviral interferons (IFNs). Moreover, the discovery of TLRs has also enabled the identification of other families of innate immune receptors (reviewed in[1]). Together, the knowledge generated in the field of TLRs over the past decade has resulted in a significant paradigm shift in our understanding of innate immunity and its role in the development of a long-lasting, pathogen-specific adaptive immune responses (reviewed in[2,7]). In this article, we briefly summarize current advances in the field of TLRs, their signaling and how we might target TLR signaling in order to mitigate disease or enhance specific immunity.

The evidence thus far points to a role for TLRs in immune and inflammatory diseases, including allergies, autoimmune disorders and cancer (reviewed in[8]). To date, many viruses have been shown to activate the innate immune system through TLRs, assigning to TLRs an important role in controlling viral infections (reviewed in[9]). The following sections provide examples of TLR–virus interactions and their outcomes, as well as recent advances in our understanding of the role of TLRs in antiviral innate immunity, with a focus on the studies designed for developing novel TLR-targeting drugs that exert antiviral activity or serve as adjuvants for vaccines.