Pattern recognition receptors for respiratory syncytial virus infection and design of vaccines

Abstract

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illness in infants and young children. Host immune response has been implicated in both the protection and immunopathological mechanisms. Pattern recognition receptors (PRRs) expressed on innate immune cells during RSV infection recognize the RSV-associated molecular patterns and activate innate immune cells as well as mediate airway inflammation, protective immune response, and pulmonary immunopathology. The resident and recruited innate immune cells play important roles in the protection and pathogenesis of an RSV disease by expressing these PRRs. Agonist-binding PRRs are the basis of many adjuvants that are essential for most vaccines. In the present review, we highlight recent advances in the innate immune recognition of and responses to RSV through PRRs, including toll-like receptors (TLRs), retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). We also describe the role of PRRs in the design of RSV vaccines.

Introduction

Respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract infection in infants and young children worldwide (Collins et al., 2001). Recent evidence suggests that RSV is an increasing cause of morbidity and mortality in the elderly and transplant patients as well as patients with chronic obstructive pulmonary disease (Thompson et al., 2003). Despite the importance of RSV as a respiratory pathogen, no licensed vaccines and effective therapy strategy are available, although palivizumab, a humanized monoclonal antibody, has been used for immunoprophylaxis against RSV in high-risk infants and young children (The IMpact-RSV Study Group, 1998). Understanding of the mechanisms that maintain the respiratory illness is limited (Collins and Melero, 2011). In-depth understanding of RSV-infection mechanisms and the host immune responses involved is essential to the development of effective vaccines. The host immune response to RSV has been implicated in both the protection and immunopathological mechanisms.

Successfully protecting the host from pathogens involves rapid activation of innate immune responses that serve as the first line of defense against invading pathogens and tailors the adaptive immune responses. Activation of innate immunity depends on the recognition of pathogen-associated molecular patterns (PAMPs) that are specific for the pathogen, but absent in the host using pattern recognition receptors (PRRs) expressed on sentinel cells. To date, three classes of PRRs have been identified, including toll-like receptors (TLRs), retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), and nucleotide-binding oligomerization domain (NOD)-like receptor (NLRs) (Ohto et al., 2007, Kumar et al., 2009). TLRs on the cell surface and endosomal compartments recognize a wide range of PAMPs and play a central role in initiating innate immune responses. There are currently 11 known human TLRs (Leulier and Lemaitre, 2008). RLRs, such as RIG-I and MDA5, belong to the RNA helicase family and have been identified as essential cytosolic receptors for intracellular viral RNAs, mediating the anti-viral programs via type I IFN induction (Yoneyama et al., 2005). The NLRs constitute a large cytosolic receptor family. The NLR family members NOD1, NOD2, and NALP3 recognize PAMPs in the cytosol as well as play a role in innate immunity (Akira et al., 2006). The cytosolic NLR and RLR families contribute to the immune response against pathogens in collaboration with the membrane-bound TLRs (Yoneyama and Fujita T, 2008). All these PRRs recognize various PAMPs and activate transcription factors NF-κB, mitogen-activated protein kinases (MAPKs), and/or members of the interferon regulatory factor (IRF) family, which regulate the expression of inflammatory cytokines and type I interferons (Medzhitov, 2007). RSV can be recognized by these three classes of PRRs. Airway resident leukocytes, such as dendritic cells (DCs) and macrophages as well as recruited proinflammatory granulocytes (neutrophils and eosinophils), are markedly involved in mediating airway inflammation and asthma pathophysiology by expressing these PRRs during RSV infection (Amanatidou et al., 2009, Murawski et al., 2009). Adjuvants are essential for enhancing vaccine efficacy. Agonist-binding PRRs are the basis of many adjuvants. These molecules exert their adjuvant function by interacting with TLRs, NLRs, RLRs, and signal through MyD88-dependent and MyD88-independent pathways (Higgins and Mills, 2010). In the present review, we highlight recent advances in the innate immune recognition of and responses to RSV through PRRs, which resulted in appropriate antiviral responses and/or pulmonary immunopathology. We also describe the role of PRRs in the design of RSV vaccines.