ReviewPattern recognition receptors for respiratory syncytial virus infection and design of 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.
Section snippets
TLR-mediated innate immune recognition of RSV
TLRs are found on a wide range of cells such as macrophages, DCs, epithelial cells, eosinophils, and neutrophils. TLR1, TLR2, TLR4, TLR5, and TLR6 reside on the cell surface as well as recognize microbial surface molecules and/or products, such as LPS or RSV fusion (F) protein. TLR3, TLR7, TLR8, and TLR9 are expressed in intracellular vesicles as well as recognize viral nucleic acids. Ligand recognition by TLRs, except TLR3, leads to the activation of the MyD88-dependent pathway, whereas TLR3
RLRs as sensors of RSV infection
RLRs are the critical sensors of viral infection in most cell types including macrophage and conventional DCs. RIG-I and MDA5 contain a DExD/H box RNA-binding helicase domain as well as two caspase activation and recruitment domains (CARDs) (Fujita et al., 2007). RIG-I is activated by 5’ triphosphate structure of viral RNA independently of single or double strand (Hornung et al., 2006). Scagnolari et al. (2009) reported that the relative gene expression levels of MDA5 and RIG-I were
NLRs involved in RSV recognition
NLRs consist of three domains characterized by an N-terminal effector and a central nucleotide-binding (NBD) domains as well as a C-terminal multiple leucine-rich repeats (LRR) (Ting et al., 2008). The NLR family is divided into five subfamilies according to their effector domain (Chen et al., 2009). NOD1 and NOD2 are well-characterized, which recognize distinct motifs in peptidoglycan structures of intracellular bacteria (Millmann-Born et al., 2010) as well as induce pro-inflammatory and
Innate immune cells respond to RSV infection by PRRs
Two major types of DCs, namely, myeloid/conventional (mDCs/cDCs) and plasmacytoid (pDCs), have been discovered. DCs are the major antigen-presenting cells following RSV infection (Lukens et al., 2009). RSV infects cDCs and mDCs, increasing surface expression of maturation markers as well as cytokine production (Johnson et al., 2011). RIG-I is expressed in both pDCs and cDC (Kato et al., 2005). NLR signaling enhances DC-mediated cross-priming in vivo (Asano et al., 2010). cDCs have a relatively
Design of RSV vaccines
Since triggering via PRR expressed on different innate immune cells induces host's immune response, PRR ligands can be harnessed to enhance the induction and regulate the types of vaccine-specific responses. Adjuvants are essential factors for the development of modern vaccines that promote various types of immune responses. The ability of agonists interacting with PRRs to modulate immunity provides a promising new tool for novel adjuvant development and contributes to understanding the
Conclusion
The binding of RSV surface proteins to TLR1, TLR2, TLR4, and TLR6, as well as RSV RNAs to TLR3, TLR7, RLRs, and NLRs activates important innate immune pathways. This phenomenon also promotes the expression of inflammatory cytokines and chemokines (which activate and/or recruit innate, as well as adaptive, immune cells), resulting in the clearance of RSV or immunopathology. Understanding the interaction between RSV and its host is crucial for the development of novel therapeutic strategies as
Acknowledgments
The present work was supported by grants from the Chinese National Natural Science Foundation (No. 30972801), the 100 Innovation Talents Project of Hebei Higher Education (CPRC030), and Specialized Research Fund for the Doctoral Program of Higher Education, State Education Ministry (No. 20091323120005).
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2015, Current Opinion in ImmunologyCitation Excerpt :hRSV recognition by AECs leads to the secretion of a broad spectrum of cytokines and chemokines [22]. These molecules promote the recruitment of cells to the peribronchiolar space, including eosinophils, neutrophils and monocytes, as well as the onset of an anti-viral response (Figure 1) [22,24]. A study, comparing nasal-derived and bronchial-derived epithelia from the same individuals, showed a similar pro-inflammatory chemokine response (CXCL10, CCL5, and CXCL11) in vitro upon hRSV infection [5•].
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2015, FEBS LettersCitation Excerpt :Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and Retinoic acid-inducible gene (RIG-1)-I-like receptors (RLRs) are the pattern recognition receptors (PRR) involved in detecting pathogen components, such as single- and double-stranded viral RNAs [45,46]. Several TLRs are known to activate innate responses after virus infection, including TLR2, TLR3, TLR4, TLR7 and TLR8 [45,46]. TLR2 and TLR4 are expressed on the cell surface whereas TLR3, TLR7 and TLR8 are localized within cytoplasmatic compartments, such as endosomes [47–49].
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2014, Antiviral ResearchCitation Excerpt :It was also reported that there was a correlation between RSV protection and levels of F specific antibodies (Kasel et al., 1987). RSV F is known to stimulate Toll-like receptor 4 (Zeng et al., 2012), which might be contributing to higher immune responses to F compared to G in the groups of live RSV and FFG VLP. Taken together, these results in this study suggest that uniquely combined FFG VLP can induce long-lived IgG2a antibody responses specific for RSV F. Mice immunized with FFG VLP showed long term protection against RSV without causing lung disease.
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2014, Respiratory InvestigationCitation Excerpt :RIG-I recognizes the 5'-triphosphate motif of RSV ssRNA as well as its dsRNA product [20], while MDA5 recognizes HRV dsRNA and poly IC. Additionally, HRV is recognized by RIG-I and TLR3 [20]. Both RIG-I and MDA5 initiate signaling through IFN-β promoter stimulator 1 (IPS-1), which is also known as MAVS/Cardif/VISA [21–24].